Bio


I am a physician scientist with interests in cardiomyopathies, rare and undiagnosed diseases, therapeutics and genomics. I am a physician with interest and experience treating patients with hypertrophic cardiomyopathy, neuromuscular disease associated cardiomyopathies including adults with Duchenne and Becker muscular dystrophies, myotonic dystrophy, limb girdle muscular dystrophies, inherited dilated cardiomyopathies, advanced heart failure, mechanical circulatory support/LVADs, heart and multiorgan transplant, and competitive athletes with cardiac disease. I am Director of the Stanford Center for Undiagnosed Diseases, a clinical site of the Undiagnosed Diseases Network.. I have extensive translational science efforts, as site PI for ongoing clinical trials for hypertrophic cardiomyopathy and dilated cardiomyopathy and for cardiomyopathy consortia including NONCOMPACT, PPCM and the Precision Medicine Study/DCM Consortium. I am Co-PI of the GREGoR Stanford Site, a research center of the GREGoR Consortium, and Co-PI of the NIH-funded Bioinformatics Center of the Molecular Transducers of Physical Activity Consortium. Our laboratory efforts focus on advancing diagnostic and therapeutic approaches in ultrarare diseases, with a focus on RNA-based diagnostics and therapeutics. I pursue projects and collaborations at the intersection of striated muscle genetics, genomics, therapeutics and clinical investigation.

Clinical Focus


  • Cardiology
  • Cardiomyopathy, Hypertrophic, Familial
  • Heart Failure
  • Mechanical Circulatory Support
  • Undiagnosed Diseases
  • Myotonic Dystrophy associated Cardiomyopathy
  • Cardiovascular Genetics
  • Cardiac Amyloid
  • Heart Transplantation
  • Arrhythmogenic Right Ventricular Cardiomyopathy
  • Dilated Cardiomyopathies
  • Muscular Dystrophy associated Cardiomyopathy
  • Sports Cardiology
  • Duchenne and Becker Muscular Dystrophy
  • BAG3 associated cardiomyopathy
  • Advanced Heart Failure and Transplant Cardiology

Administrative Appointments


  • Director, Center for Undiagnosed Diseases at Stanford (2014 - Present)
  • Adult Medical Director, Center for Undiagnosed Diseases at Stanford (2015 - Present)

Boards, Advisory Committees, Professional Organizations


  • Member, American Heart Association (2012 - Present)
  • Member, American College of Cardiology (2017 - Present)
  • Member, American Society of Human Genetics (2016 - Present)

Professional Education


  • Fellowship: Stanford University Advanced Heart Failure and Transplant Fellowship (2013) CA
  • Fellowship: Stanford University Cardiovascular Medicine Fellowship (2012) CA
  • Residency: Stanford University Internal Medicine Residency (2007) CA
  • Medical Education: Pritzker School of Medicine University of Chicago Registrar (2005) IL
  • Board Certification: American Board of Internal Medicine, Advanced Heart Failure and Transplant Cardiology (2014)
  • Board Certification: American Board of Internal Medicine, Cardiovascular Disease (2012)
  • Bachelor of Arts, Williams College, History and Biology (1998)

Community and International Work


  • Undiagnosed Diseases - Latin America

    Topic

    Undiagnosed Diseases and Genetics

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

Current Research and Scholarly Interests


Translational research in rare and undiagnosed diseases. Basic and clinical research in cardiomyopathy genetics, mechanisms, screening, and treatment. Investigating novel agents for treatment of hypertrophic cardiomyopathy and new mechanisms in heart failure. Cardiovascular screening and genetics in competitive athletes, disease gene discovery in cardiomyopathy and rare disease. Informatics approaches to rare disease and multiomics. Molecular transducers of physical activity bioinformatics.

Clinical Trials


  • A Prospective Registry Study to Assess Real-world Patient Characteristics, Treatment Patterns, and Longitudinal Outcomes in Patients Receiving Mavacamten and Other Treatments for Symptomatic Obstructive Hypertrophic Cardiomyopathy (Obstructive HCM) Recruiting

    The purpose of this study is to evaluate the safety of mavacamten in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) treated in the real-world setting. The registry study also provide a real-world understanding of the current obstructive HCM patient population, treatment patterns, and clinical relevant outcomes for patients with symptomatic obstructive HCM in the US.

    View full details

  • Clinical and Genetic Evaluation of Individuals With Undiagnosed Disorders Through the Undiagnosed Diseases Network Recruiting

    Without an explanation for severe and sometimes life-threatening symptoms, patients and their families are left in a state of unknown. Many individuals find themselves being passed from physician to physician, undergoing countless and often repetitive tests in the hopes of finding answers and insight about what the future may hold. This long and arduous journey to find a diagnosis does not end for many patients- the Office of Rare Diseases Research (ORDR) notes that 6% of individuals seeking their assistance have an undiagnosed disorder. In 2008, the National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) was established with the goal of providing care and answers for these individuals with mysterious conditions who have long eluded diagnosis. The NIH UDP is a joint venture of the NIH ORDR, the National Human Genome Research Institute Intramural Research Program (NHGRI-IRP), and the NIH Clinical Research Center (CRC) (1-3). The goals of the NIH UDP are to: (1) provide answers for patients with undiagnosed diseases; (2) generate new knowledge about disease mechanisms; (3) assess the application of new approaches to phenotyping and the use of genomic technologies; and (4) identify potential therapeutic targets, if possible. To date, the UDP has evaluated 3300 medical records and admitted 750 individuals with rare and undiagnosed conditions to the NIH Clinical Center. The NIH UDP has identified more than 70 rare disease diagnoses and several new conditions. The success of the NIH UDP prompted the NIH Common Fund to support the establishment of a network of medical research centers, the Undiagnosed Diseases Network (UDN), for fiscal years 2013-2020. The clinical sites will perform extensive phenotyping, genetic analyses, and functional studies of potential disease-causing variants. The testing performed on patients involves medically indicated studies intended to help reach a diagnosis, as well as research investigations that include a skin biopsy, blood draws, and DNA analysis. In addition, the UDN will further the goals of the UDP by permitting the sharing of personally identifiable phenotypic and genotypic information within the network. By sharing participant information and encouraging collaboration, the UDN hopes to improve the understanding of rare conditions and advance the diagnostic process and care for individuals with undiagnosed diseases.

    View full details

  • A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation Not Recruiting

    This is a randomized, double-blind, placebo-controlled study in patients with dilated cardiomyopathy (DCM) due to a mutation of the gene encoding the lamin A/C protein (LMNA). The study will further evaluate a dose level of study drug (ARRY-371797) that has shown preliminary efficacy and safety in this patient population. After the primary analysis has been performed, eligible patients may receive open-label treatment with ARRY-371797.

    Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Marino, 650-725-6911.

    View full details

  • A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy Not Recruiting

    This is a randomized, double-blind, placebo-controlled, multi-center study in the United States (U.S.) that will evaluate the effect of mavacamten treatment on reducing the number of septal reduction therapy (SRT) procedures performed in subjects with symptomatic obstructive hypertrophic cardiomyopathy (oHCM [also known as HOCM]) who are eligible for SRT based on ACCF/AHA 2011 and/or ESC 2014 guidelines.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nicole Howard, (650) 725 - 6911.

    View full details

  • Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM (SEQUOIA-HCM) Not Recruiting

    The purpose of this study is to evaluate the efficacy and safety of aficamten (CK-3773274) in adults with symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract obstruction

    Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Marino, 650-725-6911.

    View full details

  • Single-Ascending Dose Study of JK07 in Subjects With HFpEF Not Recruiting

    A phase 1, randomized, double-blind, placebo-controlled single-ascending dose study to assess JK07 in adult subjects with heart failure with preserved ejection fraction.

    Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Marino, 650-725-6911.

    View full details

  • Study of JK07 in Subjects With Heart Failure With Reduced Ejection Fraction (HFrEF) Not Recruiting

    This is a Phase 1, randomized, double-blind, placebo-controlled, single-ascending dose study to assess the safety, tolerability, immunogenicity, PK, and exploratory efficacy of JK07 in subjects 18 to 80 years of age with HFrEF ≤40%. Initially 5 cohorts are planned with the option to expand the study to a total of 7 cohorts. The size of the cohorts will range from 5 to 9 subjects. Each cohort will include one single active unblinded sentinel subject receiving a single IV dose of JK07 prior to randomized single dose administration of JK07 or placebo [3:1] in the remainder of the cohort.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nicole Howard, (650) 725 - 6911.

    View full details

2023-24 Courses


Stanford Advisees


Graduate and Fellowship Programs


All Publications


  • Effects of Mavacamten on Measures of Cardiopulmonary Exercise Testing Beyond Peak Oxygen Consumption: A Secondary Analysis of the EXPLORER-HCM Randomized Trial. JAMA cardiology Wheeler, M. T., Olivotto, I., Elliott, P. M., Saberi, S., Owens, A. T., Maurer, M. S., Masri, A., Sehnert, A. J., Edelberg, J. M., Chen, Y., Florea, V., Malhotra, R., Wang, A., Oreziak, A., Myers, J. 2023

    Abstract

    Importance: Mavacamten, a cardiac myosin inhibitor, improved peak oxygen uptake (pVO2) in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) in the EXPLORER-HCM study. However, the full extent of mavacamten's effects on exercise performance remains unclear.Objective: To investigate the effect of mavacamten on exercise physiology using cardiopulmonary exercise testing (CPET).Design, Setting, and Participants: Exploratory analyses of the data from the EXPLORER-HCM study, a randomized, double-blind, placebo-controlled, phase 3 trial that was conducted in 68 cardiovascular centers in 13 countries. In total, 251 patients with symptomatic obstructive HCM were enrolled.Interventions: Patients were randomly assigned in a 1:1 ratio to mavacamten or placebo.Main Outcomes and Measures: The following prespecified exploratory cardiovascular and performance parameters were assessed with a standardized treadmill or bicycle ergometer test protocol at baseline and week 30: carbon dioxide output (VCO2), minute ventilation (VE), peak VE/VCO2 ratio, ventilatory efficiency (VE/VCO2 slope), peak respiratory exchange ratio (RER), peak circulatory power, ventilatory power, ventilatory threshold, peak metabolic equivalents (METs), peak exercise time, partial pressure of end-tidal carbon dioxide (PETCO2), and VO2/workload slope.Results: Two hundred fifty-one patients were enrolled. The mean (SD) age was 58.5 (11.9) years and 59% of patients were male. There were significant improvements with mavacamten vs placebo in the following peak-exercise CPET parameters: peak VE/VCO2 ratio (least squares [LS] mean difference, -2.2; 95% CI, -3.05 to -1.26; P<.001), peak METs (LS mean difference, 0.4; 95% CI, 0.17-0.60; P<.001), peak circulatory power (LS mean difference, 372.9 mL/kg/min*mm Hg; 95% CI, 153.12-592.61; P=.001), and peak PETCO2 (LS mean difference, 2.0 mm Hg; 95% CI, 1.12-2.79; P<.001). Mavacamten also improved peak exercise time compared with placebo (LS mean difference, 0.7 minutes; 95% CI, 0.13-1.24; P = .02). There was a significant improvement in nonpeak-exercise CPET parameters, such as VE/VCO2 slope (LS mean difference, -2.6; 95% CI, -3.58 to -1.52; P<.001) and ventilatory power (LS mean difference, 0.6 mm Hg; 95% CI, 0.29-0.90; P<.001) favoring mavacamten vs placebo.Conclusions and Relevance: Mavacamten improved a range of CPET parameters beyond pVO2, indicating consistent and broad benefits on maximal exercise capacity. Although improvements in peak-exercise CPET parameters are clinically meaningful, the favorable effects of mavacamten on submaximal exertional tolerance provide further insights into the beneficial impact of mavacamten in patients with obstructive HCM.Trial Registration: ClinicalTrials.gov Identifier: NCT03470545.

    View details for DOI 10.1001/jamacardio.2022.5099

    View details for PubMedID 36652223

  • Effect of beta-blocker therapy on the response to mavacamten in patients with symptomatic obstructive hypertrophic cardiomyopathy. European journal of heart failure Wheeler, M. T., Jacoby, D., Elliott, P. M., Saberi, S., Hegde, S. M., Lakdawala, N. K., Myers, J., Sehnert, A. J., Edelberg, J. M., Li, W., Olivotto, I. 2022

    Abstract

    AIMS: In the EXPLORER-HCM trial, mavacamten improved exercise capacity and symptoms in patients with obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten effects on the primary endpoint, a composite of peak oxygen consumption (VO2 ) and New York Heart Association (NYHA) class, were greater in patients not receiving background beta-blockers than in those receiving beta-blockers. We sought to determine if the effect of background treatment was consistent across other clinically meaningful parameters.METHODS AND RESULTS: Subgroup analyses by beta-blocker use were performed in patients with oHCM from the EXPLORER-HCM and mavacamten long-term extension (MAVA-LTE) studies. In EXPLORER-HCM, 189 patients (75.3%) were receiving beta-blockers, and 62 (24.7%) were receiving non-dihydropyridine calcium-channel blockers or no background HCM medication; 170 patients (90.4%) receiving beta-blockers had chronotropic incompetence. Improvements in peak VO2 at week 30 with mavacamten versus placebo were lower with beta-blockers (mean difference [95% confidence interval (CI)]: 1.04 [0.12, 1.95] mL/kg/min) than without beta-blockers (mean difference [95% CI]: 2.69 [1.29, 4.09] mL/kg/min); improvements in non-heart rate-dependent parameters (VE /VCO2 slope) appeared unaffected by beta-blockers. Improvements in functional capacity parameters at week 30 with mavacamten versus placebo were independent of beta-blockade for post-exercise left ventricular outflow tract gradient (mean difference [95% CI]: -37.9 [-48.0, -27.9] mmHg with beta-blockers; -33.5 [-53.6, -13.3] mmHg without beta-blockers), proportion of patients with reduction of ≥1 NYHA class, Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores and NT-proBNP. Mavacamten benefits were reproduced and maintained in MAVA-LTE regardless of beta-blockade.CONCLUSION: Mavacamten improved measures of functional capacity, LVOT obstruction, symptom burden and biomarkers in patients with HCM regardless of beta-blocker use. Beta-blocker use was often associated with chronotropic incompetence, affecting peak VO2 and other heart rate-dependent measures, but had minimal impact on heart-rate independent measures. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ejhf.2737

    View details for PubMedID 36404399

  • Guide to the female student athlete ECG: A comprehensive study of 3466 young, racially diverse athletes. The American journal of medicine Harris, C. S., Froelicher, V. F., Wheeler, M. T. 2022

    Abstract

    OBJECTIVES: The 12-lead electrocardiogram (ECG) is used in the preparticipation screening exam for athletes. Despite known differences in ECG findings by sex, only QTc prolongation is given a sex specific threshold. We hypothesize that our large dataset - with diversity in age, race, and sport participation - can be utilized to improve ECG screening in female student athletes.METHODS: Computerized 12-lead ECGs were recorded and analyzed in female athletes who underwent preparticipation screening exam between 06/2010 and 09/2021. The quantitative, empirical 2017 international criteria for electrocardiographic interpretation were compared to either the 99th percentile in our cohort or the percentile that corresponded to the known disease prevalence.RESULTS: Of 3466 female athletes with ECGs as part of preparticipation screening exam, the 2017 international criteria classified 2.1% of athletes with at least one ECG abnormality requiring cardiological evaluation. Rates were similar across age, race/ethnicity, and sporting discipline. Using ranges based on our population, 2.7% of athletes would require additional workup. Surprisingly, ST depression up to 0.03 mV was a normal finding in this cohort. If RS voltage extremes were considered findings requiring follow up, an additional 9.6% of the athlete population would be flagged using current definitions. This number decreases to 2.7% if using the 99th percentile in this cohort.CONCLUSION: These results highlight a difference in the reported prevalence of ECG abnormalities when comparing empirically derived thresholds to statistically derived ranges. Consideration of new metrics specific to the female athlete population has the potential to further refine athlete ECG screening.

    View details for DOI 10.1016/j.amjmed.2022.07.013

    View details for PubMedID 35981651

  • 2022 HRS expert consensus statement on evaluation and management of arrhythmic risk in neuromuscular disorders. Heart rhythm Groh, W. J., Bhakta, D., Tomaselli, G. F., Aleong, R. G., Teixeira, R. A., Amato, A., Asirvatham, S. J., Cha, Y., Corrado, D., Duboc, D., Goldberger, Z. D., Horie, M., Hornyak, J. E., Jefferies, J. L., Kaab, S., Kalman, J. M., Kertesz, N. J., Lakdawala, N. K., Lambiase, P. D., Lubitz, S. A., McMillan, H. J., McNally, E. M., Milone, M., Namboodiri, N., Nazarian, S., Patton, K. K., Russo, V., Sacher, F., Santangeli, P., Shen, W., Sobral Filho, D. C., Stambler, B. S., Stollberger, C., Wahbi, K., Wehrens, X. H., Weiner, M. M., Wheeler, M. T., Zeppenfeld, K. 2022

    Abstract

    This international multidisciplinary document is intended to guide electrophysiologists, cardiologists, other clinicians, and health care professionals in caring for patients with arrhythmic complications of neuromuscular disorders (NMDs). The document presents an overview of arrhythmias in NMDs followed by detailed sections on specific disorders: Duchenne muscular dystrophy, Becker muscular dystrophy, and limb-girdle muscular dystrophy type 2; myotonic dystrophy type 1 and type 2; Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B; facioscapulohumeral muscular dystrophy; and mitochondrial myopathies, including Friedreich ataxia and Kearns-Sayre syndrome, with an emphasis on managing arrhythmic cardiac manifestations. End-of-life management of arrhythmias in patients with NMDs is also covered. The document sections were drafted by the writing committee members according to their area of expertise. The recommendations represent the consensus opinion of the expert writing group, graded by class of recommendation and level of evidence utilizing defined criteria. The recommendations were made available for public comment; the document underwent review by Heart Rhythm Society Scientific and Clinical Documents Committee and external review and endorsement by the partner and collaborating societies. Changes were incorporated based on these reviews. By using a breadth of accumulated available evidence, the document is designed to provide practical and actionable clinical information and recommendations for the diagnosis and management of arrhythmias and thus improve the care of patients with NMDs.

    View details for DOI 10.1016/j.hrthm.2022.04.022

    View details for PubMedID 35500790

  • Prevalence and Cumulative Risk of Familial Idiopathic Dilated Cardiomyopathy. JAMA Huggins, G. S., Kinnamon, D. D., Haas, G. J., Jordan, E., Hofmeyer, M., Kransdorf, E., Ewald, G. A., Morris, A. A., Owens, A., Lowes, B., Stoller, D., Tang, W. H., Garg, S., Trachtenberg, B. H., Shah, P., Pamboukian, S. V., Sweitzer, N. K., Wheeler, M. T., Wilcox, J. E., Katz, S., Pan, S., Jimenez, J., Aaronson, K. D., Fishbein, D. P., Smart, F., Wang, J., Gottlieb, S. S., Judge, D. P., Moore, C. K., Mead, J. O., Ni, H., Burke, W., Hershberger, R. E., DCM Precision Medicine Study of the DCM Consortium 1800; 327 (5): 454-463

    Abstract

    Importance: Idiopathic dilated cardiomyopathy (DCM) aggregates in families, and early detection in at-risk family members can provide opportunity to initiate treatment prior to late-phase disease. Most studies have included only White patients, yet Black patients with DCM have higher risk of heart failure-related hospitalization and death.Objective: To estimate the prevalence of familial DCM among DCM probands and the age-specific cumulative risk of DCM in first-degree relatives across race and ethnicity groups.Design, Setting, and Participants: A family-based, cross-sectional study conducted by a multisite consortium of 25 US heart failure programs. Participants included patients with DCM (probands), defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes, and their first-degree relatives. Enrollment commenced June 7, 2016; proband and family member enrollment concluded March 15, 2020, and April 1, 2021, respectively.Exposures: The presence of DCM in a proband.Main Outcomes and Measures: Familial DCM defined by DCM in at least 1 first-degree relative; expanded familial DCM defined by the presence of DCM or either left ventricular enlargement or left ventricular systolic dysfunction without known cause in at least 1 first-degree relative.Results: The study enrolled 1220 probands (median age, 52.8 years [IQR, 42.4-61.8]; 43.8% female; 43.1% Black and 8.3% Hispanic) and screened 1693 first-degree relatives for DCM. A median of 28% (IQR, 0%-60%) of living first-degree relatives were screened per family. The crude prevalence of familial DCM among probands was 11.6% overall. The model-based estimate of the prevalence of familial DCM among probands at a typical US advanced heart failure program if all living first-degree relatives were screened was 29.7% (95% CI, 23.5% to 36.0%) overall. The estimated prevalence of familial DCM was higher in Black probands than in White probands (difference, 11.3% [95% CI, 1.9% to 20.8%]) but did not differ significantly between Hispanic probands and non-Hispanic probands (difference, -1.4% [95% CI, -15.9% to 13.1%]). The estimated prevalence of expanded familial DCM was 56.9% (95% CI, 50.8% to 63.0%) overall. Based on age-specific disease status at enrollment, estimated cumulative risks in first-degree relatives at a typical US advanced heart failure program reached 19% (95% CI, 13% to 24%) by age 80 years for DCM and 33% (95% CI, 27% to 40%) for expanded DCM inclusive of partial phenotypes. The DCM hazard was higher in first-degree relatives of non-Hispanic Black probands than non-Hispanic White probands (hazard ratio, 1.89 [95% CI, 1.26 to 2.83]).Conclusions and Relevance: In a US cross-sectional study, there was substantial estimated prevalence of familial DCM among probands and modeled cumulative risk of DCM among their first-degree relatives.Trial Registration: ClinicalTrials.gov Identifier: NCT03037632.

    View details for DOI 10.1001/jama.2021.24674

    View details for PubMedID 35103767

  • TOWARDS TRANSCRIPTOMICS AS A PRIMARY TOOL FOR RARE DISEASE INVESTIGATION. Cold Spring Harbor molecular case studies Montgomery, S. B., Bernstein, J. A., Wheeler, M. T. 2022

    Abstract

    In the past five years transcriptome or RNA-sequencing (RNA-seq) has steadily emerged as a complementary assay for rare disease diagnosis and discovery. In this perspective, we summarize several recent developments and challenges in use of RNA-seq for rare disease investigation. Using an accessible patient sample, such as blood, skin, or muscle, RNA-seq enables the assay of expressed RNA transcripts. Analysis of RNA-seq allows the identification of aberrant or outlier gene expression and alternative splicing as functional evidence to support rare disease study and diagnosis. Further, many types of variant effects can be profiled beyond coding variants, as the consequences of non-coding variants that impact gene expression and splicing can be directly observed. This is particularly apparent for structural variants which disproportionately underlie outlier gene expression and for splicing variants where RNA-seq can both measure aberrant canonical splicing and detect deep intronic effects. However, a major potential limitation of RNA-seq in rare disease investigation is the developmental and cell type-specificity of gene expression as a pathogenic variant's effect may be limited to a specific spatiotemporal context and access to a patient's tissue sample from the relevant tissue and timing of disease expression may not be possible. We speculate that as advances in computational methods and emerging experimental techniques overcome both developmental and cell type-specificity, there will be broadening use of RNA sequencing and multi-omics in rare disease diagnosis and delivery of precision health.

    View details for DOI 10.1101/mcs.a006198

    View details for PubMedID 35217565

  • Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms. Circulation. Genomic and precision medicine Lindholm, M. E., Jimenez-Morales, D., Zhu, H., Seo, K., Amar, D., Zhao, C., Raja, A., Madhvani, R., Abramowitz, S., Espenel, C., Sutton, S., Caleshu, C., Berry, G. J., Motonaga, K. S., Dunn, K., Platt, J., Ashley, E. A., Wheeler, M. T. 2021: CIRCGEN121003419

    Abstract

    BACKGROUND: ACTN2 (alpha-actinin 2) anchors actin within cardiac sarcomeres. The mechanisms linking ACTN2 mutations to myocardial disease phenotypes are unknown. Here, we characterize patients with novel ACTN2 mutations to reveal insights into the physiological function of ACTN2.METHODS: Patients harboring ACTN2 protein-truncating variants were identified using a custom mutation pipeline. In patient-derived iPSC-cardiomyocytes, we investigated transcriptional profiles using RNA sequencing, contractile properties using video-based edge detection, and cellular hypertrophy using immunohistochemistry. Structural changes were analyzed through electron microscopy. For mechanistic studies, we used coimmunoprecipitation for ACTN2, followed by mass-spectrometry to investigate protein-protein interaction, and protein tagging followed by confocal microscopy to investigate introduction of truncated ACTN2 into the sarcomeres.RESULTS: Patient-derived iPSC-cardiomyocytes were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca2+-signaling. In heterozygous indel cells, the truncated protein incorporates into cardiac sarcomeres, leading to aberrant Z-disc ultrastructure. In homozygous stop-gain cells, affinity-purification mass-spectrometry reveals an intricate ACTN2 interactome with sarcomere and sarcolemma-associated proteins. Loss of the C-terminus of ACTN2 disrupts interaction with ACTN1 and GJA1, 2 sarcolemma-associated proteins, which may contribute to the clinical arrhythmic and relaxation defects. The causality of the stop-gain mutation was verified using CRISPR-Cas9 gene editing.CONCLUSIONS: Together, these data advance our understanding of the role of ACTN2 in the human heart and establish recessive inheritance of ACTN2 truncation as causative of disease.

    View details for DOI 10.1161/CIRCGEN.121.003419

    View details for PubMedID 34802252

  • Variable clinical severity in TANGO2 deficiency: Case series and literature review. American journal of medical genetics. Part A Schymick, J., Leahy, P., Cowan, T., Ruzhnikov, M. R., Gates, R., Fernandez, L., Pramanik, G., Undiagnosed Diseases Network, Yarlagadda, V., Wheeler, M., Bernstein, J. A., Enns, G. M., Lee, C. 2021

    Abstract

    Biallelic pathogenic variants in the TANGO2 (transport and Golgi organization 2 homolog) gene have been identified as causing a rare metabolic disorder characterized by susceptibility to recurrent rhabdomyolysis, lactic acidosis, encephalopathy, and life-threatening tachyarrhythmias. Recently published reports suggest variable clinical severity and phenotypes. This study details five new patients from two families with biallelic pathogenic variants in the TANGO2 gene identified by whole exome sequencing and includes the largest number of affected individuals from a single family reported to date. We document significant intrafamilial variability and highlight that milder phenotypes may be underrecognized. We present biochemical and clinical data to help highlight the features that aid in consideration of this condition in the differential with disorders of fatty acid oxidation. We also present a comprehensive literature review summarizing the molecular, clinical, and biochemical findings for 92 individuals across 13 publications. Of the 27 pathogenic variants reported to date, the recurrent exons 3-9 deletion represents the most common variant seen in 42% of individuals with TANGO2 deficiency. Common clinical features seen in >70% of all individuals include acute metabolic crisis, rhabdomyolysis, neurologic abnormalities, developmental delay, and intellectual disability. Findings such as elevated creatine kinase, hypothyroidism, ketotic hypoglycemia, QT prolongation, or abnormalities of long-chain acylcarnitines and urine dicarboxylic acids should raise clinical suspicion for this life-threatening condition.

    View details for DOI 10.1002/ajmg.a.62543

    View details for PubMedID 34668327

  • The genetics of human performance. Nature reviews. Genetics Kim, D. S., Wheeler, M. T., Ashley, E. A. 2021

    Abstract

    Human physiology is likely to have been selected for endurance physical activity. However, modern humans have become largely sedentary, with physical activity becoming a leisure-time pursuit for most. Whereas inactivity is a strong risk factor for disease, regular physical activity reduces the risk of chronic disease and mortality. Although substantial epidemiological evidence supports the beneficial effects of exercise, comparatively little is known about the molecular mechanisms through which these effects operate. Genetic and genomic analyses have identified genetic variation associated with human performance and, together with recent proteomic, metabolomic and multi-omic analyses, are beginning to elucidate the molecular genetic mechanisms underlying the beneficial effects of physical activity on human health.

    View details for DOI 10.1038/s41576-021-00400-5

    View details for PubMedID 34522035

  • Mapping the human genetic architecture of COVID-19. Nature COVID-19 Host Genetics Initiative 2021

    Abstract

    The genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 disease severity1,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. We describe the results of three genome-wide association meta-analyses comprised of up to 49,562 COVID-19 patients from 46 studies across 19 countries. We reported 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian Randomization analyses support a causal role for smoking and body mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19, with unprecedented speed, was made possible by the community of human genetic researchers coming together to prioritize sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

    View details for DOI 10.1038/s41586-021-03767-x

    View details for PubMedID 34237774

  • Findings From Cardiovascular Evaluation of National Collegiate Athletic Association Division I Collegiate Student-Athletes After Asymptomatic or Mildly Symptomatic SARS-CoV-2 Infection. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine Hwang, C. E., Kussman, A., Christle, J. W., Froelicher, V., Wheeler, M. T., Moneghetti, K. J. 2021

    Abstract

    OBJECTIVE: The risk of myocardial damage after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been controversial. The purpose of this study is to report the incidence of abnormal cardiovascular findings in National Collegiate Athletic Association (NCAA) Division I student-athletes with a history of SARS-CoV-2 infection.DESIGN: This is a case series of student-athletes with SARS-CoV-2 infection and their subsequent cardiac work-up, including troponin level, electrocardiogram, and echocardiogram. Additional testing was ordered as clinically indicated.SETTING: This study was conducted at a single NCAA Division I institution.PARTICIPANTS: Student-athletes were included if they tested positive for SARS-CoV-2 by PCR or antibody testing [immunoglobulin G (IgG)] from April 15, 2020 to October 31, 2020.INTERVENTION: Cardiac testing was conducted as part of postinfection screening.MAIN OUTCOME MEASURES: This study was designed to quantify abnormal cardiovascular screening results and cardiac diagnoses after SARS-CoV-2 infection in Division I collegiate athletes.RESULTS: Fifty-five student-athletes tested positive for SARS-CoV-2. Of these, 14 (26%) had a positive IgG and 41 (74%) had a positive PCR test. Eight abnormal cardiovascular screening evaluations necessitated further testing including cardiac magnetic resonance imaging (cMRI). Two athletes received new cardiac diagnoses, one probable early cardiomyopathy and one pericarditis, whereas the remaining 6 had normal cMRIs.CONCLUSIONS: These data support recent publications which recommend the de-escalation of cardiovascular testing such as cardiac MRI or echocardiogram for athletes who have recovered from asymptomatic or mildly symptomatic SARS-CoV-2 infection. Continued follow-up of these athletes for sequelae of SARS-CoV-2 is critical.

    View details for DOI 10.1097/JSM.0000000000000954

    View details for PubMedID 34173780

  • Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England) Olivotto, I., Oreziak, A., Barriales-Villa, R., Abraham, T. P., Masri, A., Garcia-Pavia, P., Saberi, S., Lakdawala, N. K., Wheeler, M. T., Owens, A., Kubanek, M., Wojakowski, W., Jensen, M. K., Gimeno-Blanes, J., Afshar, K., Myers, J., Hegde, S. M., Solomon, S. D., Sehnert, A. J., Zhang, D., Li, W., Bhattacharya, M., Edelberg, J. M., Waldman, C. B., Lester, S. J., Wang, A., Ho, C. Y., Jacoby, D., EXPLORER-HCM study investigators, Bartunek, J., Bondue, A., Van Craenenbroeck, E., Kubanek, M., Zemanek, D., Jensen, M., Mogensen, J., Thune, J. J., Charron, P., Hagege, A., Lairez, O., Trochu, J., Axthelm, C., Duengen, H., Frey, N., Mitrovic, V., Preusch, M., Schulz-Menger, J., Seidler, T., Arad, M., Halabi, M., Katz, A., Monakier, D., Paz, O., Viskin, S., Zwas, D., Olivotto, I., Brunner-La Rocca, H. P., Michels, M., Dudek, D., Oko-Sarnowska, Z., Oreziak, A., Wojakowski, W., Cardim, N., Pereira, H., Barriales-Villa, R., Garcia Pavia, P., Gimeno Blanes, J., Hidalgo Urbano, R., Rincon Diaz, L. M., Elliott, P., Yousef, Z., Abraham, T., Afshar, K., Alvarez, P., Bach, R., Becker, R., Choudhury, L., Fermin, D., Jacoby, D., Jefferies, J., Kramer, C., Lakdawala, N., Lester, S., Marian, A., Masri, A., Maurer, M., Nagueh, S., Owens, A., Owens, D., Rader, F., Saberi, S., Sherrid, M., Shirani, J., Symanski, J., Turer, A., Wang, A., Wever-Pinzon, O., Wheeler, M., Wong, T., Yamani, M. 2020

    Abstract

    BACKGROUND: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy.METHODS: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545.FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group.INTERPRETATION: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition.FUNDING: MyoKardia.

    View details for DOI 10.1016/S0140-6736(20)31792-X

    View details for PubMedID 32871100

  • Molecular Transducers of Physical Activity Consortium (MoTrPAC): Mapping the Dynamic Responses to Exercise. Cell Sanford, J. A., Nogiec, C. D., Lindholm, M. E., Adkins, J. N., Amar, D., Dasari, S., Drugan, J. K., Fernandez, F. M., Radom-Aizik, S., Schenk, S., Snyder, M. P., Tracy, R. P., Vanderboom, P., Trappe, S., Walsh, M. J., Molecular Transducers of Physical Activity Consortium, Adkins, J. N., Amar, D., Dasari, S., Drugan, J. K., Evans, C. R., Fernandez, F. M., Li, Y., Lindholm, M. E., Nogiec, C. D., Radom-Aizik, S., Sanford, J. A., Schenk, S., Snyder, M. P., Tomlinson, L., Tracy, R. P., Trappe, S., Vanderboom, P., Walsh, M. J., Alekel, D. L., Bekirov, I., Boyce, A. T., Boyington, J., Fleg, J. L., Joseph, L. J., Laughlin, M. R., Maruvada, P., Morris, S. A., McGowan, J. A., Nierras, C., Pai, V., Peterson, C., Ramos, E., Roary, M. C., Williams, J. P., Xia, A., Cornell, E., Rooney, J., Miller, M. E., Ambrosius, W. T., Rushing, S., Stowe, C. L., Rejeski, W. J., Nicklas, B. J., Pahor, M., Lu, C., Trappe, T., Chambers, T., Raue, U., Lester, B., Bergman, B. C., Bessesen, D. H., Jankowski, C. M., Kohrt, W. M., Melanson, E. L., Moreau, K. L., Schauer, I. E., Schwartz, R. S., Kraus, W. E., Slentz, C. A., Huffman, K. M., Johnson, J. L., Willis, L. H., Kelly, L., Houmard, J. A., Dubis, G., Broskey, N., Goodpaster, B. H., Sparks, L. M., Coen, P. M., Cooper, D. M., Haddad, F., Rankinen, T., Ravussin, E., Johannsen, N., Harris, M., Jakicic, J. M., Newman, A. B., Forman, D. D., Kershaw, E., Rogers, R. J., Nindl, B. C., Page, L. C., Stefanovic-Racic, M., Barr, S. L., Rasmussen, B. B., Moro, T., Paddon-Jones, D., Volpi, E., Spratt, H., Musi, N., Espinoza, S., Patel, D., Serra, M., Gelfond, J., Burns, A., Bamman, M. M., Buford, T. W., Cutter, G. R., Bodine, S. C., Esser, K., Farrar, R. P., Goodyear, L. J., Hirshman, M. F., Albertson, B. G., Qian, W., Piehowski, P., Gritsenko, M. A., Monore, M. E., Petyuk, V. A., McDermott, J. E., Hansen, J. N., Hutchison, C., Moore, S., Gaul, D. A., Clish, C. B., Avila-Pacheco, J., Dennis, C., Kellis, M., Carr, S., Jean-Beltran, P. M., Keshishian, H., Mani, D. R., Clauser, K., Krug, K., Mundorff, C., Pearce, C., Ivanova, A. A., Ortlund, E. A., Maner-Smith, K., Uppal, K., Zhang, T., Sealfon, S. C., Zavlasky, E., Nair, V., Li, S., Jain, N., Ge, Y., Sun, Y., Nudelman, G., Ruf-Zamojski, F., Smith, G., Pincas, N., Rubenstein, A., Amper, M. A., Seenarine, N., Lappalainen, T., Lanza, I. R., Nair, K. S., Klaus, K., Montgomery, S. B., Smith, K. S., Gay, N. R., Zhao, B., Hung, C. J., Zebarjadi, N., Balliu, B., Fresard, L., Burant, C. F., Li, J. Z., Kachman, M., Soni, T., Raskind, A. B., Gerszten, R., Robbins, J., Ilkayeva, O., Muehlbauer, M. J., Newgard, C. B., Ashley, E. A., Wheeler, M. T., Jimenez-Morales, D., Raja, A., Dalton, K. P., Zhen, J., Kim, Y. S., Christle, J. W., Marwaha, S., Chin, E. T., Hershman, S. G., Hastie, T., Tibshirani, R., Rivas, M. A. 2020; 181 (7): 1464–74

    Abstract

    Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ systems, and decreases the risk for premature mortality. However, a gap remains in identifying the detailed molecular signals induced by exercise that benefits health and prevents disease. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this gap and generate a molecular map of exercise. Preclinical and clinical studies will examine the systemic effects of endurance and resistance exercise across a range of ages and fitness levels by molecular probing of multiple tissues before and after acute and chronic exercise. From this multi-omic and bioinformatic analysis, a molecular map of exercise will be established. Altogether, MoTrPAC will provide a public database that is expected to enhance our understanding of the health benefits of exercise and to provide insight into how physical activity mitigates disease.

    View details for DOI 10.1016/j.cell.2020.06.004

    View details for PubMedID 32589957

  • Yield of whole exome sequencing in undiagnosed patients facing insurance coverage barriers to genetic testing. Journal of genetic counseling Reuter, C. M., Kohler, J. N., Bonner, D., Zastrow, D., Fernandez, L., Dries, A., Marwaha, S., Davidson, J., Brokamp, E., Herzog, M., Hong, J., Macnamara, E., Rosenfeld, J. A., Schoch, K., Spillmann, R., Undiagnosed Diseases Network, Loscalzo, J., Krier, J., Stoler, J., Sweetser, D., Palmer, C. G., Phillips, J. A., Shashi, V., Adams, D. A., Yang, Y., Ashley, E. A., Fisher, P. G., Mulvihill, J. J., Bernstein, J. A., Wheeler, M. T. 2019

    Abstract

    BACKGROUND: Despite growing evidence of diagnostic yield and clinical utility of whole exome sequencing (WES) in patients with undiagnosed diseases, there remain significant cost and reimbursement barriers limiting access to such testing. The diagnostic yield and resulting clinical actions of WES for patients who previously faced insurance coverage barriers have not yet been explored.METHODS: We performed a retrospective descriptive analysis of clinical WES outcomes for patients facing insurance coverage barriers prior to clinical WES and who subsequently enrolled in the Undiagnosed Diseases Network (UDN). Clinical WES was completed as a result of participation in the UDN. Payer type, molecular diagnostic yield, and resulting clinical actions were evaluated.RESULTS: Sixty-six patients in the UDN faced insurance coverage barriers to WES at the time of enrollment (67% public payer, 26% private payer). Forty-two of 66 (64%) received insurance denial for clinician-ordered WES, 19/66 (29%) had health insurance through a payer known not to cover WES, and 5/66 (8%) had previous payer denial of other genetic tests. Clinical WES results yielded a molecular diagnosis in 23 of 66 patients (35% [78% pediatric, 65% neurologic indication]). Molecular diagnosis resulted in clinical actions in 14 of 23 patients (61%).CONCLUSIONS: These data demonstrate that a substantial proportion of patients who encountered insurance coverage barriers to WES had a clinically actionable molecular diagnosis, supporting the notion that WES has value as a covered benefit for patients who remain undiagnosed despite objective clinical findings.

    View details for DOI 10.1002/jgc4.1161

    View details for PubMedID 31478310

  • Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts. Nature medicine Frésard, L. n., Smail, C. n., Ferraro, N. M., Teran, N. A., Li, X. n., Smith, K. S., Bonner, D. n., Kernohan, K. D., Marwaha, S. n., Zappala, Z. n., Balliu, B. n., Davis, J. R., Liu, B. n., Prybol, C. J., Kohler, J. N., Zastrow, D. B., Reuter, C. M., Fisk, D. G., Grove, M. E., Davidson, J. M., Hartley, T. n., Joshi, R. n., Strober, B. J., Utiramerur, S. n., Lind, L. n., Ingelsson, E. n., Battle, A. n., Bejerano, G. n., Bernstein, J. A., Ashley, E. A., Boycott, K. M., Merker, J. D., Wheeler, M. T., Montgomery, S. B. 2019

    Abstract

    It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene1. The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches2-5. For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases6-8. This includes muscle biopsies from patients with undiagnosed rare muscle disorders6,9, and cultured fibroblasts from patients with mitochondrial disorders7. However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.

    View details for DOI 10.1038/s41591-019-0457-8

    View details for PubMedID 31160820

  • Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder AMERICAN JOURNAL OF HUMAN GENETICS Olahova, M., Yoon, W., Thompson, K., Jangam, S., Fernandez, L., Davidson, J. M., Kyle, J. E., Grove, M. E., Fisk, D. G., Kohler, J. N., Holmes, M., Dries, A. M., Huang, Y., Zhao, C., Contrepois, K., Zappala, Z., Fresard, L., Waggott, D., Zink, E. M., Kim, Y., Heyman, H. M., Stratton, K. G., Webb-Robertson, B. M., Snyder, M., Merker, J. D., Montgomery, S. B., Fisher, P. G., Feichtinger, R. G., Mayr, J. A., Hall, J., Barbosa, I. A., Simpson, M. A., Deshpande, C., Waters, K. M., Koeller, D. M., Metz, T. O., Morris, A. A., Schelley, S., Cowan, T., Friederich, M. W., McFarland, R., Van Hove, J. K., Enns, G. M., Yamamoto, S., Ashley, E. A., Wangler, M. F., Taylor, R. W., Bellen, H. J., Bernstein, J. A., Wheeler, M. T., Undiagnosed Diseases Network 2018; 102 (3): 494–504

    Abstract

    ATP synthase, H+ transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T>G (p.Val106Gly), presented with acute encephalopathy in childhood. Cultured skin fibroblasts from these individuals exhibited impaired assembly of F1FO ATP synthase and subsequent reduced complex V activity. Cells from subject 1 also exhibited a significant decrease in mitochondrial cristae. Knockdown of Drosophila ATPsynδ, the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation.

    View details for PubMedID 29478781

  • Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease. The New England journal of medicine Splinter, K. n., Adams, D. R., Bacino, C. A., Bellen, H. J., Bernstein, J. A., Cheatle-Jarvela, A. M., Eng, C. M., Esteves, C. n., Gahl, W. A., Hamid, R. n., Jacob, H. J., Kikani, B. n., Koeller, D. M., Kohane, I. S., Lee, B. H., Loscalzo, J. n., Luo, X. n., McCray, A. T., Metz, T. O., Mulvihill, J. J., Nelson, S. F., Palmer, C. G., Phillips, J. A., Pick, L. n., Postlethwait, J. H., Reuter, C. n., Shashi, V. n., Sweetser, D. A., Tifft, C. J., Walley, N. M., Wangler, M. F., Westerfield, M. n., Wheeler, M. T., Wise, A. L., Worthey, E. A., Yamamoto, S. n., Ashley, E. A. 2018

    Abstract

    Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added.We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care.A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes.The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).

    View details for PubMedID 30304647

  • Effect of Moderate-Intensity Exercise Training on Peak Oxygen Consumption in Patients With Hypertrophic Cardiomyopathy A Randomized Clinical Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Saberi, S., Wheeler, M., Bragg-Gresham, J., Hornsby, W., Agarwal, P. P., Attili, A., Concannon, M., Dries, A. M., Shmargad, Y., Salisbury, H., Kumar, S., Herrera, J., Myers, J., Helms, A. S., Ashley, E. A., Day, S. M. 2017; 317 (13): 1349-1357

    Abstract

    Formulating exercise recommendations for patients with hypertrophic cardiomyopathy is challenging because of concern about triggering ventricular arrhythmias and because a clinical benefit has not been previously established in this population.To determine whether moderate-intensity exercise training improves exercise capacity in adults with hypertrophic cardiomyopathy.A randomized clinical trial involving 136 patients with hypertrophic cardiomyopathy was conducted between April 2010 and October 2015 at 2 academic medical centers in the United States (University of Michigan Health System and Stanford University Medical Center). Date of last follow-up was November 2016.Participants were randomly assigned to 16 weeks of moderate-intensity exercise training (n = 67) or usual activity (n = 69).The primary outcome measure was change in peak oxygen consumption from baseline to 16 weeks.Among the 136 randomized participants (mean age, 50.4 [SD, 13.3] years; 42% women), 113 (83%) completed the study. At 16 weeks, the change in mean peak oxygen consumption was +1.35 (95% CI, 0.50 to 2.21) mL/kg/min among participants in the exercise training group and +0.08 (95% CI, -0.62 to 0.79) mL/kg/min among participants in the usual-activity group (between-group difference, 1.27 [95% CI, 0.17 to 2.37]; P = .02). There were no occurrences of sustained ventricular arrhythmia, sudden cardiac arrest, appropriate defibrillator shock, or death in either group.In this preliminary study involving patients with hypertrophic cardiomyopathy, moderate-intensity exercise compared with usual activity resulted in a statistically significant but small increase in exercise capacity at 16 weeks. Further research is needed to understand the clinical importance of this finding in patients with hypertrophic cardiomyopathy, as well as the long-term safety of exercise at moderate and higher levels of intensity.clinicaltrials.gov Identifier: NCT01127061.

    View details for DOI 10.1001/jama.2017.2503

    View details for Web of Science ID 000398434200019

    View details for PubMedID 28306757

  • Regional Variation in Cardiovascular Genes Enables a Tractable Genome Editing Strategy. Circulation. Genomic and precision medicine Krysov, V. A., Wilson, R. H., Ten, N. S., Youlton, N., De Jong, H. N., Sutton, S., Huang, Y., Reuter, C. M., Grove, M. E., Wheeler, M. T., Ashley, E. A., Parikh, V. N. 2024: e004370

    Abstract

    To realize the potential of genome engineering therapeutics, tractable strategies must be identified that balance personalized therapy with the need for off-the-shelf availability. We hypothesized that regional clustering of pathogenic variants can inform the design of rational prime editing therapeutics to treat the majority of genetic cardiovascular diseases with a limited number of reagents.We collated 2435 high-confidence pathogenic/likely pathogenic (P/LP) variants in 82 cardiovascular disease genes from ClinVar. We assessed the regional density of these variants by defining a regional clustering index. We then combined a highly active base editor with prime editing to demonstrate the feasibility of a P/LP hotspot-directed genome engineering therapeutic strategy in vitro.P/LP variants in cardiovascular disease genes display higher regional density than rare variants found in the general population. P/LP missense variants displayed higher average regional density than P/LP truncating variants. Following hypermutagenesis at a pathogenic hotspot, mean prime editing efficiency across introduced variants was 57±27%.Designing therapeutics that target pathogenic hotspots will not only address known missense P/LP variants but also novel P/LP variants identified in these hotspots as well. Moreover, the clustering of P/LP missense rather than truncating variants in these hotspots suggests that prime editing technology is particularly valuable for dominant negative disease. Although prime editing technology in relation to cardiac health continues to improve, this study presents an approach to targeting the most impactful regions of the genome for inherited cardiovascular disease.

    View details for DOI 10.1161/CIRCGEN.123.004370

    View details for PubMedID 38506054

  • Quantifying assumptions underlying peak oxygen consumption equations across the body mass spectrum. Clinical obesity Busque, V., Christle, J. W., Moneghetti, K. J., Cauwenberghs, N., Kouznetsova, T., Blumberg, Y., Wheeler, M. T., Ashley, E., Haddad, F., Myers, J. 2024: e12653

    Abstract

    The goal of this study is to quantify the assumptions associated with the Wasserman-Hansen (WH) and Fitness Registry and the Importance of Exercise: A National Database (FRIEND) predictive peak oxygen consumption (pVO2 ) equations across body mass index (BMI). Assumptions in pVO2 for both equations were first determined using a simulation and then evaluated using exercise data from the Stanford Exercise Testing registry. We calculated percent-predicted VO2 (ppVO2 ) values for both equations and compared them using the Bland-Altman method. Assumptions associated with pVO2 across BMI categories were quantified by comparing the slopes of age-adjusted VO2 ratios (pVO2 /pre-exercise VO2 ) and ppVO2 values for different BMI categories. The simulation revealed lower predicted fitness among adults with obesity using the FRIEND equation compared to the WH equations. In the clinical cohort, we evaluated 2471 patients (56.9% male, 22% with BMI >30 kg/m2 , pVO2 26.8 mlO2 /kg/min). The Bland-Altman plot revealed an average relative difference of -1.7% (95% CI: -2.1 to -1.2%) between WH and FRIEND ppVO2 values with greater differences among those with obesity. Analysis of the VO2 ratio to ppVO2 slopes across the BMI spectrum confirmed the assumption of lower fitness in those with obesity, and this trend was more pronounced using the FRIEND equation. Peak VO2 estimations between the WH and FRIEND equations differed significantly among individuals with obesity. The FRIEND equation resulted in a greater attributable reduction in pVO2 associated with obesity relative to the WH equations. The outlined relationships between BMI and predicted VO2 may better inform the clinical interpretation of ppVO2 values during cardiopulmonary exercise test evaluations.

    View details for DOI 10.1111/cob.12653

    View details for PubMedID 38475989

  • Knowledge and attitudes on implementing cardiovascular pharmacogenomic testing. Clinical and translational science Russell, C., Campion, M., Grove, M. E., Matsuda, K., Klein, T. E., Ashley, E., Naik, H., Wheeler, M. T., Scott, S. A. 2024; 17 (3): e13737

    Abstract

    Pharmacogenomics has the potential to inform drug dosing and selection, reduce adverse events, and improve medication efficacy; however, provider knowledge of pharmacogenomic testing varies across provider types and specialties. Given that many actionable pharmacogenomic genes are implicated in cardiovascular medication response variability, this study aimed to evaluate cardiology providers' knowledge and attitudes on implementing clinical pharmacogenomic testing. Sixty-one providers responded to an online survey, including pharmacists (46%), physicians (31%), genetic counselors (15%), and nurses (8%). Most respondents (94%) reported previous genetics education; however, only 52% felt their genetics education prepared them to order a clinical pharmacogenomic test. In addition, most respondents (66%) were familiar with pharmacogenomics, with genetic counselors being most likely to be familiar (p < 0.001). Only 15% of respondents had previously ordered a clinical pharmacogenomic test and a total of 36% indicated they are likely to order a pharmacogenomic test in the future; however, the vast majority of respondents (89%) were interested in pharmacogenomic testing being incorporated into diagnostic cardiovascular genetic tests. Moreover, 84% of providers preferred pharmacogenomic panel testing compared to 16% who preferred single gene testing. Half of the providers reported being comfortable discussing pharmacogenomic results with their patients, but the majority (60%) expressed discomfort with the logistics of test ordering. Reported barriers to implementation included uncertainty about the clinical utility and difficulty choosing an appropriate test. Taken together, cardiology providers have moderate familiarity with pharmacogenomics and limited experience with test ordering; however, they are interested in incorporating pharmacogenomics into diagnostic genetic tests and ordering pharmacogenomic panels.

    View details for DOI 10.1111/cts.13737

    View details for PubMedID 38421234

  • Prevalence of frequent premature ventricular contractions and nonsustained ventricular tachycardia in older women screened for atrial fibrillation in the Women's Health Initiative. Heart rhythm Gomez, S. E., Larson, J., Hlatky, M. A., Rodriguez, F., Wheeler, M., Greenland, P., LaMonte, M., Froelicher, V., Stefanick, M. L., Wallace, R., Kooperberg, C., Tinker, L. F., Schoenberg, J., Soliman, E. Z., Vitolins, M. Z., Saquib, N., Nuño, T., Haring, B., Perez, M. V. 2024

    Abstract

    Frequent premature ventricular contractions (PVCs) and nonsustained ventricular tachycardia (NSVT) have been associated with cardiovascular disease and mortality. Their prevalence, especially in ambulatory populations, is under-studied and limited by few female participants and the use of short-duration (24-48 hour) monitoring.Report the prevalence of frequent PVCs and NSVT in a community-based population of women likely to undergo ECG screening using sequential patch monitoring.Participants from the Women's Health Initiative Strong and Healthy (WHISH) trial with no history of atrial fibrillation (AF) but 5-year predicted risk of incident AF ≥ 5% by CHARGE-AF score were randomly selected to undergo screening with 7-day ECG patch monitors at baseline, 6 months, and 12 months. Recordings were reviewed for PVCs and NSVT (> 5 beats); data was analyzed using multivariate regression models.There were 1,067 participants who underwent ECG screening at baseline, 866 at 6-months and 777 at 12-months. Frequent PVCs were found on at least one patch from 4.3% of participants and one or more episodes of NSVT was found in 12 (1.1%) women. PVC frequency directly correlated with CHARGE-AF score and NSVT on any patch. Detection of frequent PVCs increased with sequential monitoring.Among postmenopausal women at high risk for AF, frequent PVCs were relatively common (4.3%), and correlated with higher CHARGE-AF score. As strategies for AF screening continue to evolve, particularly in those individuals at high risk of AF, the prevalence of incidental ventricular arrhythmias is an important benchmark to guide clinical decision-making.

    View details for DOI 10.1016/j.hrthm.2024.02.040

    View details for PubMedID 38403238

  • Digitized Electrocardiography Measurements Support the Biological Plausibility of the Pathological Significance of ST Segments in Athletes. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine Montalvo, S., Froelicher, V. F., Hadley, D., Wheeler, M. T. 2024

    Abstract

    OBJECTIVE: ST segment deviations around the isoelectric line are common findings in manifest cardiovascular disease. In athletes, ST elevation is common, while ST depression is considered rare. However, clinical studies in athletes have associated ST depression with myocardial fibrosis and fatty infiltration and ST elevation with pericarditis and myocarditis. This study aims to explore the association between resting ST segment deviations and resting heart rate, an indicator of training and autonomic tone and electrocardiography (ECG) markers of exercise training effect and cardiovascular health R and T wave amplitude.DESIGN: Retrospective analysis of digitized ECG data.SETTING: Institutional setting.PARTICIPANTS: Seven thousand eight hundred thirty-six (male athletes = 4592, female athletes = 3244) healthy asymptomatic athletes (14-35 years).MAIN OUTCOME MEASURES: A series of correlations and regressions were conducted between ST depression (<0.0 V) and ST elevation (>0.0 V), on R and T wave amplitudes, and heart rate in leads V2, V5, and aVF.RESULTS: Positive correlations between ST elevation and R and T wave (S wave in V2) amplitudes and leads V5, V2, and aVF in male and female athletes (range of r = 0.1-0.54). In addition, there was a negative correlation between ST elevation and HR for male and female athletes. Finally, there was a negative correlation between ST depression and R wave and HR for male and female athletes in V5 (P < 0.01).CONCLUSIONS: In athletes, ST segment elevation is correlated with R and T wave amplitudes and negatively correlated with HR. In addition, ST segment elevation is correlated with low heart rate, consistent with its higher prevalence in athletes. ST segment depression is not influenced by HR but is negatively associated with R and T wave amplitudes.

    View details for DOI 10.1097/JSM.0000000000001199

    View details for PubMedID 38407231

  • Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy. Annals of clinical and translational neurology Donkervoort, S., Mohassel, P., O'Leary, M., Bonner, D. E., Hartley, T., Acquaye, N., Brull, A., Mozaffar, T., Saporta, M. A., Dyment, D. A., Sampson, J. B., Pajusalu, S., Austin-Tse, C., Hurth, K., Cohen, J. S., McWalter, K., Warman-Chardon, J., Crunk, A., Foley, A. R., Mammen, A. L., Wheeler, M. T., O'Donnell-Luria, A., Bönnemann, C. G. 2024

    Abstract

    ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series.We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant.We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing.This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease.

    View details for DOI 10.1002/acn3.51983

    View details for PubMedID 38311799

  • RExPRT: a machine learning tool to predict pathogenicity of tandem repeat loci. Genome biology Fazal, S., Danzi, M. C., Xu, I., Kobren, S. N., Sunyaev, S., Reuter, C., Marwaha, S., Wheeler, M., Dolzhenko, E., Lucas, F., Wuchty, S., Tekin, M., Züchner, S., Aguiar-Pulido, V. 2024; 25 (1): 39

    Abstract

    Expansions of tandem repeats (TRs) cause approximately 60 monogenic diseases. We expect that the discovery of additional pathogenic repeat expansions will narrow the diagnostic gap in many diseases. A growing number of TR expansions are being identified, and interpreting them is a challenge. We present RExPRT (Repeat EXpansion Pathogenicity pRediction Tool), a machine learning tool for distinguishing pathogenic from benign TR expansions. Our results demonstrate that an ensemble approach classifies TRs with an average precision of 93% and recall of 83%. RExPRT's high precision will be valuable in large-scale discovery studies, which require prioritization of candidate loci for follow-up studies.

    View details for DOI 10.1186/s13059-024-03171-4

    View details for PubMedID 38297326

    View details for PubMedCentralID 7425049

  • Improving Reporting of Exercise Capacity Across Age Ranges Using Novel Workload Reference Equations. The American journal of cardiology Santana, E. J., Christle, J. W., Cauwenberghs, N., Peterman, J. E., Busque, V., Gomes, B., Bagherzadeh, S. P., Moneghetti, K., Kuznetsova, T., Wheeler, M., Ashley, E., Harber, M. P., Arena, R., Kaminsky, L. A., Myers, J., Haddad, F. 2024

    Abstract

    Exercise capacity (EC) is an important predictor of survival in the general population as well as in individuals with cardiopulmonary disease. Despite its relevance, considering percent-predicted workload (%pWL) given by current equations may overestimate EC in older adults. Therefore, to improve the reporting of EC in clinical practice, our main objective was to develop workload reference equations (pWL) that better reflect the relation between workload and age. Using the Fitness Registry and the Importance of Exercise National Database (FRIEND), we analyzed a reference group of 6,966 apparently healthy participants and 1,060 participants with HF who underwent graded treadmill cardiopulmonary exercise testing. For the first group, the mean age was 44 years [18-79]; 56.5% of individuals were male and 15.4% had obesity. Peak VO2 was 11.6 ± 3.0 METs in males and 8.5±2.4 METs in females. After partition analysis, we first developed sex-specific pWL equations to allow comparisons to a healthy weight reference. For males, pWL (METs) = 14.1 - 0.9 × 10-3 × age2 and for female 11.5 - 0.87 × 10-3 × age2. We used those equations as denominators of %pWL and, based on their distribution, we determined thresholds for EC classification, with average EC defined by the range corresponding to 85-115%pWL. Compared to %pWL using current equations, the new equations yielded better-calibrated %pWL across different age ranges. We also derived body mass index-adjusted pWL equations that better assessed EC in individuals with HF. In conclusion, the novel pWL equations have the potential to impact the report of EC in practice.

    View details for DOI 10.1016/j.amjcard.2024.01.022

    View details for PubMedID 38301753

  • Impact of genome build on RNA-seq interpretation and diagnostics. medRxiv : the preprint server for health sciences Ungar, R. A., Goddard, P. C., Jensen, T. D., Degalez, F., Smith, K. S., Jin, C. A., Bonner, D. E., Bernstein, J. A., Wheeler, M. T., Montgomery, S. B. 2024

    Abstract

    Transcriptomics is a powerful tool for unraveling the molecular effects of genetic variants and disease diagnosis. Prior studies have demonstrated that choice of genome build impacts variant interpretation and diagnostic yield for genomic analyses. To identify the extent genome build also impacts transcriptomics analyses, we studied the effect of the hg19, hg38, and CHM13 genome builds on expression quantification and outlier detection in 386 rare disease and familial control samples from both the Undiagnosed Diseases Network (UDN) and Genomics Research to Elucidate the Genetics of Rare Disease (GREGoR) Consortium. We identified 2,800 genes with build-dependent quantification across six routinely-collected biospecimens, including 1,391 protein-coding genes and 341 known rare disease genes. We further observed multiple genes that only have detectable expression in a subset of genome builds. Finally, we characterized how genome build impacts the detection of outlier transcriptomic events. Combined, we provide a database of genes impacted by build choice, and recommend that transcriptomics-guided analyses and diagnoses are cross-referenced with these data for robustness.

    View details for DOI 10.1101/2024.01.11.24301165

    View details for PubMedID 38260490

    View details for PubMedCentralID PMC10802764

  • Arrhythmias including Atrial Fibrillation and Congenital Heart Disease in Kleefstra Syndrome: a possible epigenetic link. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology Vasireddi, S. K., Draksler, T. Z., Bouman, A., Kummeling, J., Wheeler, M., Reuter, C., Srivastava, S., Harris, J., Fisher, P. G., Narayan, S. M., Wang, P. J., Badhwar, N., Kleefstra, T., Perez, M. V. 2024

    Abstract

    BACKGROUND: Kleefstra syndrome (KS), often diagnosed in early childhood, is a rare genetic disorder due to haploinsufficiency of EHMT1 and is characterized by neuromuscular and intellectual developmental abnormalities. Although congenital heart disease (CHD) is common, the prevalence of arrhythmias and CHD subtypes in KS is unknown.METHODS: Inspired by a novel case series of KS patients with atrial tachyarrhythmias in the USA, we evaluate the two largest known KS registries for arrhythmias and CHD: Radboudumc (50 patients) based on health record review at Radboud University Medical Center in the Netherlands, and GenIDA (163 patients) based on world-wide surveys of patient families.RESULTS: Three KS patients (aged 17-25 years) presented with atrial tachyarrhythmias without manifest CHD. In the international KS registries, the median(IQR) age was considerably younger; GenIDA/Radboudumc at 10/13.5 (12/13) years respectively. Both registries had a 40% prevalence of cardiovascular abnormalities, the majority being CHD, including septal defects, vascular malformations, and valvular disease. Interestingly, 4 (8%) patients in the Radboudumc registry reported arrhythmias without CHD, including one AF, two with supraventricular tachycardias (SVTs), and one with non-sustained ventricular tachycardia. The GenIDA registry reported one patient with AF and another with chronic ectopic atrial tachycardia. In total, atrial tachyarrhythmias were noted in six young KS patients (6/213 or 3%) with at least four (3 AF and 1 AT) without structural heart disease.CONCLUSION: In addition to a high prevalence of CHD, evolving data reveals early-onset atrial tachyarrhythmias in young KS patients, including AF, even in the absence of structural heart disease.

    View details for DOI 10.1093/europace/euae003

    View details for PubMedID 38195854

  • Mavacamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy: Interim Results From the MAVA-LTE Study, EXPLORER-LTE Cohort. JACC. Heart failure Rader, F., Oręziak, A., Choudhury, L., Saberi, S., Fermin, D., Wheeler, M. T., Abraham, T. P., Garcia-Pavia, P., Zwas, D. R., Masri, A., Owens, A., Hegde, S. M., Seidler, T., Fox, S., Balaratnam, G., Sehnert, A. J., Olivotto, I. 2024; 12 (1): 164-177

    Abstract

    Data assessing the long-term safety and efficacy of mavacamten treatment for symptomatic obstructive hypertrophic cardiomyopathy are needed.The authors sought to evaluate interim results from the EXPLORER-Long Term Extension (LTE) cohort of MAVA-LTE (A Long-Term Safety Extension Study of Mavacamten in Adults Who Have Completed EXPLORER-HCM; NCT03723655).After mavacamten or placebo withdrawal at the end of the parent EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545), patients could enroll in MAVA-LTE. Patients received mavacamten 5 mg once daily; adjustments were made based on site-read echocardiograms.Between April 9, 2019, and March 5, 2021, 231 of 244 eligible patients (94.7%) enrolled in MAVA-LTE (mean age: 60 years; 39% female). At data cutoff (August 31, 2021) 217 (93.9%) remained on treatment (median time in study: 62.3 weeks; range: 0.3-123.9 weeks). At 48 weeks, patients showed improvements in left ventricular outflow tract (LVOT) gradients (mean change ± SD from baseline: resting: -35.6 ± 32.6 mm Hg; Valsalva: -45.3 ± 35.9 mm Hg), N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (median: -480 ng/L; Q1-Q3: -1,104 to -179 ng/L), and NYHA functional class (67.5% improved by ≥1 class). LVOT gradients and NT-proBNP reductions were sustained through 84 weeks in patients who reached this timepoint. Over 315 patient-years of exposure, 8 patients experienced an adverse event of cardiac failure, and 21 patients had an adverse event of atrial fibrillation, including 11 with no prior history of atrial fibrillation. Twelve patients (5.2%) developed transient reductions in site-read echocardiogram left ventricular ejection fraction of <50%, resulting in temporary treatment interruption; all recovered. Ten patients discontinued treatment due to treatment-emergent adverse events.Mavacamten treatment showed clinically important and durable improvements in LVOT gradients, NT-proBNP levels, and NYHA functional class, consistent with EXPLORER-HCM. Mavacamten treatment was well tolerated over a median 62-week follow-up.

    View details for DOI 10.1016/j.jchf.2023.09.028

    View details for PubMedID 38176782

  • Biallelic variants in POLR3A encoding catalytic subunit of human RNA polymerase III cause primary microcephaly through perturbation of the mTOR signaling pathway Makhdoom, E., Asif, M., Abu Bakar, M., Sheraz, K., Alawbethani, S., Hoehne, W., Anjum, I., Fatima, A., Baig, J., Georgomanolis, T., Budde, B., Irshad, S., Zastrow, D., Kohler, J., Wheeler, M., Bernstein, J., Cirak, S., Nuernberg, P., Baig, S. M., Latif, F., Hussain, M., Batool, T., Hussain, G., Anwar, H. SPRINGERNATURE. 2024: 504-505
  • Quantitative metrics of the LV trabeculated layer by cardiac CT and cardiac MRI in patients with suspected noncompaction cardiomyopathy. European radiology Manohar, A., Vigneault, D. M., Kwon, D. H., Caliskan, K., Budde, R. P., Hirsch, A., Lee, S. P., Lee, W., Owens, A., Litt, H., Haddad, F., Mistelbauer, G., Wheeler, M., Rubin, D., Tang, W. H., Nieman, K. 2023

    Abstract

    To compare cardiac computed tomography (CCT) and cardiac magnetic resonance (CMR) for the quantitative assessment of the left ventricular (LV) trabeculated layer in patients with suspected noncompaction cardiomyopathy (NCCM).Subjects with LV excessive trabeculation who underwent both CMR and CCT imaging as part of the prospective international multicenter NONCOMPACT clinical study were included. For each subject, short-axis CCT and CMR slices were matched. Four quantitative metrics were estimated: 1D noncompacted-to-compacted ratio (NCC), trabecular-to-myocardial area ratio (TMA), trabecular-to-endocardial cavity area ratio (TCA), and trabecular-to-myocardial volume ratio (TMV). In 20 subjects, end-diastolic and mid-diastolic CCT images were compared for the quantification of the trabeculated layer. Relationships between the metrics were investigated using linear regression models and Bland-Altman analyses.Forty-eight subjects (49.9 ± 12.8 years; 28 female) were included in this study. NCC was moderately correlated (r = 0.62), TMA and TMV were strongly correlated (r = 0.78 and 0.78), and TCA had excellent correlation (r = 0.92) between CMR and CCT, with an underestimation bias from CCT of 0.3 units, and 5.1, 4.8, and 5.4 percent-points for the 4 metrics, respectively. TMA, TCA, and TMV had excellent correlations (r = 0.93, 0.96, 0.94) and low biases (- 3.8, 0.8,  - 3.8 percent-points) between the end-diastolic and mid-diastolic CCT images.TMA, TCA, and TMV metrics of the LV trabeculated layer in patients with suspected NCCM demonstrated high concordance between CCT and CMR images. TMA and TCA were highly reproducible and demonstrated minimal differences between mid-diastolic and end-diastolic CCT images.The results indicate similarity of CCT to CMR for quantifying the LV trabeculated layer, and the small differences in quantification between end-diastole and mid-diastole demonstrate the potential for quantifying the LV trabeculated layer from clinically performed coronary CT angiograms.• Data on cardiac CT for quantifying the left ventricular trabeculated layer are limited. • Cardiac CT yielded highly reproducible metrics of the left ventricular trabeculated layer that correlated well with metrics defined by cardiac MR. • Cardiac CT appears to be equivalent to cardiac MR for the quantification of the left ventricular trabeculated layer.

    View details for DOI 10.1007/s00330-023-10526-1

    View details for PubMedID 38114847

    View details for PubMedCentralID 10317841

  • Assessing the Assisted Six-Minute Cycling Test as a Measure of Endurance in Non-Ambulatory Patients with Spinal Muscular Atrophy (SMA). Journal of clinical medicine Tang, W. J., Gu, B., Montalvo, S., Dunaway Young, S., Parker, D. M., de Monts, C., Ataide, P., Ni Ghiollagain, N., Wheeler, M. T., Tesi Rocha, C., Christle, J. W., He, Z., Day, J. W., Duong, T. 2023; 12 (24)

    Abstract

    Assessing endurance in non-ambulatory individuals with Spinal Muscular Atrophy (SMA) has been challenging due to limited evaluation tools. The Assisted 6-Minute Cycling Test (A6MCT) is an upper limb ergometer assessment used in other neurologic disorders to measure endurance. To study the performance of the A6MCT in the non-ambulatory SMA population, prospective data was collected on 38 individuals with SMA (13 sitters; 25 non-sitters), aged 5 to 74 years (mean = 30.3; SD = 14.1). The clinical measures used were A6MCT, Revised Upper Limb Module (RULM), Adapted Test of Neuromuscular Disorders (ATEND), and Egen Klassifikation Scale 2 (EK2). Perceived fatigue was assessed using the Fatigue Severity Scale (FSS), and effort was assessed using the Rate of Perceived Exertion (RPE). Data were analyzed for: (1) Feasibility, (2) Clinical discrimination, and (3) Associations between A6MCT with clinical characteristics and outcomes. Results showed the A6MCT was feasible for 95% of the tested subjects, discriminated between functional groups (p = 0.0086), and was significantly associated with results obtained from RULM, ATEND, EK2, and Brooke (p < 0.0001; p = 0.029; p < 0.001; p = 0.005). These findings indicate the A6MCT's potential to evaluate muscular endurance in non-ambulatory SMA individuals, complementing clinician-rated assessments. Nevertheless, further validation with a larger dataset is needed for broader application.

    View details for DOI 10.3390/jcm12247582

    View details for PubMedID 38137651

    View details for PubMedCentralID PMC10743820

  • Long-term effects of mavacamten treatment in obstructive hypertrophic cardiomyopathy (HCM): updated cumulative analysis of the EXPLORER cohort of MAVA-long-term extension (LTE) study up to 120 weeks Garcia-Pavia, P., Oreziak, A., Masri, A., Barriales-Villa, R., Abraham, T. P., Owens, A. T., Lakdawala, N. K., Saberi, S., Wang, A., Wheeler, M. T., Choudhury, L., Balaratnam, G., Fox, S., Hegde, S. M., Olivotto, I. OXFORD UNIV PRESS. 2023
  • Changes in standard of care (SOC) medication during long-term mavacamten treatment for obstructive hypertrophic cardiomyopathy (HCM): results from the EXPLORER cohort of MAVA-Long-Term Extension (LTE) Lakdawala, N., Afshar, K., Barriales-Villa, R., Gimeno-Blanes, J., Michels, M., Saberi, S., Wheeler, M. T., Balaratnam, G., Shah, A., Chen, Y. M., Sehnert, A. J., Abraham, T. P. OXFORD UNIV PRESS. 2023
  • Improved Cardiac Performance and Decreased Arrhythmia in Hypertrophic Cardiomyopathy With Non-β-Blocking R-Enantiomer Carvedilol. Circulation Seo, K., Yamamoto, Y., Kirillova, A., Kawana, M., Yadav, S., Huang, Y., Wang, Q., Lane, K. V., Pruitt, B. L., Perez, M. V., Bernstein, D., Wu, J. C., Wheeler, M. T., Parikh, V. N., Ashley, E. A. 2023

    Abstract

    Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. β-Adrenergic receptor antagonists (β-blockers) are the first-line therapy for HCM. However, β-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-rate reduction and noncardiac effects can lead to reduced cardiac output and fatigue. Mavacamten, myosin ATPase inhibitor recently approved by the US Food and Drug Administration, has demonstrated the ability to ameliorate hypercontractility without lowering heart rate, but its benefits are so far limited to patients with left ventricular (LV) outflow tract obstruction, and its effect on arrhythmia is unknown.We screened 21 β-blockers for their impact on myocyte contractility and evaluated the antiarrhythmic properties of the most promising drug in a ventricular myocyte arrhythmia model. We then examined its in vivo effect on LV function by hemodynamic pressure-volume loop analysis. The efficacy of the drug was tested in vitro and in vivo compared with current therapeutic options (metoprolol, verapamil, and mavacamten) for HCM in an established mouse model of HCM (Myh6R403Q/+ [myosin heavy chain 6]) and iPSC cardiomyocytes derived from patients with HCM (MYH7R403Q/+) [myosin heavy chain 7]).We identified that carvedilol, a β-blocker not commonly used in HCM, suppresses contractile function and arrhythmia by inhibiting RyR2 (ryanodine receptor type 2). Unlike metoprolol (a β1-blocker), carvedilol markedly reduced LV contractility through RyR2 inhibition, while maintaining stroke volume through α1-adrenergic receptor inhibition in vivo. Clinically available carvedilol is a racemic mixture, and the R-enantiomer, devoid of β-blocking effect, retains the ability to inhibit both α1-receptor and RyR2, thereby suppressing contractile function and arrhythmias without lowering heart rate and cardiac output. In Myh6R403Q/+ mice, R-carvedilol normalized hyperdynamic contraction, suppressed arrhythmia, and increased cardiac output better than metoprolol, verapamil, and mavacamten. The ability of R-carvedilol to suppress contractile function was well retained in MYH7R403Q/+ induced pluripotent stem cell cardiomyocytes.R-enantiomer carvedilol attenuates hyperdynamic contraction, suppresses arrhythmia, and at the same time, improves cardiac output without lowering heart rate by dual blockade of α1-adrenergic receptor and RyR2 in mouse and human models of HCM. This combination of therapeutic effects is unique among current therapeutic options for HCM and may particularly benefit patients without LV outflow tract obstruction.

    View details for DOI 10.1161/CIRCULATIONAHA.123.065017

    View details for PubMedID 37850394

  • The functional impact of rare variation across the regulatory cascade. Cell genomics Li, T., Ferraro, N., Strober, B. J., Aguet, F., Kasela, S., Arvanitis, M., Ni, B., Wiel, L., Hershberg, E., Ardlie, K., Arking, D. E., Beer, R. L., Brody, J., Blackwell, T. W., Clish, C., Gabriel, S., Gerszten, R., Guo, X., Gupta, N., Johnson, W. C., Lappalainen, T., Lin, H. J., Liu, Y., Nickerson, D. A., Papanicolaou, G., Pritchard, J. K., Qasba, P., Shojaie, A., Smith, J., Sotoodehnia, N., Taylor, K. D., Tracy, R. P., Van Den Berg, D., Wheeler, M. T., Rich, S. S., Rotter, J. I., Battle, A., Montgomery, S. B. 2023; 3 (10): 100401

    Abstract

    Each human genome has tens of thousands of rare genetic variants; however, identifying impactful rare variants remains a major challenge. We demonstrate how use of personal multi-omics can enable identification of impactful rare variants by using the Multi-Ethnic Study of Atherosclerosis, which included several hundred individuals, with whole-genome sequencing, transcriptomes, methylomes, and proteomes collected across two time points, 10 years apart. We evaluated each multi-omics phenotype's ability to separately and jointly inform functional rare variation. By combining expression and protein data, we observed rare stop variants 62 times and rare frameshift variants 216 times as frequently as controls, compared to 13-27 times as frequently for expression or protein effects alone. We extended a Bayesian hierarchical model, "Watershed," to prioritize specific rare variants underlying multi-omics signals across the regulatory cascade. With this approach, we identified rare variants that exhibited large effect sizes on multiple complex traits including height, schizophrenia, and Alzheimer's disease.

    View details for DOI 10.1016/j.xgen.2023.100401

    View details for PubMedID 37868038

    View details for PubMedCentralID PMC10589633

  • Assessment of maximal effort for weaker individuals with NMD during the assisted six-minute cycling test Blumberg, Y., De Monts, C., Tang, W., Montalvo, S., Ataide, P., Young, S., Wheeler, M., Ashley, E., Myers, J., Day, J., Christle, J., Duong, T. PERGAMON-ELSEVIER SCIENCE LTD. 2023: S187
  • Genomics Research with Undiagnosed Children: Ethical Challenges at the Boundaries of Research and Clinical Care JOURNAL OF PEDIATRICS Halley, M. C., Young, J. L., Tang, C., Mintz, K. T., Lucas-Griffin, S., Maghiro, A., Ashley, E. A., Tabor, H. K., Undiagnosed Diseases Network 2023; 261
  • Personalized digital behaviour interventions increase short-term physical activity: a randomized control crossover trial substudy of the MyHeart Counts Cardiovascular Health Study. European heart journal. Digital health Javed, A., Kim, D. S., Hershman, S. G., Shcherbina, A., Johnson, A., Tolas, A., O'Sullivan, J. W., McConnell, M. V., Lazzeroni, L., King, A. C., Christle, J. W., Oppezzo, M., Mattsson, C. M., Harrington, R. A., Wheeler, M. T., Ashley, E. A. 2023; 4 (5): 411-419

    Abstract

    Physical activity is associated with decreased incidence of the chronic diseases associated with aging. We previously demonstrated that digital interventions delivered through a smartphone app can increase short-term physical activity.We offered enrolment to community-living iPhone-using adults aged ≥18 years in the USA, UK, and Hong Kong who downloaded the MyHeart Counts app. After completion of a 1-week baseline period, e-consented participants were randomized to four 7-day interventions. Interventions consisted of: (i) daily personalized e-coaching based on the individual's baseline activity patterns, (ii) daily prompts to complete 10 000 steps, (iii) hourly prompts to stand following inactivity, and (iv) daily instructions to read guidelines from the American Heart Association (AHA) website. After completion of one 7-day intervention, participants subsequently randomized to the next intervention of the crossover trial. The trial was completed in a free-living setting, where neither the participants nor investigators were blinded to the intervention. The primary outcome was change in mean daily step count from baseline for each of the four interventions, assessed in a modified intention-to-treat analysis (modified in that participants had to complete 7 days of baseline monitoring and at least 1 day of an intervention to be included in analyses). This trial is registered with ClinicalTrials.gov, NCT03090321.Between 1 January 2017 and 1 April 2022, 4500 participants consented to enrol in the trial (a subset of the approximately 50 000 participants in the larger MyHeart Counts study), of whom 2458 completed 7 days of baseline monitoring (mean daily steps 4232 ± 73) and at least 1 day of one of the four interventions. Personalized e-coaching prompts, tailored to an individual based on their baseline activity, increased step count significantly (+402 ± 71 steps from baseline, P = 7.1⨯10-8). Hourly stand prompts (+292 steps from baseline, P = 0.00029) and a daily prompt to read AHA guidelines (+215 steps from baseline, P = 0.021) were significantly associated with increased mean daily step count, while a daily reminder to complete 10 000 steps was not (+170 steps from baseline, P = 0.11). Digital studies have a significant advantage over traditional clinical trials in that they can continuously recruit participants in a cost-effective manner, allowing for new insights provided by increased statistical power and refinement of prior signals. Here, we present a novel finding that digital interventions tailored to an individual are effective in increasing short-term physical activity in a free-living cohort. These data suggest that participants are more likely to react positively and increase their physical activity when prompts are personalized. Further studies are needed to determine the effects of digital interventions on long-term outcomes.

    View details for DOI 10.1093/ehjdh/ztad047

    View details for PubMedID 37794870

    View details for PubMedCentralID PMC10545510

  • Generation of two induced pluripotent stem cell lines from Duchenne muscular dystrophy patients. Stem cell research Liu, W., Zeng, W., Kong, X., Htet, M., Yu, R., Wheeler, M., Day, J. W., Wu, J. C. 2023; 72: 103207

    Abstract

    Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder that leads to death in early adulthood. Patients with DMD have null mutations leading to loss of functional dystrophin protein. Here we generated two DMD induced pluripotent stem cell (iPSC) lines, one with deletion of exon 51 and the other with a single nucleotide nonsense mutation (c.10171C > T). Both lines expressed high levels of pluripotency markers, had the capability of differentiating into derivatives of the three germ layers, and possessed normal karyotypes. These iPSC lines can serve as powerful tools to model DMD in vitro and as a platform for therapeutic development.

    View details for DOI 10.1016/j.scr.2023.103207

    View details for PubMedID 37740996

  • Cardiac Remodeling in Subclinical Hypertrophic Cardiomyopathy: The VANISH Randomized Clinical Trial. JAMA cardiology Vissing, C. R., Axelsson Raja, A., Day, S. M., Russell, M. W., Zahka, K., Lever, H. M., Pereira, A. C., Colan, S. D., Margossian, R., Murphy, A. M., Canter, C., Bach, R. G., Wheeler, M. T., Rossano, J. W., Owens, A. T., Benson, L., Mestroni, L., Taylor, M. R., Patel, A. R., Wilmot, I., Thrush, P., Soslow, J. H., Becker, J. R., Seidman, C. E., Lakdawala, N. K., Cirino, A. L., McMurray, J. J., MacRae, C. A., Solomon, S. D., Bundgaard, H., Orav, E. J., Ho, C. Y., Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Investigators, Krieger, J. E., Sacilotto, L., Arteaga, E., Antunes, M. O., Ashley, E., Lin, K. Y., Hall, E. K., Choudhury, L., Pahl, E., Vargas, J. D., Lewis, G. D., Desai, A. S. 2023

    Abstract

    Importance: Valsartan has shown promise in attenuating cardiac remodeling in patients with early-stage sarcomeric hypertrophic cardiomyopathy (HCM). Genetic testing can identify individuals at risk of HCM in a subclinical stage who could benefit from therapies that prevent disease progression.Objective: To explore the potential for valsartan to modify disease development, and to characterize short-term phenotypic progression in subclinical HCM.Design, Setting, and Participants: The multicenter, double-blind, placebo-controlled Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) randomized clinical trial was conducted from April 2014 to July 2019 at 17 sites in 4 countries (Brazil, Canada, Denmark, and the US), with 2 years of follow-up. The prespecified exploratory VANISH cohort studied here included sarcomere variant carriers with subclinical HCM and early phenotypic manifestations (reduced E' velocity, electrocardiographic abnormalities, or an increased left ventricular [LV] wall thickness [LVWT] to cavity diameter ratio) but no LV hypertrophy (LVH). Data were analyzed between March and December 2022.Interventions: Treatment with placebo or valsartan (80 mg/d for children weighing <35 kg, 160 mg/d for children weighing ≥35 kg, or 320 mg/d for adults aged ≥18 years).Main Outcomes and Measures: The primary outcome was a composite z score incorporating changes in 9 parameters of cardiac remodeling (LV cavity volume, LVWT, and LV mass; left atrial [LA] volume; E' velocity and S' velocity; and serum troponin and N-terminal prohormone of brain natriuretic peptide levels).Results: This study included 34 participants, with a mean (SD) age of 16(5) years (all were White). A total of 18 participants (8 female [44%] and 10 male [56%]) were randomized to valsartan and 16 (9 female [56%] and 7 male [44%]) were randomized to placebo. No statistically significant effects of valsartan on cardiac remodeling were detected (mean change in composite z score compared with placebo: -0.01 [95% CI, -0.29 to 0.26]; P=.92). Overall, 2-year phenotypic progression was modest, with only a mild increase in LA volume detected (increased by 3.5 mL/m2 [95% CI, 1.4-6.0 mL/m2]; P=.002). Nine participants (26%) had increased LVWT, including 6 (18%) who developed clinically overt HCM. Baseline LA volume index (LAVI; 35 vs 28 mL/m2; P=.01) and average interventricular septum thickness (8.5 vs 7.0 mm; P=.009) were higher in participants who developed HCM.Conclusions and Relevance: In this exploratory cohort, valsartan was not proven to slow progression of subclinical HCM. Minimal changes in markers of cardiac remodeling were observed, although nearly one-fifth of patients developed clinically overt HCM. Transition to disease was associated with greater baseline interventricular septum thickness and LAVI. These findings highlight the importance of following sarcomere variant carriers longitudinally and the critical need to improve understanding of factors that drive disease penetrance and progression.Trial Registration: ClinicalTrials.gov Identifier: NCT01912534.

    View details for DOI 10.1001/jamacardio.2023.2808

    View details for PubMedID 37672268

  • A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels. Nature metabolism Dutta, D., Kanca, O., Byeon, S. K., Marcogliese, P. C., Zuo, Z., Shridharan, R. V., Park, J. H., Lin, G., Ge, M., Heimer, G., Kohler, J. N., Wheeler, M. T., Kaipparettu, B. A., Pandey, A., Bellen, H. J. 2023

    Abstract

    In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the cellular lipidome is not well defined. Here we show that loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration. We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes, indicating an interplay between ceramide and iron metabolism. Mutations in human MECR cause pediatric-onset neurodegeneration, and we show that human-derived fibroblasts display similar elevated ceramide levels and impaired iron homeostasis. In summary, this study identifies a role of mecr/MECR in ceramide and iron metabolism, providing a mechanistic link between mtFAS and neurodegeneration.

    View details for DOI 10.1038/s42255-023-00873-0

    View details for PubMedID 37653044

    View details for PubMedCentralID 7504791

  • Rare Variant Genetics and Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study. Circulation Hofmeyer, M., Haas, G. J., Jordan, E., Cao, J., Kransdorf, E., Ewald, G. A., Morris, A. A., Owens, A., Lowes, B., Stoller, D., Wilson Tang, W. H., Garg, S., Trachtenberg, B. H., Shah, P., Pamboukian, S. V., Sweitzer, N. K., Wheeler, M. T., Wilcox, J. E., Katz, S., Pan, S., Jimenez, J., Smart, F., Wang, J., Gottlieb, S. S., Judge, D. P., Moore, C. K., Huggins, G. S., Kinnamon, D. D., Ni, H., Hershberger, R. E. 2023

    Abstract

    Dilated cardiomyopathy (DCM) can lead to advanced disease, defined herein as necessitating a durable left ventricular assist device or a heart transplant (LVAD/HT). DCM is known to have a genetic basis, but the association of rare variant genetics with advanced DCM has not been studied.We analyzed clinical and genetic sequence data from patients enrolled between 2016 and 2021 in the US multisite DCM Precision Medicine Study, which was a geographically diverse, multiracial, multiethnic cohort. Clinical evaluation included standardized patient interview and medical record query forms. DCM severity was classified into 3 groups: patients with advanced disease with LVAD/HT; patients with an implantable cardioverter defibrillator (ICD) only; or patients with no ICD or LVAD/HT. Rare variants in 36 DCM genes were classified as pathogenic or likely pathogenic or variants of uncertain significance. Confounding factors we considered included demographic characteristics, lifestyle factors, access to care, DCM duration, and comorbidities. Crude and adjusted associations between DCM severity and rare variant genetic findings were assessed using multinomial models with generalized logit link.Patients' mean (SD) age was 51.9 (13.6) years; 42% were of African ancestry, 56% were of European ancestry, and 44% were female. Of 1198 patients, 347 had LVAD/HT, 511 had an ICD, and 340 had no LVAD/HT or ICD. The percentage of patients with pathogenic or likely pathogenic variants was 26.2%, 15.9%, and 15.0% for those with LVAD/HT, ICD only, or neither, respectively. After controlling for sociodemographic characteristics and comorbidities, patients with DCM with LVAD/HT were more likely than those without LVAD/HT or ICD to have DCM-related pathogenic or likely pathogenic rare variants (odds ratio, 2.3 [95% CI, 1.5-3.6]). The association did not differ by ancestry. Rare variant genetic findings were similar between patients with DCM with an ICD and those without LVAD/HT or ICD.Advanced DCM was associated with higher odds of rare variants in DCM genes adjudicated as pathogenic or likely pathogenic, compared with individuals with less severe DCM. This finding may help assess the risk of outcomes in management of patients with DCM and their at-risk family members.URL: https://www.gov; Unique identifier: NCT03037632.

    View details for DOI 10.1161/CIRCULATIONAHA.123.064847

    View details for PubMedID 37641966

  • Beyond the exome: What's next in diagnostic testing for Mendelian conditions. American journal of human genetics Wojcik, M. H., Reuter, C. M., Marwaha, S., Mahmoud, M., Duyzend, M. H., Barseghyan, H., Yuan, B., Boone, P. M., Groopman, E. E., Délot, E. C., Jain, D., Sanchis-Juan, A., Starita, L. M., Talkowski, M., Montgomery, S. B., Bamshad, M. J., Chong, J. X., Wheeler, M. T., Berger, S. I., O'Donnell-Luria, A., Sedlazeck, F. J., Miller, D. E. 2023; 110 (8): 1229-1248

    Abstract

    Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order, and emerging technologies, such as optical genome mapping and long-read DNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to research consortia focused on elucidating the underlying cause of rare unsolved genetic disorders.

    View details for DOI 10.1016/j.ajhg.2023.06.009

    View details for PubMedID 37541186

  • Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry. JAMA Jordan, E., Kinnamon, D. D., Haas, G. J., Hofmeyer, M., Kransdorf, E., Ewald, G. A., Morris, A. A., Owens, A., Lowes, B., Stoller, D., Tang, W. H., Garg, S., Trachtenberg, B. H., Shah, P., Pamboukian, S. V., Sweitzer, N. K., Wheeler, M. T., Wilcox, J. E., Katz, S., Pan, S., Jimenez, J., Fishbein, D. P., Smart, F., Wang, J., Gottlieb, S. S., Judge, D. P., Moore, C. K., Mead, J. O., Hurst, N., Cao, J., Huggins, G. S., Cowan, J., Ni, H., Rehm, H. L., Jarvik, G. P., Vatta, M., Burke, W., Hershberger, R. E. 2023; 330 (5): 432-441

    Abstract

    Black patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients.To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM.Cross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance.Presence of DCM.Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic).A total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, -0.09 [95% CI, -0.14 to -0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, -0.06 [95% CI, -0.11 to -0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, -0.07 [95% CI, -0.22 to 0.09]) due to a larger number of non-TTN non-predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001).Patients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.

    View details for DOI 10.1001/jama.2023.11970

    View details for PubMedID 37526719

  • Assessment of Oxygen Pulse in Hypertrophic Cardiomyopathy-Reply. JAMA cardiology Wheeler, M. T., Chen, Y. M., Myers, J. 2023

    View details for DOI 10.1001/jamacardio.2023.1889

    View details for PubMedID 37405726

  • Respiratory gas kinetics in patients with congestive heart failure during recovery from peak exercise. Clinics (Sao Paulo, Brazil) Patti, A., Blumberg, Y., Hedman, K., Neunhäuserer, D., Haddad, F., Wheeler, M., Ashley, E., Moneghetti, K. J., Myers, J., Christle, J. W. 2023; 78: 100225

    Abstract

    Cardiopulmonary Exercise Testing (CPX) is essential for the assessment of exercise capacity for patients with Chronic Heart Failure (CHF). Respiratory gas and hemodynamic parameters such as Ventilatory Efficiency (VE/VCO2 slope), peak oxygen uptake (peak VO2), and heart rate recovery are established diagnostic and prognostic markers for clinical populations. Previous studies have suggested the clinical value of metrics related to respiratory gas collected during recovery from peak exercise, particularly recovery time to 50% (T1/2) of peak VO2. The current study explores these metrics in detail during recovery from peak exercise in CHF.Patients with CHF who were referred for CPX and healthy individuals without formal diagnoses were assessed for inclusion. All subjects performed CPX on cycle ergometers to volitional exhaustion and were monitored for at least five minutes of recovery. CPX data were analyzed for overshoot of respiratory exchange ratio (RER=VCO2/VO2), ventilatory equivalent for oxygen (VE/VO2), end-tidal partial pressure of oxygen (PETO2), and T1/2 of peak VO2 and VCO2.Thirty-two patients with CHF and 30 controls were included. Peak VO2 differed significantly between patients and controls (13.5 ± 3.8 vs. 32.5 ± 9.8 mL/Kg*min-1, p < 0.001). Mean Left Ventricular Ejection Fraction (LVEF) was 35.9 ± 9.8% for patients with CHF compared to 61.1 ± 8.2% in the control group. The T1/2 of VO2, VCO2 and VE was significantly higher in patients (111.3 ± 51.0, 132.0 ± 38.8 and 155.6 ± 45.5s) than in controls (58.08 ± 13.2, 74.3 ± 21.1, 96.7 ± 36.8s; p < 0.001) while the overshoot of PETO2, VE/VO2 and RER was significantly lower in patients (7.2 ± 3.3, 41.9 ± 29.1 and 25.0 ± 13.6%) than in controls (10.1 ± 4.6, 62.1 ± 17.7 and 38.7 ± 15.1%; all p < 0.01). Most of the recovery metrics were significantly correlated with peak VO2 in CHF patients, but not with LVEF.Patients with CHF have a significantly blunted recovery from peak exercise. This is reflected in delays of VO2, VCO2, VE, PETO2, RER and VE/VO2, reflecting a greater energy required to return to baseline. Abnormal respiratory gas kinetics in CHF was negatively correlated with peak VO2 but not baseline LVEF.

    View details for DOI 10.1016/j.clinsp.2023.100225

    View details for PubMedID 37356413

  • Genomics Research with Undiagnosed Children: Ethical Challenges at the Boundaries of Research and Clinical Care. The Journal of pediatrics Halley, M. C., Young, J. L., Tang, C., Mintz, K. T., Lucas-Griffin, S., Maghiro, A. S., Ashley, E. A., Tabor, H. K. 2023: 113537

    Abstract

    To explore the perspectives of parents of undiagnosed children enrolled in genomic diagnosis research regarding their motivations for enrolling their children, their understanding of the potential burdens and benefits, and the extent to which their experiences ultimately aligned with or diverged from their original expectations.In-depth interviews were conducted with parents, audio-recorded and transcribed. A structured codebook was applied to each transcript, after which iterative memoing was used to identify themes.Fifty-four parents participated, including 17 (31.5%) whose child received a diagnosis through research. Themes describing parents' expectations and experiences of genomic diagnosis research included: 1) the extent to which parents' motivations for participation focused on their hope that it would directly benefit their child; 2) the ways in which parents' frustrations regarding the research process confused the dual clinical and research goals of their participation; and 3) the limited clinical benefits parents ultimately experienced for their children.Our results suggest that parents of undiagnosed children seeking enrollment in genomic diagnosis research are at risk of a form of therapeutic misconception - in this case, diagnostic misconception. These findings indicate the need to examine the processes and procedures associated with this research in order to appropriately communicate and balance the potential burdens and benefits of study participation.

    View details for DOI 10.1016/j.jpeds.2023.113537

    View details for PubMedID 37271495

  • Screening for Dilated Cardiomyopathy in At-Risk First-Degree Relatives. Journal of the American College of Cardiology Ni, H., Jordan, E., Kinnamon, D. D., Cao, J., Haas, G. J., Hofmeyer, M., Kransdorf, E., Ewald, G. A., Morris, A. A., Owens, A., Lowes, B., Stoller, D., Tang, W. H., Garg, S., Trachtenberg, B. H., Shah, P., Pamboukian, S. V., Sweitzer, N. K., Wheeler, M. T., Wilcox, J. E., Katz, S., Pan, S., Jimenez, J., Fishbein, D. P., Smart, F., Wang, J., Gottlieb, S. S., Judge, D. P., Moore, C. K., Huggins, G. S., Hershberger, R. E. 2023; 81 (21): 2059-2071

    Abstract

    Cardiovascular screening is recommended for first-degree relatives (FDRs) of patients with dilated cardiomyopathy (DCM), but the yield of FDR screening is uncertain for DCM patients without known familial DCM, for non-White FDRs, or for DCM partial phenotypes of left ventricular enlargement (LVE) or left ventricular systolic dysfunction (LVSD).This study examined the yield of clinical screening among reportedly unaffected FDRs of DCM patients.Adult FDRs of DCM patients at 25 sites completed screening echocardiograms and ECGs. Mixed models accounting for site heterogeneity and intrafamilial correlation were used to compare screen-based percentages of DCM, LVSD, or LVE by FDR demographics, cardiovascular risk factors, and proband genetics results.A total of 1,365 FDRs were included, with a mean age of 44.8 ± 16.9 years, 27.5% non-Hispanic Black, 9.8% Hispanic, and 61.7% women. Among screened FDRs, 14.1% had new diagnoses of DCM (2.1%), LVSD (3.6%), or LVE (8.4%). The percentage of FDRs with new diagnoses was higher for those aged 45 to 64 years than 18 to 44 years. The age-adjusted percentage of any finding was higher among FDRs with hypertension and obesity but did not differ statistically by race and ethnicity (16.2% for Hispanic, 15.2% for non-Hispanic Black, and 13.1% for non-Hispanic White) or sex (14.6% for women and 12.8% for men). FDRs whose probands carried clinically reportable variants were more likely to be identified with DCM.Cardiovascular screening identified new DCM-related findings among 1 in 7 reportedly unaffected FDRs regardless of race and ethnicity, underscoring the value of clinical screening in all FDRs.

    View details for DOI 10.1016/j.jacc.2023.03.419

    View details for PubMedID 37225358

  • The Reply. The American journal of medicine Harris, C. S., Froelicher, V. F., Wheeler, M. T. 2023; 136 (5): e106

    View details for DOI 10.1016/j.amjmed.2023.01.042

    View details for PubMedID 37137577

  • The genetic determinants of recurrent somatic mutations in 43,693 blood genomes. Science advances Weinstock, J. S., Laurie, C. A., Broome, J. G., Taylor, K. D., Guo, X., Shuldiner, A. R., O'Connell, J. R., Lewis, J. P., Boerwinkle, E., Barnes, K. C., Chami, N., Kenny, E. E., Loos, R. J., Fornage, M., Redline, S., Cade, B. E., Gilliland, F. D., Chen, Z., Gauderman, W. J., Kumar, R., Grammer, L., Schleimer, R. P., Psaty, B. M., Bis, J. C., Brody, J. A., Silverman, E. K., Yun, J. H., Qiao, D., Weiss, S. T., Lasky-Su, J., DeMeo, D. L., Palmer, N. D., Freedman, B. I., Bowden, D. W., Cho, M. H., Vasan, R. S., Johnson, A. D., Yanek, L. R., Becker, L. C., Kardia, S., He, J., Kaplan, R., Heckbert, S. R., Smith, N. L., Wiggins, K. L., Arnett, D. K., Irvin, M. R., Tiwari, H., Correa, A., Raffield, L. M., Gao, Y., de Andrade, M., Rotter, J. I., Rich, S. S., Manichaikul, A. W., Konkle, B. A., Johnsen, J. M., Wheeler, M. M., Custer, B. S., Duggirala, R., Curran, J. E., Blangero, J., Gui, H., Xiao, S., Williams, L. K., Meyers, D. A., Li, X., Ortega, V., McGarvey, S., Gu, C. C., Chen, Y. I., Lee, W. J., Shoemaker, M. B., Darbar, D., Roden, D., Albert, C., Kooperberg, C., Desai, P., Blackwell, T. W., Abecasis, G. R., Smith, A. V., Kang, H. M., Mathias, R., Natarajan, P., Jaiswal, S., Reiner, A. P., Bick, A. G. 2023; 9 (17): eabm4945

    Abstract

    Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

    View details for DOI 10.1126/sciadv.abm4945

    View details for PubMedID 37126548

  • Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. Nature Weinstock, J. S., Gopakumar, J., Burugula, B. B., Uddin, M. M., Jahn, N., Belk, J. A., Bouzid, H., Daniel, B., Miao, Z., Ly, N., Mack, T. M., Luna, S. E., Prothro, K. P., Mitchell, S. R., Laurie, C. A., Broome, J. G., Taylor, K. D., Guo, X., Sinner, M. F., von Falkenhausen, A. S., Kääb, S., Shuldiner, A. R., O'Connell, J. R., Lewis, J. P., Boerwinkle, E., Barnes, K. C., Chami, N., Kenny, E. E., Loos, R. J., Fornage, M., Hou, L., Lloyd-Jones, D. M., Redline, S., Cade, B. E., Psaty, B. M., Bis, J. C., Brody, J. A., Silverman, E. K., Yun, J. H., Qiao, D., Palmer, N. D., Freedman, B. I., Bowden, D. W., Cho, M. H., DeMeo, D. L., Vasan, R. S., Yanek, L. R., Becker, L. C., Kardia, S. L., Peyser, P. A., He, J., Rienstra, M., Van der Harst, P., Kaplan, R., Heckbert, S. R., Smith, N. L., Wiggins, K. L., Arnett, D. K., Irvin, M. R., Tiwari, H., Cutler, M. J., Knight, S., Muhlestein, J. B., Correa, A., Raffield, L. M., Gao, Y., de Andrade, M., Rotter, J. I., Rich, S. S., Tracy, R. P., Konkle, B. A., Johnsen, J. M., Wheeler, M. M., Smith, J. G., Melander, O., Nilsson, P. M., Custer, B. S., Duggirala, R., Curran, J. E., Blangero, J., McGarvey, S., Williams, L. K., Xiao, S., Yang, M., Gu, C. C., Chen, Y. I., Lee, W. J., Marcus, G. M., Kane, J. P., Pullinger, C. R., Shoemaker, M. B., Darbar, D., Roden, D. M., Albert, C., Kooperberg, C., Zhou, Y., Manson, J. E., Desai, P., Johnson, A. D., Mathias, R. A., Blackwell, T. W., Abecasis, G. R., Smith, A. V., Kang, H. M., Satpathy, A. T., Natarajan, P., Kitzman, J. O., Whitsel, E. A., Reiner, A. P., Bick, A. G., Jaiswal, S. 2023

    Abstract

    Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

    View details for DOI 10.1038/s41586-023-05806-1

    View details for PubMedID 37046083

    View details for PubMedCentralID 4624443

  • Participation in a national diagnostic research study: assessing the patient experience. Orphanet journal of rare diseases Rosenfeld, L. E., LeBlanc, K., Nagy, A., Ego, B. K., Undiagnosed Diseases Network, McCray, A. T., Acosta, M. T., Adam, M., Adams, D. R., Alvarez, R. L., Alvey, J., Amendola, L., Andrews, A., Ashley, E. A., Bacino, C. A., Bademci, G., Balasubramanyam, A., Baldridge, D., Bale, J., Bamshad, M., Barbouth, D., Bayrak-Toydemir, P., Beck, A., Beggs, A. H., Behrens, E., Bejerano, G., Bellen, H. J., Bennett, J., Berg-Rood, B., Bernstein, J. A., Berry, G. T., Bican, A., Bivona, S., Blue, E., Bohnsack, J., Bonner, D., Botto, L., Boyd, B., Briere, L. C., Brokamp, E., Brown, G., Burke, E. A., Burrage, L. C., Butte, M. J., Byers, P., Byrd, W. E., Carey, J., Carrasquillo, O., Cassini, T., Chang, T. C., Chanprasert, S., Chao, H., Clark, G. D., Coakley, T. R., Cobban, L. A., Cogan, J. D., Coggins, M., Cole, F. S., Colley, H. A., Cooper, C. M., Cope, H., Corona, R., Craigen, W. J., Crouse, A. B., Cunningham, M., D'Souza, P., Dai, H., Dasari, S., Davis, J., Dayal, J. G., Dell'Angelica, E. C., Dipple, K., Doherty, D., Dorrani, N., Doss, A. L., Douine, E. D., Duncan, L., Earl, D., Eckstein, D. J., Emrick, L. T., Eng, C. M., Falk, M., Fieg, E. L., Fisher, P. G., Fogel, B. L., Forghani, I., Gahl, W. A., Glass, I., Gochuico, B., Goddard, P. C., Godfrey, R. A., Golden-Grant, K., Grajewski, A., Hadley, D., Hahn, S., Halley, M. C., Hamid, R., Hassey, K., Hayes, N., High, F., Hing, A., Hisama, F. M., Holm, I. A., Hom, J., Horike-Pyne, M., Huang, A., Hutchison, S., Introne, W., Isasi, R., Izumi, K., Jamal, F., Jarvik, G. P., Jarvik, J., Jayadev, S., Jean-Marie, O., Jobanputra, V., Karaviti, L., Kennedy, J., Ketkar, S., Kiley, D., Kilich, G., Kobren, S. N., Kohane, I. S., Kohler, J. N., Korrick, S., Kozuira, M., Krakow, D., Krasnewich, D. M., Kravets, E., Lalani, S. R., Lam, B., Lam, C., Lanpher, B. C., Lanza, I. R., Lee, B. H., Levitt, R., Lewis, R. A., Liu, P., Liu, X. Z., Longo, N., Loo, S. K., Loscalzo, J., Maas, R. L., Macnamara, E. F., MacRae, C. A., Maduro, V. V., Mahoney, R., Malicdan, M. C., Mamounas, L. A., Manolio, T. A., Mao, R., Maravilla, K., Marom, R., Marth, G., Martin, B. A., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., McCauley, J., McConkie-Rosell, A., McGee, E., Mefford, H., Merritt, J. L., Might, M., Mirzaa, G., Morava, E., Moretti, P., Mulvihill, J., Nakano-Okuno, M., Nelson, S. F., Newman, J. H., Nicholas, S. K., Nickerson, D., Nieves-Rodriguez, S., Novacic, D., Oglesbee, D., Orengo, J. P., Pace, L., Pak, S., Pallais, J. C., Palmer, C. G., Papp, J. C., Parker, N. H., Phillips, J. A., Posey, J. E., Potocki, L., Swerdzewski, B. N., Quinlan, A., Rao, D. A., Raper, A., Raskind, W., Renteria, G., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Rosenwasser, N., Rossignol, F., Ruzhnikov, M., Sacco, R., Sampson, J. B., Saporta, M., Schaechter, J., Schedl, T., Schoch, K., Scott, D. A., Scott, C. R., Shashi, V., Shin, J., Silverman, E. K., Sinsheimer, J. S., Sisco, K., Smith, E. C., Smith, K. S., Solem, E., Solnica-Krezel, L., Solomon, B., Spillmann, R. C., Stoler, J. M., Sullivan, K., Sullivan, J. A., Sun, A., Sutton, S., Sweetser, D. A., Sybert, V., Tabor, H. K., Tan, Q. K., Tan, A. L., Tekin, M., Telischi, F., Thorson, W., Tifft, C. J., Toro, C., Tran, A. A., Ungar, R. A., Urv, T. K., Vanderver, A., Velinder, M., Viskochil, D., Vogel, T. P., Wahl, C. E., Walker, M., Wallace, S., Walley, N. M., Wambach, J., Wan, J., Wang, L., Wangler, M. F., Ward, P. A., Wegner, D., Hubshman, M. W., Wener, M., Wenger, T., Westerfield, M., Wheeler, M. T., Whitlock, J., Wolfe, L. A., Worley, K., Xiao, C., Yamamoto, S., Yang, J., Zhang, Z., Zuchner, S. 2023; 18 (1): 73

    Abstract

    INTRODUCTION: The Undiagnosed Diseases Network (UDN), a clinical research study funded by the National Institutes of Health, aims to provide answers for patients with undiagnosed conditions and generate knowledge about underlying disease mechanisms. UDN evaluations involve collaboration between clinicians and researchers and go beyond what is possible in clinical settings. While medical and research outcomes of UDN evaluations have been explored, this is the first formal assessment of the patient and caregiver experience.METHODS: We invited UDN participants and caregivers to participate in focus groups via email, newsletter, and a private participant Facebook group. We developed focus group questions based on research team expertise, literature focused on patients with rare and undiagnosed conditions, and UDN participant and family member feedback. In March 2021, we conducted, recorded, and transcribed four 60-min focus groups via Zoom. Transcripts were evaluated using a thematic analysis approach.RESULTS: The adult undiagnosed focus group described the UDN evaluation as validating and an avenue for access to medical providers. They also noted that the experience impacted professional choices and helped them rely on others for support. The adult diagnosed focus group described the healthcare system as not set up for rare disease. In the pediatric undiagnosed focus group, caregivers discussed a continued desire for information and gratitude for the UDN evaluation. They also described an ability to rule out information and coming to terms with not having answers. The pediatric diagnosed focus group discussed how the experience helped them focus on management and improved communication. Across focus groups, adults (undiagnosed/diagnosed) noted the comprehensiveness of the evaluation. Undiagnosed focus groups (adult/pediatric) discussed a desire for ongoing communication and care with the UDN. Diagnosed focus groups (adult/pediatric) highlighted the importance of the diagnosis they received in the UDN. The majority of the focus groups noted a positive future orientation after participation.CONCLUSION: Our findings are consistent with prior literature focused on the patient experience of rare and undiagnosed conditions and highlight benefits from comprehensive evaluations, regardless of whether a diagnosis is obtained. Focus group themes also suggest areas for improvement and future research related to the diagnostic odyssey.

    View details for DOI 10.1186/s13023-023-02695-5

    View details for PubMedID 37032333

  • Genetic Signature of Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study Hofmeyer, M., Haas, G., Kransdorf, E., Ewald, G., Morris, A., Owens, A., Lowes, B., Stoller, D., Tang, W., Garg, S., Trachtenberg, B., Shah, P., Pamboukian, S., Sweitzer, N., Wheeler, M., Wilcox, J., Katz, S., Pan, S., Jimenez, J., Smart, F., Wang, J., Gottlieb, S., Judge, D., Moore, C., Huggins, G., Jordan, E., Kinnamon, D., Ni, H., Hershberger, R. E. ELSEVIER SCIENCE INC. 2023: S176
  • Transforming Growth Factor-β Analysis of the VANISH Trial Cohort. Circulation. Heart failure Kim, Y., Mastali, M., Van Eyk, J. E., Orav, E. J., Vissing, C. R., Day, S. M., Axelsson Raja, A., Russell, M. W., Zahka, K., Lever, H. M., Pereira, A. C., Murphy, A. M., Canter, C., Bach, R. G., Wheeler, M. T., Rossano, J. W., Owens, A. T., Bundgaard, H., Benson, L., Mestroni, L., Taylor, M. R., Patel, A. R., Wilmot, I., Thrush, P., Soslow, J. H., Becker, J. R., Seidman, C. E., Ho, C. Y. 2023: e010314
  • Effectiveness of the Family Heart Talk Communication Tool in Improving Family Member Screening for Dilated Cardiomyopathy: Results of a Randomized Trial. Circulation Kinnamon, D. D., Jordan, E., Haas, G. J., Hofmeyer, M., Kransdorf, E., Ewald, G. A., Morris, A. A., Owens, A., Lowes, B., Stoller, D., Wilson Tang, W. H., Garg, S., Trachtenberg, B. H., Shah, P., Pamboukian, S. V., Sweitzer, N. K., Wheeler, M. T., Wilcox, J. E., Katz, S., Pan, S., Jimenez, J., Aaronson, K. D., Fishbein, D. P., Smart, F., Wang, J., Gottlieb, S. S., Judge, D. P., Moore, C. K., Mead, J. O., Huggins, G. S., Ni, H., Burke, W., Hershberger, R. E., DCM (Dilated Cardiomyopathy) Precision Medicine Study of the DCM Consortium 2023

    Abstract

    BACKGROUND: Managing disease risk among first-degree relatives of probands diagnosed with a heritable disease is central to precision medicine. A critical component is often clinical screening, which is particularly important for conditions like dilated cardiomyopathy (DCM) that remain asymptomatic until severe disease develops. Nonetheless, probands are frequently ill-equipped to disseminate genetic risk information that motivates at-risk relatives to complete recommended clinical screening. An easily implemented remedy for this key issue has been elusive.METHODS: The DCM Precision Medicine Study developed Family Heart Talk, a booklet designed to help probands with DCM communicate genetic risk and the need for cardiovascular screening to their relatives. The effectiveness of the Family Heart Talk booklet in increasing cardiovascular clinical screening uptake among first-degree relatives was assessed in a multicenter, open-label, cluster-randomized, controlled trial. The primary outcome measured in eligible first-degree relatives was completion of screening initiated within 12 months after proband enrollment. Because probands randomized to the intervention received the booklet at the enrollment visit, eligible first-degree relatives were limited to those who were alive and not enrolled on the same day as the proband.RESULTS: Between June 2016 and March 2020, 1241 probands were randomized (1:1) to receive Family Heart Talk (n=621) or not (n=620) within strata defined by site and self-identified race/ethnicity (non-Hispanic Black, non-Hispanic White, or Hispanic). Final analyses included 550 families (n=2230 eligible first-degree relatives) in the Family Heart Talk arm and 561 (n=2416) in the control arm. A higher percentage of eligible first-degree relatives completed screening in the Family Heart Talk arm (19.5% versus 16.0%), and the odds of screening completion among these first-degree relatives were higher in the Family Heart Talk arm after adjustment for proband randomization stratum, sex, and age quartile (odds ratio, 1.30 [1-sided 95% CI, 1.08-]). A prespecified subgroup analysis did not find evidence of heterogeneity in the adjusted intervention odds ratio across race/ethnicity strata (P=0.90).CONCLUSIONS: Family Heart Talk, a booklet that can be provided to patients with DCM by clinicians with minimal additional time investment, was effective in increasing cardiovascular clinical screening among first-degree relatives of patients with DCM.REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT03037632.

    View details for DOI 10.1161/CIRCULATIONAHA.122.062507

    View details for PubMedID 36938756

  • Beyond the exome: what's next in diagnostic testing for Mendelian conditions. ArXiv Wojcik, M. H., Reuter, C. M., Marwaha, S., Mahmoud, M., Duyzend, M. H., Barseghyan, H., Yuan, B., Boone, P. M., Groopman, E. E., Délot, E. C., Jain, D., Sanchis-Juan, A., Starita, L. M., Talkowski, M., Montgomery, S. B., Bamshad, M. J., Chong, J. X., Wheeler, M. T., Berger, S. I., O'Donnell-Luria, A., Sedlazeck, F. J., Miller, D. E. 2023

    Abstract

    Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order and emerging technologies, such as optical genome mapping and long-read DNA or RNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to a consortium such as GREGoR, which is focused on elucidating the underlying cause of rare unsolved genetic disorders.

    View details for DOI 10.1002/ajmg.a.63053

    View details for PubMedID 36713248

    View details for PubMedCentralID PMC9882576

  • The mitochondrial multi-omic response to exercise training across tissues. bioRxiv : the preprint server for biology Amar, D., Gay, N. R., Jimenez-Morales, D., Beltran, P. M., Ramaker, M. E., Raja, A. N., Zhao, B., Sun, Y., Marwaha, S., Gaul, D., Hershman, S. G., Xia, A., Lanza, I., Fernandez, F. M., Montgomery, S. B., Hevener, A. L., Ashley, E. A., Walsh, M. J., Sparks, L. M., Burant, C. F., Rector, R. S., Thyfault, J., Wheeler, M. T., Goodpaster, B. H., Coen, P. M., Schenk, S., Bodine, S. C., Lindholm, M. E. 2023

    Abstract

    Mitochondria are adaptable organelles with diverse cellular functions critical to whole-body metabolic homeostasis. While chronic endurance exercise training is known to alter mitochondrial activity, these adaptations have not yet been systematically characterized. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) mapped the longitudinal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats endurance trained for 1, 2, 4 or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart and skeletal muscle, while we detected mild responses in the brain, lung, small intestine and testes. The colon response was characterized by non-linear dynamics that resulted in upregulation of mitochondrial function that was more prominent in females. Brown adipose and adrenal tissues were characterized by substantial downregulation of mitochondrial pathways. Training induced a previously unrecognized robust upregulation of mitochondrial protein abundance and acetylation in the liver, and a concomitant shift in lipid metabolism. The striated muscles demonstrated a highly coordinated response to increase oxidative capacity, with the majority of changes occurring in protein abundance and post-translational modifications. We identified exercise upregulated networks that are downregulated in human type 2 diabetes and liver cirrhosis. In both cases HSD17B10, a central dehydrogenase in multiple metabolic pathways and mitochondrial tRNA maturation, was the main hub. In summary, we provide a multi-omic, cross-tissue atlas of the mitochondrial response to training and identify candidates for prevention of disease-associated mitochondrial dysfunction.

    View details for DOI 10.1101/2023.01.13.523698

    View details for PubMedID 36711881

    View details for PubMedCentralID PMC9882193

  • Generation of two human iPSC lines with Exon 3 mutations in BCL2-Associated Athanogene 3 (BAG3) from dilated cardiomyopathy patients. Stem cell research Zushin, P. H., Zhou, Y., Li, A., Ashley, E. A., Wheeler, M. T., Wu, J. C. 2023; 67: 103019

    Abstract

    Dilated cardiomyopathies (DCM) are one of the main causes of heart failure as one ages. BAG3 is a chaperone protein that is heavily implicated in the development of DCM and speed of progression toward heart failure. Here we generate two human iPSC lines from individuals with mutations in exon 3 of BAG3 and provide validation of their pluripotency and ability to differentiate toward the three primary germ layers. These two cell lines can help our understanding of BAG3 and its role in DCM by providing a good model for BAG3 inactivation and insufficiency.

    View details for DOI 10.1016/j.scr.2023.103019

    View details for PubMedID 36642055

  • Plain Language Summary of Publication of the safety and efficacy of ARRY-371797 in people with dilated cardiomyopathy and a faulty LMNA gene. Future cardiology MacRae, C. A., Taylor, M. R., Mestroni, L., Moses, J., Ashley, E. A., Wheeler, M. T., Lakdawala, N. K., Hershberger, R. E., Sandor, V., Saunders, M. E., Oliver, C., Lee, P. A., Judge, D. P. 2023

    Abstract

    WHAT IS THIS PLAIN LANGUAGE SUMMARY ABOUT?: This plain language summary describes the results of a study looking at the effects of a medicine called ARRY-371797 (also known as PF-07265803) in people with dilated cardiomyopathy (DCM for short) caused by a faulty LMNA gene. This condition is called LMNA-related DCM. DCM happens when the heart becomes bigger and weaker than normal, impacting functional capacity and leading to symptoms of heart failure. This means the heart is not able to pump blood around the body as easily, and people are unable to do as much in their daily lives (like getting dressed and going shopping). People may inherit a faulty LMNA gene from one of their parents, or a faulty LMNA gene may develop when mistakes happen during cell growth and replication. ARRY-371797 targets a specific mechanism in the body that can lead to heart problems in people with a faulty LMNA gene. As ARRY-371797 is not currently approved for use outside of clinical trials, it doesn't currently have an easily recognizable trade name.WHAT WERE THE RESULTS?: 12 American people (average age 50years) with LMNA-related DCM took part in the study and received 400mg or 100mg of ARRY-371797 twice daily for 48weeks. People knew which dose of ARRY-371797 they were taking. People were checked after 4, 12, 24, 36 and 48weeks of taking ARRY-371797 to see how far they could walk in the 6-minute walk test (6MWT for short). The level of NT-proBNP in their blood was also measured. NT-proBNP is a biomarker used to measure the severity of heart failure. A biomarker is something found in the body that can be measured to indicate the extent of a disease. -After taking ARRY-371797 for 12weeks, people were able to walk further in the 6MWT and had lower levels of NT-proBNP in their blood. This suggests improvement in functional capacity (exercise tolerance) and heart function. Researchers also asked people about their quality of life using the Kansas City Cardiomyopathy Questionnaire (KCCQ for short), and looked for any side effects. -Researchers saw some improvement in KCCQ scores. -Researchers saw no major side effects that they considered to be related to ARRY-371797 treatment. A side effect is something that people feel was caused by a medicine or treatment. Overall, this study showed that people with LMNA-related DCM who took ARRY-371797 had improved functional capacity (exercise tolerance), improved heart function, and improved quality of life. Phase 2 study (NCT02057341) Phase 2 long-term extension study (NCT02351856) Phase 3 REALM-DCM study (NCT03439514).

    View details for DOI 10.2217/fca-2022-0099

    View details for PubMedID 36718638

  • HOMOZYGOUS FRAMESHIFT VARIANT IN LYSOSOME-ASSOCIATED MEMBRANE GLYCOPROTEIN 3 IN A PATIENT WITH INTERSTITIAL LUNG DISEASE DUE TO POSSIBLE SURFACTANT PROTEIN DYSFUNCTION Keehan, L., Bonner, D., Kravets, E., Kohler, J., Reuter, C., Marwaha, S., Network, U., Fisher, P., Ashley, E., Wheeler, M., Bernstein, J. A. SAGE PUBLICATIONS LTD. 2023: NP389
  • CHARACTERIZATION OF TWO NOVEL DNASE1L3 VARIANTS IN A PATIENT WITH A MONOGENIC FORM OF SYSTEMIC LUPUS ERYTHEMATOSUS Leon, A., Vera, P. L., Bonner, D., Kohler, J., Reuter, C., Zastrow, D., Majcherska, M., Fernandez, L., McCormack, C., Marwaha, S., Fisher, P., Ashley, E., Maller, J., Hsu, J., Balboni, Bernstein, J., Wheeler, M., Gomez-Ospina, N. SAGE PUBLICATIONS LTD. 2023: NP391-NP392
  • Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant. Circulation. Genomic and precision medicine Hoorntje, E. T., Burns, C., Marsili, L., Corden, B., Parikh, V. N., Te Meerman, G. J., Gray, B., Adiyaman, A., Bagnall, R. D., Barge-Schaapveld, D. Q., van den Berg, M. P., Bootsma, M., Bosman, L. P., Correnti, G., Duflou, J., Eppinga, R. N., Fatkin, D., Fietz, M., Haan, E., Jongbloed, J. D., Hauer, A. D., Lam, L., van Lint, F. H., Lota, A., Marcelis, C., McCarthy, H. J., van Mil, A. M., Oldenburg, R. A., Pachter, N., Planken, R. N., Reuter, C., Semsarian, C., van der Smagt, J. J., Thompson, T., Vohra, J., Volders, P. G., van Waning, J. I., Whiffin, N., van den Wijngaard, A., Amin, A. S., Wilde, A. A., van Woerden, G., Yeates, L., Zentner, D., Ashley, E. A., Wheeler, M. T., Ware, J. S., van Tintelen, J. P., Ingles, J. 2022: e003672

    Abstract

    Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy.Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed.There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions, resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 gnomAD control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001).In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

    View details for DOI 10.1161/CIRCGEN.121.003672

    View details for PubMedID 36580316

  • Intrinsic Atrial Myopathy Precedes Left Ventricular Dysfunction and Predicts Atrial Fibrillation in Lamin A/C Cardiomyopathy. Circulation. Genomic and precision medicine Tremblay-Gravel, M., Ichimura, K., Picard, K., Kawano, Y., Dries, A. M., Haddad, F., Lakdawala, N. K., Wheeler, M. T., Parikh, V. N. 2022: e003480

    Abstract

    BACKGROUND: In Lamin A/C (LMNA) cardiomyopathy, atrial fibrillation (AF) commonly occurs before dilated cardiomyopathy, and the ability to predict its incidence is limited. We hypothesized that left atrial (LA) echocardiographic phenotyping can identify atrial myopathy and harbingers of AF.METHODS: Echocardiograms from patients with pathogenic or likely pathogenic variants in LMNA (n=77) with and without reduced left ventricular ejection fraction (LVEF, <50%) were compared to healthy individuals (n=70) and patients with Titin truncating variant cardiomyopathy (n=35) with similar LVEF, sex, and age distributions. Echocardiographic analysis, blinded to genotype, included strain and volumetric measures of left ventricular and atrial function. The primary outcome was incident AF.RESULTS: At baseline, 43% of the patients with pathogenic or likely pathogenic LMNA variants had a history of AF, including 26% of those with LVEF ≥50%. Compared with healthy subjects, the patients with pathogenic or likely pathogenic LMNA variants and LVEF ≥50% had reduced LA contractile strain (LMNA, 11.8±6.1% versus control, 15.0±4.2%; P=0.003). Compared to LVEF-matched Titin truncating variant cardiomyopathy patients, the patients with pathogenic or likely pathogenic LMNA variants and LVEF <50% displayed no difference in LA size, but a worse LA contractile dysfunction (6.4±4.7% versus 12.6±9.6%; P=0.02). Over a median follow-up of 2.8 (1.2-5.7) years, LA contractile strain was the only significant predictor of AF in multivariable Cox regression (hazard ratio, 4.0 [95% CI, 1.04-15.2]).CONCLUSIONS: LMNA cardiomyopathy is associated with early intrinsic atrial myopathy reflected by high AF prevalence and reduced LA contractile strain, even in the absence of LV dysfunction and LA dilation. Whether LA strain can be used as a monitoring strategy to detect and mitigate AF complications requires validation.

    View details for DOI 10.1161/CIRCGEN.121.003480

    View details for PubMedID 36548481

  • Efficacy and Safety of ARRY-371797 in LMNA-Related Dilated Cardiomyopathy: A Phase 2 Study. Circulation. Genomic and precision medicine MacRae, C. A., Taylor, M. R., Mestroni, L., Moses, J., Ashley, E. A., Wheeler, M. T., Lakdawala, N. K., Hershberger, R. E., Sandor, V., Saunders, M. E., Oliver, C., Lee, P. A., Judge, D. P. 2022: e003730

    Abstract

    BACKGROUND: Lamin A/C gene (LMNA)-related dilated cardiomyopathy is a serious and life-threatening condition with a high unmet medical need. This phase 2 study assessed the effects of the oral selective p38 mitogen-activated protein kinase inhibitor ARRY-371797 on functional capacity and cardiac function in patients with LMNA-related dilated cardiomyopathy.METHODS: Patients with LMNA-related dilated cardiomyopathy in New York Heart Association class II-IIIA, on background heart failure treatment, received ARRY-371797 100 or 400 mg twice daily for 48 weeks. The primary end point was change from baseline in the 6-minute walk test distance at 12 weeks. Secondary end points included changes over time in 6-minute walk test distance, NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration, left ventricular ejection fraction, and quality-of-life scores on the Kansas City Cardiomyopathy Questionnaire. Data from the 2 dose groups were combined.RESULTS: Twelve patients were enrolled; median (minimum, maximum) 6-minute walk test distance at baseline was 314 (246, 412) m. At week 12, the mean (80% CI) increase from baseline in 6-minute walk test distance was 69 (39, 100) m (median, 47 m). Median NT-proBNP concentration declined from 1409 pg/mL at baseline to 848 pg/mL at week 12. Mean left ventricular ejection fraction was stable at week 12. There was a trend toward improvement in Kansas City Cardiomyopathy Questionnaire Overall and Clinical Summary scores at week 12. No clinically significant drug-related safety concerns were identified.CONCLUSIONS: ARRY-371797 was well tolerated and resulted in increases in functional capacity and lower concentrations of cardiac biomarker NT-proBNP in patients with LMNA-related dilated cardiomyopathy.REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02057341.

    View details for DOI 10.1161/CIRCGEN.122.003730

    View details for PubMedID 36515663

  • A concurrent dual analysis of genomic data augments diagnoses: experiences of two clinical sites in the Undiagnosed Diseases Network. Genetics in medicine : official journal of the American College of Medical Genetics Spillmann, R. C., Tan, Q. K., Reuter, C., Schoch, K., Kohler, J., Bonner, D., Zastrow, D., Alkelai, A., Baugh, E., Cope, H., Marwaha, S., Wheeler, M. T., Bernstein, J. A., Shashi, V. 2022

    Abstract

    Next generation sequencing (NGS) has revolutionized the diagnostic process for rare/ultra-rare conditions. However, diagnosis rates differ between analytical pipelines. In the NIH-Undiagnosed Diseases Network (UDN) study, each individual's NGS data are concurrently analyzed by the UDN sequencing core laboratory and the clinical sites. We examined the outcomes of this practice.A retrospective review was performed at two UDN clinical sites, to compare variants, and diagnoses/candidate genes identified with the dual analyses of the NGS data.Ninety-five individuals had 100 diagnoses/candidate genes. There was 59% concordance between the UDN sequencing core laboratories and the clinical sites in identifying diagnoses/candidate genes. The core laboratory provided more diagnoses, while the clinical sites prioritized more research variants/candidate genes (p <0.001). The clinical sites solely identified 15% of the diagnoses/candidate genes. The differences between the two pipelines were more often due to variant prioritization disparities, than variant detection.The unique dual analysis of NGS data in the UDN synergistically enhances outcomes. The core laboratory provides a clinical analysis with more diagnoses and the clinical sites prioritized more research variants/candidate genes. Implementing such concurrent dual analyses in other genomic research studies and clinical settings can improve both variant detection and prioritization.

    View details for DOI 10.1016/j.gim.2022.12.001

    View details for PubMedID 36481303

  • Serial 7-Day Electrocardiogram PatchScreening for AF inHigh-Risk Older Women by the CHARGE-AF Score. JACC. Clinical electrophysiology Lin, J. Y., Larson, J., Schoenberg, J., Sepulveda, A., Tinker, L., Wheeler, M., Albert, C., Manson, J. E., Wells, G., Martin, L. W., Froelicher, V., LaMonte, M., Kooperberg, C., Hlatky, M. A., Greenland, P., Stefanick, M. L., Perez, M. V. 2022; 8 (12): 1523-1534

    Abstract

    BACKGROUND: Asymptomatic atrial fibrillation (AF) is associated with an increased risk of stroke. The yield of serial electrocardiographic (ECG) screening for AF is unknown.OBJECTIVES: The aim of this study was to determine the frequency of AF detected by serial, 7-day ECG patch screenings in older women identified as having an elevated risk of AF according to the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology)-AF clinical prediction score.METHODS: Postmenopausal women with a 5-year predicted risk of new-onset AF≥5% according to CHARGE-AF were recruited from the ongoing WHISH (Women's Health Initiative Strong and Healthy) randomized trial of a physical activity intervention. Participants with AF at baseline by self-report or medical records review were excluded. Screening with 7-day ECG patch monitors was performed at baseline, 6months, and 12months from study enrollment.RESULTS: On baseline monitoring, 2.5% of the cohort had AF detected, increasing to 3.7% by 6months and 4.9% cumulatively by 12months. Yield of patch screening was higher among participants with a higher (≥10%) CHARGE-AF score: 4.2% had AF detected at baseline, 5.9% at 6months, and 7.2% at 12months. Most participants with patch-identified AF never had a clinical diagnosis of AF (36 of 46 [78%]).CONCLUSIONS: Older women with an elevated CHARGE-AF score had a high prevalence of AF on 7-day ECG patch screening. Serial screening over 12months substantially increased the detection of AF. These data can be useful in helping identify high-risk participants for enrollment in future studies of the management of asymptomatic AF.(Women'sHealth Initiative Silent Atrial Fibrillation Recording Study [WHISH STAR]; NCT05366803.).

    View details for DOI 10.1016/j.jacep.2022.08.024

    View details for PubMedID 36543503

  • Premature ventricular contractions (PVCs) in young athletes. Progress in cardiovascular diseases Gomez, S. E., Hwang, C. E., Kim, D. S., Froelicher, V. F., Wheeler, M. T., Perez, M. V. 2022

    Abstract

    There is a growing body of literature focusing on the morphology, management, and outcomes of PVCs in athletes. This review summarizes this literature and establishes recommendations on management, treatment, and indications for specialist referral in this patient population. The sports medicine physician's responses and recommendation should be made in conjunction with the athletes wishes. Medications or ablations are not always necessary in all athletes if they are followed with regular evaluations.

    View details for DOI 10.1016/j.pcad.2022.10.011

    View details for PubMedID 36309100

  • Generation of two induced pluripotent stem cell lines from dilated cardiomyopathy patients carrying TTN mutations. Stem cell research Zhang, T. T., Zhao, S. R., Alamana, C., Shen, M., Parikh, V., Wheeler, M. T., Wu, J. C. 2022; 65: 102941

    Abstract

    Dilated cardiomyopathy (DCM) is a common heart disease that can lead to heart failure and sudden cardiac death. Mutations in the TTN gene are the most frequent cause of DCM. Here, we generated two human induced pluripotent stem cell (iPSC) lines from the peripheral blood mononuclear cells (PBMCs) of two DCM patients carrying c.94816C>T and c.104188A>G mutations in TTN, respectively. The two lines exhibited a normal morphology, full expression of pluripotency markers, a normal karyotype and the ability of trilineage differentiation. The two lines can serve as useful tools for drug screening and mechanism studies on DCM.

    View details for DOI 10.1016/j.scr.2022.102941

    View details for PubMedID 36270069

  • Case-Control cardiopulmonary exercise testing for patients with neuromuscular disease Duong, T., Parker, D., Stevens, V., Young, S., Tang, W., Myers, J., Ashley, E., Wheeler, M., Christle, J. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S75
  • Deconvoluting complex correlates of COVID-19 severity with a multi-omic pandemic tracking strategy. Nature communications Parikh, V. N., Ioannidis, A. G., Jimenez-Morales, D., Gorzynski, J. E., De Jong, H. N., Liu, X., Roque, J., Cepeda-Espinoza, V. P., Osoegawa, K., Hughes, C., Sutton, S. C., Youlton, N., Joshi, R., Amar, D., Tanigawa, Y., Russo, D., Wong, J., Lauzon, J. T., Edelson, J., Mas Montserrat, D., Kwon, Y., Rubinacci, S., Delaneau, O., Cappello, L., Kim, J., Shoura, M. J., Raja, A. N., Watson, N., Hammond, N., Spiteri, E., Mallempati, K. C., Montero-Martín, G., Christle, J., Kim, J., Kirillova, A., Seo, K., Huang, Y., Zhao, C., Moreno-Grau, S., Hershman, S. G., Dalton, K. P., Zhen, J., Kamm, J., Bhatt, K. D., Isakova, A., Morri, M., Ranganath, T., Blish, C. A., Rogers, A. J., Nadeau, K., Yang, S., Blomkalns, A., O'Hara, R., Neff, N. F., DeBoever, C., Szalma, S., Wheeler, M. T., Gates, C. M., Farh, K., Schroth, G. P., Febbo, P., deSouza, F., Cornejo, O. E., Fernandez-Vina, M., Kistler, A., Palacios, J. A., Pinsky, B. A., Bustamante, C. D., Rivas, M. A., Ashley, E. A. 2022; 13 (1): 5107

    Abstract

    The SARS-CoV-2 pandemic has differentially impacted populations across race and ethnicity. A multi-omic approach represents a powerful tool to examine risk across multi-ancestry genomes. We leverage a pandemic tracking strategy in which we sequence viral and host genomes and transcriptomes from nasopharyngeal swabs of 1049 individuals (736 SARS-CoV-2 positive and 313 SARS-CoV-2 negative) and integrate them with digital phenotypes from electronic health records from a diverse catchment area in Northern California. Genome-wide association disaggregated by admixture mapping reveals novel COVID-19-severity-associated regions containing previously reported markers of neurologic, pulmonary and viral disease susceptibility. Phylodynamic tracking of consensus viral genomes reveals no association with disease severity or inferred ancestry. Summary data from multiomic investigation reveals metagenomic and HLA associations with severe COVID-19. The wealth of data available from residual nasopharyngeal swabs in combination with clinical data abstracted automatically at scale highlights a powerful strategy for pandemic tracking, and reveals distinct epidemiologic, genetic, and biological associations for those at the highest risk.

    View details for DOI 10.1038/s41467-022-32397-8

    View details for PubMedID 36042219

  • Impact of SARS-Cov-2 infection in patients with hypertrophic cardiomyopathy: results of an international multicentre registry. ESC heart failure Gimeno, J. R., Olivotto, I., Rodríguez, A. I., Ho, C. Y., Fernández, A., Quiroga, A., Espinosa, M. A., Gómez-González, C., Robledo, M., Tojal-Sierra, L., Day, S. M., Owens, A., Barriales-Villa, R., Larrañaga, J. M., Rodríguez-Palomares, J., González-Del-Hoyo, M., Piqueras-Flores, J., Reza, N., Chumakova, O., Ashley, E. A., Parikh, V., Wheeler, M., Jacoby, D., Pereira, A. C., Saberi, S., Helms, A. S., Villacorta, E., Gallego-Delgado, M., de Castro, D., Domínguez, F., Ripoll-Vera, T., Zorio-Grima, E., Sánchez-Martínez, J. C., García-Álvarez, A., Arbelo, E., Mogollón, M. V., Fuentes-Cañamero, M. E., Grande, E., Peña, C., Monserrat, L., Lakdawala, N. K. 2022; 9 (4): 2189-2198

    Abstract

    To describe the natural history of SARS-CoV-2 infection in patients with hypertrophic cardiomyopathy (HCM) compared with a control group and to identify predictors of adverse events.Three hundred and five patients [age 56.6 ± 16.9 years old, 191 (62.6%) male patients] with HCM and SARS-Cov-2 infection were enrolled. The control group consisted of 91 131 infected individuals. Endpoints were (i) SARS-CoV-2 related mortality and (ii) severe clinical course [death or intensive care unit (ICU) admission]. New onset of atrial fibrillation, ventricular arrhythmias, shock, stroke, and cardiac arrest were also recorded. Sixty-nine (22.9%) HCM patients were hospitalized for non-ICU level care, and 21 (7.0%) required ICU care. Seventeen (5.6%) died: eight (2.6%) of respiratory failure, four (1.3%) of heart failure, two (0.7%) suddenly, and three (1.0%) due to other SARS-CoV-2-related complications. Covariates associated with mortality in the multivariable were age {odds ratio (OR) per 10 year increase 2.25 [95% confidence interval (CI): 1.12-4.51], P = 0.0229}, baseline New York Heart Association class [OR per one-unit increase 4.01 (95%CI: 1.75-9.20), P = 0.0011], presence of left ventricular outflow tract obstruction [OR 5.59 (95%CI: 1.16-26.92), P = 0.0317], and left ventricular systolic impairment [OR 7.72 (95%CI: 1.20-49.79), P = 0.0316]. Controlling for age and sex and comparing HCM patients with a community-based SARS-CoV-2 cohort, the presence of HCM was associated with a borderline significant increased risk of mortality OR 1.70 (95%CI: 0.98-2.91, P = 0.0600).Over one-fourth of HCM patients infected with SARS-Cov-2 required hospitalization, including 6% in an ICU setting. Age and cardiac features related to HCM, including baseline functional class, left ventricular outflow tract obstruction, and systolic impairment, conveyed increased risk of mortality.

    View details for DOI 10.1002/ehf2.13964

    View details for PubMedID 36255281

  • Wnt Signaling Interactor WTIP (Wilms Tumor Interacting Protein) Underlies Novel Mechanism for Cardiac Hypertrophy. Circulation. Genomic and precision medicine De Jong, H. N., Dewey, F. E., Cordero, P., Victorio, R. A., Kirillova, A., Huang, Y., Madhvani, R., Seo, K., Werdich, A. A., Lan, F., Orcholski, M., Robert Liu, W., Erbilgin, A., Wheeler, M. T., Chen, R., Pan, S., Kim, Y. M., Bommakanti, K., Marcou, C. A., Martijn Bos, J., Haddad, F., Ackerman, M., Vasan, R. S., MacRae, C., Wu, J. C., de Jesus Perez, V., Snyder, M., Parikh, V. N., Ashley, E. A. 2022: 101161CIRCGEN121003563

    Abstract

    BACKGROUND: The study of hypertrophic cardiomyopathy (HCM)-a severe Mendelian disease-can yield insight into the mechanisms underlying the complex trait of cardiac hypertrophy. To date, most genetic variants associated with HCM have been found in sarcomeric genes. Here, we describe a novel HCM-associated variant in the noncanonical Wnt signaling interactor WTIP (Wilms tumor interacting protein) and provide evidence of a role for WTIP in complex disease.METHODS: In a family affected by HCM, we used exome sequencing and identity-by-descent analysis to identify a novel variant in WTIP (p.Y233F). We knocked down WTIP in isolated neonatal rat ventricular myocytes with lentivirally delivered shRNAs and in Danio rerio via morpholino injection. We performed weighted gene coexpression network analysis for WTIP in human cardiac tissue, as well as association analysis for WTIP variation and left ventricular hypertrophy. Finally, we generated induced pluripotent stem cell-derived cardiomyocytes from patient tissue, characterized size and calcium cycling, and determined the effect of verapamil treatment on calcium dynamics.RESULTS: WTIP knockdown caused hypertrophy in neonatal rat ventricular myocytes and increased cardiac hypertrophy, peak calcium, and resting calcium in D rerio. Network analysis of human cardiac tissue indicated WTIP as a central coordinator of prohypertrophic networks, while common variation at the WTIP locus was associated with human left ventricular hypertrophy. Patient-derived WTIP p.Y233F-induced pluripotent stem cell-derived cardiomyocytes recapitulated cellular hypertrophy and increased resting calcium, which was ameliorated by verapamil.CONCLUSIONS: We demonstrate that a novel genetic variant found in a family with HCM disrupts binding to a known Wnt signaling protein, misregulating cardiomyocyte calcium dynamics. Further, in orthogonal model systems, we show that expression of the gene WTIP is important in complex cardiac hypertrophy phenotypes. These findings, derived from the observation of a rare Mendelian disease variant, uncover a novel disease mechanism with implications across diverse forms of cardiac hypertrophy.

    View details for DOI 10.1161/CIRCGEN.121.003563

    View details for PubMedID 35671065

  • Generation of two induced pluripotent stem cell lines carrying the phospholamban R14del mutation for modeling ARVD/C. Stem cell research Vera, C. D., Manhas, A., Shenoy, S. P., Wheeler, M. T., Sallam, K., Wu, J. C. 2022; 63: 102834

    Abstract

    The phospholamban (PLN) R14del mutation is associated with arrhythmogenic right ventricular dysplasia (ARVD/C). ARVD/C is a cardiac disease characterized by arrhythmias and structural abnormalities in the right ventricle. Because PLN is a regulator of calcium release, this mutation can have deleterious effects on tissue integrity and contraction. This mutation is a trinucleotide (AGA) deletion that leads to an arginine deletion at position 14 of the PLN structure. Here we show two lines carrying this mutation with typical iPSC morphology, pluripotency, karyotype, ability to differentiate into the three germ layers in vitro, and readily availability for studying pathological mechanisms or ARVD/C.

    View details for DOI 10.1016/j.scr.2022.102834

    View details for PubMedID 35700631

  • Impact of SARS-Cov-2 infection in patients with hypertrophic cardiomyopathy: results of an international multicentre registry ESC HEART FAILURE Gimeno, J. R., Olivotto, I., Isabel Rodriguez, A., Ho, C. Y., Fernandez, A., Quiroga, A., Angeles Espinosa, M., Gomez-Gonzalez, C., Robledo, M., Tojal-Sierra, L., Day, S. M., Owens, A., Barriales-Villa, R., Maria Larranaga, J., Rodriguez-Palomares, J., Gonzalez-del-Hoyo, M., Piqueras-Flores, J., Reza, N., Chumakova, O., Ashley, E. A., Parikh, V., Wheeler, M., Jacoby, D., Pereira, A. C., Saberi, S., Helms, A. S., Villacorta, E., Gallego-Delgado, M., Castro, D., Dominguez, F., Ripoll-Vera, T., Zorio-Grima, E., Carlos Sanchez-Martinez, J., Garcia-Alvarez, A., Arbelo, E., Victoria Mogollon, M., Eugenia Fuentes-Canamero, M., Grande, E., Pena, C., Monserrat, L., Lakdawala, N. K., Dilema Int Cardiomyopathy Heart Fa 2022

    View details for DOI 10.1002/ehf2.13964

    View details for Web of Science ID 000805160500001

  • The Response to Cardiac Resynchronization Therapy in LMNA cardiomyopathy. European journal of heart failure Sidhu, K., Castrini, A. I., Parikh, V., Reza, N., Owens, A., Tremblay-Gravel, M., Wheeler, M. T., Mestroni, L., Taylor, M., Graw, S., Gigli, M., Merlo, M., Paldino, A., Sinagra, G., Judge, D. P., Ramos, H., Mesubi, O., Brown, E., Turnbull, S., Kumar, S., Roy, D., Tedrow, U. B., Ngo, L., Haugaa, K., Lakdawala, N. K. 2022

    Abstract

    AIMS: Cardiac implantable electronic device (CIED) therapy is fundamental to the management of LMNA-cardiomyopathy due to the high frequency of atrioventricular block and ventricular tachyarrhythmias. We aim to define the role of cardiac resynchronization therapy (CRT) in impacting heart failure in LMNA-cardiomyopathy.METHODS AND RESULTS: From 9 referral centers, LMNA-cardiomyopathy patients who underwent CRT with available pre- and post- echocardiograms were identified retrospectively. Factors associated with CRT response were identified [defined as improvement in left ventricular ejection fraction (LVEF) ≥5% 6-months post-implant] and the associated impact on the primary outcome of death, implantation of a left ventricular assist device or cardiac transplantation was assessed. We identified 105 patients (51±10years) undergoing CRT, including 70 (67%) who underwent CRT as a CIED upgrade. The mean change in LVEF ~6 months post CRT was +4±9%. A CRT response occurred in 40 (38%) patients and was associated with lower baseline LVEF or a high percentage of right ventricular pacing prior to CRT in patients with pre-existing CIED. In patients with an ESC Class I guideline indication for CRT, response rates were 61%. A CRT response was evident at thresholds of LVEF ≤45% or percent pacing ≥50%. There was a 1.3 year estimated median difference in event-free survival in those who responded to CRT (p=0.04).CONCLUSION: Systolic function improves in patients with LMNA-cardiomyopathy who undergo CRT, especially with strong guideline indications for implantation. Post CRT improvements in LVEF are associated with survival benefits in this population with otherwise limited options.

    View details for DOI 10.1002/ejhf.2463

    View details for PubMedID 35229420

  • Perceived utility and disutility of genomic sequencing for pediatric patients: Perspectives from parents with diverse sociodemographic characteristics. American journal of medical genetics. Part A Halley, M. C., Young, J. L., Fernandez, L., Kohler, J. N., Undiagnosed Diseases Network, Bernstein, J. A., Wheeler, M. T., Tabor, H. K. 1800

    Abstract

    Given the limited therapeutic options for most rare diseases diagnosed through genomic sequencing (GS) and the proportion of patients who remain undiagnosed even after GS, it is important to characterize a broader range of benefits and potential harms of GS from the perspectives of families with diverse sociodemographic characteristics. We recruited parents of children enrolled in the Undiagnosed Diseases Network. Parents completed an in-depth interview, and we conducted a comparative content analysis of the data. Parents (n=30) were demographically diverse, with 43.3% identifying as Hispanic, 33.3% primarily Spanish-speaking, and widely variable household income and education. Parents reported minimal changes in their child's health status following GS but did report a range of other forms of perceived utility, including improvements in their child's healthcare management and access, in their own psychological well-being, and in disease-specific social connections and research opportunities. Parents who received a diagnosis more frequently perceived utility across all domains; however, disutility also was reported by both those with and without a diagnosis. Impacts depended on multiple mediating factors, including parents' underlying expectations and beliefs, family sociodemographic characteristics, individual disease characteristics, and prior healthcare access. Our study suggests that the perceived utility of GS varies widely among parents and may depend on multiple individual, sociodemographic, and contextual factors that are relevant for pre- and post-GS counseling, for value assessment of GS, and for policymaking related to access to new genomic technologies.

    View details for DOI 10.1002/ajmg.a.62619

    View details for PubMedID 34981646

  • Beyond race: Recruitment of diverse participants in clinical genomics research for rare disease. Frontiers in genetics Young, J. L., Halley, M. C., Anguiano, B., Fernandez, L., Bernstein, J. A., Wheeler, M. T., Tabor, H. K., Undiagnosed Diseases Network Consortium 2022; 13: 949422

    Abstract

    Purpose: Despite recent attention to increasing diversity in clinical genomics research, researchers still struggle to recruit participants from varied sociodemographic backgrounds. We examined the experiences of parents from diverse backgrounds with enrolling their children in clinical genomics research on rare diseases. We explored the barriers and facilitators parents encountered and possible impacts of sociodemographic factors on their access to research. Methods: We utilized semi-structured interviews with parents of children participating in the Undiagnosed Diseases Network. Interview data were analyzed using comparative content analysis. Results: We interviewed 13 Hispanic, 11 non-Hispanic White, four Asian, and two biracial parents. Participants discussed different pathways to clinical genomics research for rare disease as well as how sociodemographic factors shaped families' access. Themes focused on variation in: 1) reliance on providers to access research; 2) cultural norms around health communication; 3) the role of social capital in streamlining access; and 4) the importance of language-concordant research engagement. Conclusion: Our findings suggest that variables beyond race/ethnicity may influence access in clinical genomics research. Future efforts to diversify research participation should consider utilizing varied recruitment strategies to reach participants with diverse sociodemographic characteristics.

    View details for DOI 10.3389/fgene.2022.949422

    View details for PubMedID 36072659

  • Genetic counselor roles in the undiagnosed diseases network research study: Clinical care, collaboration, and curation. Journal of genetic counseling Kohler, J. N., Kelley, E. G., Boyd, B. M., Sillari, C. H., Marwaha, S., Undiagnosed Diseases Network, Wheeler, M. T., Acosta, M. T., Adam, M., Adams, D. R., Agrawal, P. B., Alejandro, M. E., Alvey, J., Amendola, L., Andrews, A., Ashley, E. A., Azamian, M. S., Bacino, C. A., Bademci, G., Baker, E., Balasubramanyam, A., Baldridge, D., Bale, J., Bamshad, M., Barbouth, D., Bayrak-Toydemir, P., Beck, A., Beggs, A. H., Behrens, E., Bejerano, G., Bennet, J., Berg-Rood, B., Bernstein, J. A., Berry, G. T., Bican, A., Bivona, S., Blue, E., Bohnsack, J., Bonnenmann, C., Bonner, D., Botto, L., Boyd, B., Briere, L. C., Brokamp, E., Brown, G., Burke, E. A., Burrage, L. C., Butte, M. J., Byers, P., Byrd, W. E., Carey, J., Carrasquillo, O., Chang, T. C., Chanprasert, S., Chao, H., Clark, G. D., Coakley, T. R., Cobban, L. A., Cogan, J. D., Coggins, M., Sessions Cole, F., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., Crouse, A. B., Cunningham, M., D'Souza, P., Dai, H., Dasari, S., Davis, J., Dayal, J. G., Deardorff, M., Dell'Angelica, E. C., Dhar, S. U., Dipple, K., Doherty, D., Dorrani, N., Doss, A. L., Douine, E. D., Draper, D. D., Duncan, L., Earl, D., Eckstein, D. J., Emrick, L. T., Eng, C. M., Esteves, C., Falk, M., Fernandez, L., Ferreira, C., Fieg, E. L., Findley, L. C., Fisher, P. G., Fogel, B. L., Forghani, I., Fresard, L., Gahl, W. A., Glass, I., Gochuico, B., Godfrey, R. A., Golden-Grant, K., Goldman, A. M., Goldrich, M. P., Goldstein, D. B., Grajewski, A., Groden, C. A., Gutierrez, I., Hahn, S., Hamid, R., Hanchard, N. A., Hassey, K., Hayes, N., High, F., Hing, A., Hisama, F. M., Holm, I. A., Hom, J., Horike-Pyne, M., Huang, A., Huang, Y., Huryn, L., Isasi, R., Jamal, F., Jarvik, G. P., Jarvik, J., Jayadev, S., Karaviti, L., Kennedy, J., Kiley, D., Kobren, S. N., Kohane, I. S., Kohler, J. N., Krakow, D., Krasnewich, D. M., Kravets, E., Korrick, S., Koziura, M., Krier, J. B., Lalani, S. R., Lam, B., Lam, C., LaMoure, G. L., Lanpher, B. C., Lanza, I. R., Latham, L., LeBlanc, K., Lee, B. H., Lee, H., Levitt, R., Lewis, R. A., Lincoln, S. A., Liu, P., Liu, X. Z., Longo, N., Loo, S. K., Loscalzo, J., Maas, R. L., MacDowall, J., Macnamara, E. F., MacRae, C. A., Maduro, V. V., Majcherska, M. M., Mak, B. C., Maclidan, M. C., Mamounas, L. A., Manolio, T. A., Mao, R., Maravilla, K., Markello, T. C., Marom, R., Marth, G., Martin, B. A., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., McCauley, J., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., McGee, E., Mefford, H., Lawrence Merritt, J., Might, M., Mirzaa, G., Morava, E., Moretti, P. M., Mosbrook-Davis, D., Mulvihill, J. J., Murdock, D. R., Nagy, A., Nakano-Okuno, M., Nath, A., Nelson, S. F., Newman, J. H., Nicholas, S. K., Nickerson, D., Nieves-Rodriguez, S., Novacic, D., Oglesbee, D., Orengo, J. P., Pace, L., Pak, S., Carl Pallais, J., Palmer, C. G., Papp, J. C., Parker, N. H., Phillips, J. A., Posey, J. E., Potocki, L., Power, B., Pusey, B. N., Quinlan, A., Raskind, W., Raja, A. N., Rao, D. A., Renteria, G., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Rosenwasser, N., Rossignol, F., Ruzhnikov, M., Sacco, R., Sampson, J. B., Samson, S. L., Saporta, M., Ron Scott, C., Schaechter, J., Schedl, T., Schoch, K., Scott, D. A., Shashi, V., Shin, J., Signer, R., Silverman, E. K., Sinsheimer, J. S., Sisco, K., Smith, E. C., Smith, K. S., Solem, E., Solnica-Krezel, L., Solomon, B., Spillmann, R. C., Stoler, J. M., Sullivan, J. A., Sullivan, K., Sun, A., Sutton, S., Sweetser, D. A., Sybert, V., Tabor, H. K., Tan, A. L., Tan, Q. K., Tekin, M., Telischi, F., Thorson, W., Thurm, A., Tifft, C. J., Toro, C., Tran, A. A., Tucker, B. M., Urv, T. K., Vanderver, A., Velinder, M., Viskochil, D., Vogel, T. P., Wahl, C. E., Wallace, S., Walley, N. M., Walsh, C. A., Walker, M., Wambach, J., Wan, J., Wang, L., Wangler, M. F., Ward, P. A., Wegner, D., Wener, M., Wenger, T., Perry, K. W., Westerfield, M., Wheeler, M. T., Whitlock, J., Wolfe, L. A., Woods, J. D., Yamamoto, S., Yang, J., Yousef, M., Zastrow, D. B., Zein, W., Zhao, C., Zuchner, S. 2021

    Abstract

    Genetic counselors (GCs) are increasingly filling important positions on research study teams, but there is limited literature describing the roles of GCs in these settings. GCs on the Undiagnosed Diseases Network (UDN) study team serve in a variety of roles across the research network and provide an opportunity to better understand genetic counselor roles in research. To quantitatively characterize the tasks regularly performed and professional fulfillment derived from these tasks, two surveys were administered to UDN GCs in a stepwise fashion. Responses from the first, free-response survey elicited the scope of tasks which informed development of a second structured, multiple-select survey. In survey 2, respondents were asked to select which roles they performed. Across 19 respondents, roles in survey 2 received a total of 947 selections averaging approximately 10 selections per role. When asked to indicate what roles they performed, respondent selected a mean of 50 roles (range 22-70). Survey 2 data were analyzed via thematic coding of responses and hierarchical cluster analysis to identify patterns in responses. From the thematic analysis, 20 non-overlapping codes emerged in seven categories: clinical interaction and care, communication, curation, leadership, participant management, research, and team management. Three themes emerged from the categories that represented the roles of GCs in the UDN: clinical care, collaboration, and curation. Cluster analyses showed that responses were more similar among individuals at the same institution than between institutions. This study highlights the ways GCs apply their unique skill set in the context of a clinical translational research network. Additionally, findings from this study reinforce the wide applicability of core skills that are part of genetic counseling training. Clinical literacy, genomics expertise and analysis, interpersonal, psychosocial and counseling skills, education, professional practice skills, and an understanding of research processes make genetic counselors well suited for such roles and poised to positively impact research experiences and outcomes for participants.

    View details for DOI 10.1002/jgc4.1493

    View details for PubMedID 34374469

  • Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation. JCI insight Beijer, D., Kim, H. J., Guo, L., O'Donovan, K., Mademan, I., Deconinck, T., Van Schil, K., Fare, C. M., Drake, L. E., Ford, A. F., Kochanski, A., Kabzinska, D., Dubuisson, N., Van den Bergh, P., Voermans, N. C., Lemmers, R. J., van der Maarel, S. M., Bonner, D., Sampson, J. B., Wheeler, M. T., Mehrabyan, A., Palmer, S., De Jonghe, P., Shorter, J., Taylor, J. P., Baets, J. 2021; 6 (14)

    Abstract

    Mutations in HNRNPA1 encoding heterogeneous nuclear ribonucleoprotein (hnRNP) A1 are a rare cause of amyotrophic lateral sclerosis (ALS) and multisystem proteinopathy (MSP). hnRNPA1 is part of the group of RNA-binding proteins (RBPs) that assemble with RNA to form RNPs. hnRNPs are concentrated in the nucleus and function in pre-mRNA splicing, mRNA stability, and the regulation of transcription and translation. During stress, hnRNPs, mRNA, and other RBPs condense in the cytoplasm to form stress granules (SGs). SGs are implicated in the pathogenesis of (neuro-)degenerative diseases, including ALS and inclusion body myopathy (IBM). Mutations in RBPs that affect SG biology, including FUS, TDP-43, hnRNPA1, hnRNPA2B1, and TIA1, underlie ALS, IBM, and other neurodegenerative diseases. Here, we characterize 4 potentially novel HNRNPA1 mutations (yielding 3 protein variants: *321Eext*6, *321Qext*6, and G304Nfs*3) and 2 known HNRNPA1 mutations (P288A and D262V), previously connected to ALS and MSP, in a broad spectrum of patients with hereditary motor neuropathy, ALS, and myopathy. We establish that the mutations can have different effects on hnRNPA1 fibrillization, liquid-liquid phase separation, and SG dynamics. P288A accelerated fibrillization and decelerated SG disassembly, whereas *321Eext*6 had no effect on fibrillization but decelerated SG disassembly. By contrast, G304Nfs*3 decelerated fibrillization and impaired liquid phase separation. Our findings suggest different underlying pathomechanisms for HNRNPA1 mutations with a possible link to clinical phenotypes.

    View details for DOI 10.1172/jci.insight.148363

    View details for PubMedID 34291734

  • Generation of three induced pluripotent stem cell lines from hypertrophic cardiomyopathy patients carrying MYH7 mutations. Stem cell research Cao, X., Jahng, J. W., Lee, C., Zha, Y., Wheeler, M. T., Sallam, K., Wu, J. C. 2021; 55: 102455

    Abstract

    MYH7 heterozygous mutations are common genetic causes of hypertrophic cardiomyopathy (HCM). HCM is characterized by hypertrophy of the left ventricle and diastolic dysfunction. We generated three human induced pluripotent stem cell (iPSC) lines from three HCM patients each carrying a single heterozygous mutation in MYH7, c.2167C>T, c.4066G>A, and c.5135G>A, respectively. All lines expressed high levels of pluripotent markers, had normal karyotype, and possessed capability of differentiation into derivatives of the three germ layers, which can serve as valuable tools for modeling HCM in vitro and investigating the pathological mechanisms related to MYH7 mutations.

    View details for DOI 10.1016/j.scr.2021.102455

    View details for PubMedID 34352619

  • "Doctors can read about it, they can know about it, but they've never lived with it": How parents use social media throughout the diagnostic odyssey. Journal of genetic counseling Deuitch, N. T., Beckman, E., Halley, M. C., Young, J. L., Reuter, C. M., Kohler, J., Bernstein, J. A., Wheeler, M. T., Undiagnosed Diseases Network, Ormond, K. E., Tabor, H. K. 2021

    Abstract

    Parents of children with undiagnosed conditions struggle to obtain information about how to treat and support their children. It can be particularly challenging to find communities and other parents who share their experiences and can provide emotional and informational support. This study sought to characterize how parents use social media, both throughout the diagnostic odyssey and post-diagnosis, to meet their informational, social, and emotional support needs. We conducted qualitative semi-structured interviews with 14 parents from the Stanford site of the Undiagnosed Diseases Network (UDN), including five whose children had received a diagnosis through study participation. Interview recordings were analyzed using inductive, team-based coding and thematic analysis based in grounded theory using Dedoose qualitative analysis software. Through this process, we identified four key themes related to social media use. First, parents struggled to find the "right" community, often seeking out groups of similar patients based on symptoms or similar conditions. Second, though they found much valuable information through social media about caring for their child, they also struggled to interpret the relevance of the information to their own child's condition. Third, the social support and access to other patients' and families' lived experiences were described as both highly valued and emotionally challenging, particularly in the case of poor outcomes for similar families. Finally, parents expressed the need to balance concerns about their child's privacy with the value of transparency and data sharing for diagnosis. Our results suggest that the needs and experiences of undiagnosed patients and families differ from those with diagnosed diseases and highlight the need for support in best utilizing social media resources at different stages of the diagnostic odyssey.

    View details for DOI 10.1002/jgc4.1438

    View details for PubMedID 34096130

  • Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy. Journal of neurogenetics Burke, E. A., Sturgeon, M., Zastrow, D. B., Fernandez, L., Prybol, C., Marwaha, S., Frothingham, E. P., Ward, P. A., Eng, C. M., Fresard, L., Montgomery, S. B., Enns, G. M., Fisher, P. G., Wolfe, L. A., Harding, B., Carrington, B., Bishop, K., Sood, R., Huang, Y., Elkahloun, A., Toro, C., Bassuk, A. G., Wheeler, M. T., Markello, T. C., Gahl, W. A., Malicdan, M. C. 2021: 1–10

    Abstract

    KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified KCTD7 compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate kctd7 knockout zebrafish. Kctd7 homozygous mutants showed global dysregulation of gene expression and increased transcription of c-fos, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of KCTD7-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.

    View details for DOI 10.1080/01677063.2021.1892095

    View details for PubMedID 33970744

  • A resource of lipidomics and metabolomics data from individuals with undiagnosed diseases SCIENTIFIC DATA Kyle, J. E., Stratton, K. G., Zink, E. M., Kim, Y., Bloodsworth, K. J., Monroe, M. E., Bacino, C. A., Bacino, C. A., Hanchard, N. A., Lewis, R. A., Rosenfeld, J. A., Scott, D. A., Tran, A. A., Ward, P. A., Burrage, L. C., Clark, G. D., Alejandro, M. E., Posey, J. E., Wangler, M. F., Lee, B. H., Craigen, W. J., Bellen, H. J., Nicholas, S. K., Bostwick, B. L., Samson, S. L., Goldman, A. M., Moretti, P. M., Eng, C. M., Muzny, D. M., Orengo, J. P., Vogel, T. P., Lalani, S. R., Murdock, D. R., Azamian, M. S., Orange, J. S., Emrick, L. T., Dhar, S. U., Balasubramanyam, A., Potocki, L., Yamamoto, S., Yang, Y., Chen, S., Jamal, F., Karaviti, L., Marom, R., Lincoln, S. A., Walsh, C. A., Beggs, A. H., Rodan, L. H., Stoler, J. M., Berry, G. T., Cobban, L. A., MacRae, C. A., Krier, J. B., Silverman, E. K., Fieg, E. L., Maas, R. L., Loscalzo, J., Aday, A., Korrick, S., Goldstein, D. B., Stong, N., Sullivan, J. A., Spillmann, R. C., Pena, L. M., Tan, Q., Walley, N. M., Jiang, Y., McConkie-Rosell, A., Schoch, K., Shashi, V., Cope, H., Holm, I. A., Kohane, I. S., McCray, A. T., Esteves, C., LeBlanc, K., Might, M., Kelley, E., Worthey, E. A., Dorset, D. C., Boone, B. E., Levy, S. E., Birch, C. L., Jones, A. L., Brown, D. M., Bick, D. P., Newberry, J., Lazar, J., May, T., Sweetser, D. A., Briere, L. C., Pallais, J., Cooper, C. M., High, F., Walker, M., Colley, H. A., Mamounas, L. A., Manolio, T. A., Burke, E. A., Godfrey, R. A., Groden, C. A., Gahl, W. A., Wolfe, L. A., Markello, T. C., Lau, C., Draper, D. D., Gould, S. E., Nehrebecky, M. E., Wahl, C. E., Batzli, G. F., Macnamara, E. F., Dayal, J. G., Eckstein, D. J., Mulvihill, J. J., Tifft, C. J., Urv, T. K., Wise, A. L., Murphy, J. L., Gropman, A. L., Howerton, E. M., Krasnewich, D. M., Johnston, J. M., Pusey, B. N., Adams, D. R., Maduro, V. V., Malicdan, M. V., Davids, M., Estwick, T., Novacic, D., Sharma, P., Toro, C., Yu, G., Behnam, B., D'Souza, P., Ferreira, C., Morimoto, M., Baker, E. H., Yang, J., Gourdine, J. F., Brush, M., Haendel, M., Ashley, E. A., Bernstein, J. A., Sampson, J. B., Zastrow, D. B., Friedman, N. D., Merker, J. D., McCormack, C. E., Fisher, P. G., Davidson, J. M., Dries, A. M., Enns, G. M., Majcherska, M. M., Reuter, C. M., Waggott, D. M., Kohler, J. N., Coakley, T. R., Smith, K. S., Wheeler, M. T., Bonner, D., Fernandez, L., Hom, J., Huang, Y., Marwaha, S., Zhao, C., Martinez-Agosto, J. A., Dell'Angelica, E. C., Papp, J. C., Douine, E. D., Nelson, S. F., Martin, M. G., Palmer, C., Parker, N. H., Butte, M. J., Yoon, A. J., Loo, S. K., Fogel, B. L., Dipple, K. M., Sinsheimer, J. S., Allard, P., Barseghyan, H., Dorrani, N., Lee, H., Vilain, E., Eskin, A., Renteria, G., Signer, R., Wan, J., Zheng, A., Westerfield, M., Phillips, J. A., Cogan, J. D., Newman, J. H., Robertson, A. K., Hamid, R., Bican, A., Brokamp, E., Duncan, L., Kozuira, M., Rives, L., Shakachite, L., Waters, K. M., Webb-Robertson, B. M., Koeller, D. M., Metz, T. O., Undiagnosed Dis Network 2021; 8 (1): 114

    Abstract

    Every year individuals experience symptoms that remain undiagnosed by healthcare providers. In the United States, these rare diseases are defined as a condition that affects fewer than 200,000 individuals. However, there are an estimated 7000 rare diseases, and there are an estimated 25-30 million Americans in total (7.6-9.2% of the population as of 2018) affected by such disorders. The NIH Common Fund Undiagnosed Diseases Network (UDN) seeks to provide diagnoses for individuals with undiagnosed disease. Mass spectrometry-based metabolomics and lipidomics analyses could advance the collective understanding of individual symptoms and advance diagnoses for individuals with heretofore undiagnosed disease. Here, we report the mass spectrometry-based metabolomics and lipidomics analyses of blood plasma, urine, and cerebrospinal fluid from 148 patients within the UDN and their families, as well as from a reference population of over 100 individuals with no known metabolic diseases. The raw and processed data are available to the research community so that they might be useful in the diagnoses of current or future patients suffering from undiagnosed disorders.

    View details for DOI 10.1038/s41597-021-00894-y

    View details for Web of Science ID 000642148100001

    View details for PubMedID 33883556

    View details for PubMedCentralID PMC8060404

  • Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain GENETICS IN MEDICINE Marbach, F., Stoyanov, G., Erger, F., Stratakis, C. A., Settas, N., London, E., Rosenfeld, J. A., Torti, E., Haldeman-Englert, C., Sklirou, E., Kessler, E., Ceulemans, S., Nelson, S. F., Martinez-Agosto, J. A., Palmer, C. S., Signer, R. H., Acosta, M. T., Adam, M., Adams, D. R., Agrawal, P. B., Alejandro, M. E., Alvey, J., Amendola, L., Andrews, A., Ashley, E. A., Azamian, M. S., Bacino, C. A., Bademci, G., Baker, E., Balasubramanyam, A., Baldridge, D., Bale, J., Bamshad, M., Barbouth, D., Bayrak-Toydemir, P., Beck, A., Beggs, A. H., Behrens, E., Bejerano, G., Bennett, J., Berg-Rood, B., Bernstein, J. A., Berry, G. T., Bican, A., Bivona, S., Blue, E., Bohnsack, J., Bonnenmann, C., Bonner, D., Botto, L., Boyd, B., Briere, L. C., Brokamp, E., Brown, G., Burke, E. A., Burrage, L. C., Butte, M. J., Byers, P., Byrd, W. E., Carey, J., Carrasquillo, O., Chang, T., Chanprasert, S., Chao, H., Clark, G. D., Coakley, T. R., Cobban, L. A., Cogan, J. D., Coggins, M., Cole, F., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., Crouse, A. B., Cunningham, M., D'Souza, P., Dai, H., Dasari, S., Davis, J., Daya, J. G., Deardorff, M., Dell'Angelica, E. C., Dhar, S. U., Dipple, K., Doherty, D., Dorrani, N., Doss, A. L., Douine, E. D., Draper, D. D., Duncan, L., Earl, D., Eckstein, D. J., Emrick, L. T., Eng, C. M., Esteves, C., Falk, M., Fernandez, L., Ferreira, C., Fieg, E. L., Findley, L. C., Fisher, P. G., Fogel, B. L., Forghani, I., Fresard, L., Gahl, W. A., Glass, I., Gochuico, B., Godfrey, R. A., Golden-Grant, K., Goldman, A. M., Goldrich, M. P., Goldstein, D. B., Grajewski, A., Groden, C. A., Gutierrez, I., Hahn, S., Hamid, R., Hanchard, N. A., Hassey, K., Hayes, N., High, F., Hing, A., Hisama, F. M., Holm, I. A., Hom, J., Horike-Pyne, M., Huang, A., Huang, Y., Huryn, L., Isasi, R., Jamal, F., Jarvik, G. P., Jarvik, J., Jayadev, S., Karaviti, L., Kennedy, J., Kiley, D., Kohane, I. S., Kohler, J. N., Korrick, S., Kozuira, M., Krakow, D., Krasnewich, D. M., Kravets, E., Krier, J. B., LaMoure, G. L., Lalani, S. R., Lam, B., Lam, C., Lanpher, B. C., Lanza, I. R., Latham, L., LeBlanc, K., Lee, B. H., Lee, H., Levitt, R., Lewis, R. A., Lincoln, S. A., Liu, P., Liu, X., Longo, N., Loo, S. K., Loscalzo, J., Maas, R. L., MacDowall, J., MacRae, C. A., Macnamara, E. F., Maduro, V. V., Majcherska, M. M., Mak, B. C., Malicdan, M. V., Mamounas, L. A., Manolio, T. A., Mao, R., Maravilla, K., Markello, T. C., Marom, R., Marth, G., Martin, B. A., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., McCauley, J., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., McGee, E., Mefford, H., Merritt, J., Might, M., Mirzaa, G., Morava, E., Moretti, P. M., Moretti, P., Mosbrook-Davis, D., Mulvihill, J. J., Murdock, D. R., Nagy, A., Nakano-Okuno, M., Nath, A., Nelson, S. F., Newman, J. H., Nicholas, S. K., Nickerson, D., Nieves-Rodriguez, S., Novacic, D., Oglesbee, D., Orengo, J. P., Pace, L., Pak, S., Pallais, J., Palmer, C. S., Papp, J. C., Parker, N. H., Phillips, J. A., Posey, J. E., Potocki, L., Power, B., Pusey, B. N., Quinlan, A., Raja, A. N., Rao, D. A., Raskind, W., Renteria, G., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Rosenwasser, N., Rossignol, F., Ruzhnikov, M., Sacco, R., Sampson, J. B., Samson, S. L., Saporta, M., Schaechter, J., Schedl, T., Schoch, K., Scott, C., Scott, D. A., Shashi, V., Shin, J., Signer, R. H., Silverman, E. K., Sinsheimer, J. S., Sisco, K., Smith, E. C., Smith, K. S., Solem, E., Solnica-Krezel, L., Ben Solomon, Spillmann, R. C., Stoler, J. M., Sullivan, J. A., Sullivan, K., Sun, A., Sutton, S., Sweetser, D. A., Sybert, V., Tabor, H. K., Tan, A. M., Tan, Q., Tekin, M., Telischi, F., Thorson, W., Thurm, A., Tifft, C. J., Toro, C., Tran, A. A., Tucker, B. M., Urv, T. K., Vanderver, A., Velinder, M., Viskochil, D., Vogel, T. P., Wahl, C. E., Walker, M., Wallace, S., Walley, N. M., Walsh, C. A., Wambach, J., Wan, J., Wang, L., Wangler, M. F., Ward, P. A., Wegner, D., Wener, M., Wenger, T., Perry, K., Westerfield, M., Wheeler, M. T., Whitlock, J., Wolfe, L. A., Woods, J. D., Yamamoto, S., Yang, J., Yousef, M., Zastrow, D. B., Zein, W., Zhao, C., Zuchner, S., Andrews, M. V., Grange, D. K., Willaert, R., Person, R., Telegrafi, A., Sievers, A., Laugsch, M., Theiss, S., Cheng, Y., Lichtarge, O., Katsonis, P., Stocco, A., Schaaf, C. P., Undiagnosed Diseases Network 2021

    Abstract

    We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA).Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development.Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs.Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

    View details for DOI 10.1038/s41436-021-01152-7

    View details for Web of Science ID 000638059400001

    View details for PubMedID 33833410

  • Genomic Context Differs Between Human Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy. Journal of the American Heart Association Puckelwartz, M. J., Pesce, L. L., Dellefave-Castillo, L. M., Wheeler, M. T., Pottinger, T. D., Robinson, A. C., Kearns, S. D., Gacita, A. M., Schoppen, Z. J., Pan, W., Kim, G., Wilcox, J. E., Anderson, A. S., Ashley, E. A., Day, S. M., Cappola, T., Dorn, G. W., McNally, E. M. 2021: e019944

    Abstract

    Background Inherited cardiomyopathies display variable penetrance and expression, and a component of phenotypic variation is genetically determined. To evaluate the genetic contribution to this variable expression, we compared protein coding variation in the genomes of those with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Methods and Results Nonsynonymous single-nucleotide variants (nsSNVs) were ascertained using whole genome sequencing from familial cases of HCM (n=56) or DCM (n=70) and correlated with echocardiographic information. Focusing on nsSNVs in 102 genes linked to inherited cardiomyopathies, we correlated the number of nsSNVs per person with left ventricular measurements. Principal component analysis and generalized linear models were applied to identify the probability of cardiomyopathy type as it related to the number of nsSNVs in cardiomyopathy genes. The probability of having DCM significantly increased as the number of cardiomyopathy gene nsSNVs per person increased. The increase in nsSNVs in cardiomyopathy genes significantly associated with reduced left ventricular ejection fraction and increased left ventricular diameter for individuals carrying a DCM diagnosis, but not for those with HCM. Resampling was used to identify genes with aberrant cumulative allele frequencies, identifying potential modifier genes for cardiomyopathy. Conclusions Participants with DCM had more nsSNVs per person in cardiomyopathy genes than participants with HCM. The nsSNV burden in cardiomyopathy genes did not correlate with the probability or manifestation of left ventricular measures in HCM. These findings support the concept that increased variation in cardiomyopathy genes creates a genetic background that predisposes to DCM and increased disease severity.

    View details for DOI 10.1161/JAHA.120.019944

    View details for PubMedID 33764162

  • Functional and structural analysis of cytokine selective IL6ST defects that cause recessive hyper-IgE syndrome. The Journal of allergy and clinical immunology Chen, Y., Zastrow, D. B., Metcalfe, R. D., Gartner, L., Krause, F., Morton, C. J., Marwaha, S., Fresard, L., Huang, Y., Zhao, C., McCormack, C., Bick, D., Worthey, E. A., Eng, C. M., Gold, J., Undiagnosed Diseases Network, Montgomery, S. B., Fisher, P. G., Ashley, E. A., Wheeler, M. T., Parker, M. W., Shanmugasundaram, V., Putoczki, T. L., Schmidt-Arras, D., Laurence, A., Bernstein, J. A., Griffin, M. D., Uhlig, H. H. 2021

    Abstract

    BACKGROUND: Biallelic variants in IL6ST cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE, eosinophilia, defective acute phase response, susceptibility to bacterial infections and skeletal abnormalities due to cytokine selective loss-of-function in GP130 with defective IL-6 and IL-11, variable OSM and IL-27 but sparing LIF signaling.OBJECTIVE: To understand the functional and structural impact of recessive HIES-associated IL6ST variants.METHODS: We investigated a patient with HIES using exome, genome and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamic simulations and structural modeling of GP130 cytokine receptor complexes were performed.RESULTS: We identify a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro, and exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant results in a more profound IL-6 and IL-11 dominated signaling defect compared to the previously identified recessive IL6ST variants p.Asn404Tyr, and p.Pro498Leu. Molecular dynamics simulations suggest that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane-proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilize the hexameric cytokine receptor complexes whereas the trimeric LIF-GP130-LIFR complex remains stable by an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently causes additional defective LIF signaling and Stuve-Wiedemann syndrome.CONCLUSION: Our data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants.

    View details for DOI 10.1016/j.jaci.2021.02.044

    View details for PubMedID 33771552

  • Identification of rare and common regulatory variants in pluripotent cells using population-scale transcriptomics. Nature genetics Bonder, M. J., Smail, C., Gloudemans, M. J., Fresard, L., Jakubosky, D., D'Antonio, M., Li, X., Ferraro, N. M., Carcamo-Orive, I., Mirauta, B., Seaton, D. D., Cai, N., Vakili, D., Horta, D., Zhao, C., Zastrow, D. B., Bonner, D. E., HipSci Consortium, iPSCORE consortium, Undiagnosed Diseases Network, PhLiPS consortium, Wheeler, M. T., Kilpinen, H., Knowles, J. W., Smith, E. N., Frazer, K. A., Montgomery, S. B., Stegle, O., Jan Bonder, M., Seaton, D., Jakubosky, D. A., Brown, C. D., Park, Y. 2021

    Abstract

    Induced pluripotent stem cells (iPSCs) are an established cellular system to study the impact of genetic variants in derived cell types and developmental contexts. However, in their pluripotent state, the disease impact of genetic variants is less well known. Here, we integrate data from 1,367 human iPSC lines to comprehensively map common and rare regulatory variants in human pluripotent cells. Using this population-scale resource, we report hundreds of new colocalization events for human traits specific to iPSCs, and find increased power to identify rare regulatory variants compared with somatic tissues. Finally, we demonstrate how iPSCs enable the identification of causal genes for rare diseases.

    View details for DOI 10.1038/s41588-021-00800-7

    View details for PubMedID 33664507

  • Commonalities across computational workflows for uncovering explanatory variants in undiagnosed cases. Genetics in medicine : official journal of the American College of Medical Genetics Kobren, S. N., Baldridge, D., Velinder, M., Krier, J. B., LeBlanc, K., Esteves, C., Pusey, B. N., Zuchner, S., Blue, E., Lee, H., Huang, A., Bastarache, L., Bican, A., Cogan, J., Marwaha, S., Alkelai, A., Murdock, D. R., Liu, P., Wegner, D. J., Paul, A. J., Undiagnosed Diseases Network, Sunyaev, S. R., Kohane, I. S., Acosta, M. T., Adam, M., Adams, D. R., Agrawal, P. B., Alejandro, M. E., Alvey, J., Amendola, L., Andrews, A., Ashley, E. A., Azamian, M. S., Bacino, C. A., Bademci, G., Baker, E., Balasubramanyam, A., Baldridge, D., Bale, J., Bamshad, M., Barbouth, D., Bayrak-Toydemir, P., Beck, A., Beggs, A. H., Behrens, E., Bejerano, G., Bennett, J., Berg-Rood, B., Bernstein, J. A., Berry, G. T., Bican, A., Bivona, S., Blue, E., Bohnsack, J., Bonnenmann, C., Bonner, D., Botto, L., Boyd, B., Briere, L. C., Brokamp, E., Brown, G., Burke, E. A., Burrage, L. C., Butte, M. J., Byers, P., Byrd, W. E., Carey, J., Carrasquillo, O., Chang, T. C., Chanprasert, S., Chao, H., Clark, G. D., Coakley, T. R., Cobban, L. A., Cogan, J. D., Coggins, M., Cole, F. S., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., Crouse, A. B., Cunningham, M., D'Souza, P., Dai, H., Dasari, S., Davis, J., Daya, J. G., Deardorff, M., Dell'Angelica, E. C., Dhar, S. U., Dipple, K., Doherty, D., Dorrani, N., Doss, A. L., Douine, E. D., Draper, D. D., Duncan, L., Earl, D., Eckstein, D. J., Emrick, L. T., Eng, C. M., Esteves, C., Falk, M., Fernandez, L., Ferreira, C., Fieg, E. L., Findley, L. C., Fisher, P. G., Fogel, B. L., Forghani, I., Fresard, L., Gahl, W. A., Glass, I., Gochuico, B., Godfrey, R. A., Golden-Grant, K., Goldman, A. M., Goldrich, M. P., Goldstein, D. B., Grajewski, A., Groden, C. A., Gutierrez, I., Hahn, S., Hamid, R., Hanchard, N. A., Hassey, K., Hayes, N., High, F., Hing, A., Hisama, F. M., Holm, I. A., Hom, J., Horike-Pyne, M., Huang, A., Huang, Y., Huryn, L., Isasi, R., Jamal, F., Jarvik, G. P., Jarvik, J., Jayadev, S., Karaviti, L., Kennedy, J., Kiley, D., Kohane, I. S., Kohler, J. N., Korrick, S., Kozuira, M., Krakow, D., Krasnewich, D. M., Kravets, E., Krier, J. B., LaMoure, G. L., Lalani, S. R., Lam, B., Lam, C., Lanpher, B. C., Lanza, I. R., Latham, L., LeBlanc, K., Lee, B. H., Lee, H., Levitt, R., Lewis, R. A., Lincoln, S. A., Liu, P., Liu, X. Z., Longo, N., Loo, S. K., Loscalzo, J., Maas, R. L., MacDowall, J., MacRae, C. A., Macnamara, E. F., Maduro, V. V., Majcherska, M. M., Mak, B. C., Malicdan, M. C., Mamounas, L. A., Manolio, T. A., Mao, R., Maravilla, K., Markello, T. C., Marom, R., Marth, G., Martin, B. A., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., McCauley, J., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., McGee, E., Mefford, H., Merritt, J. L., Might, M., Mirzaa, G., Morava, E., Moretti, P. M., Moretti, P., Mosbrook-Davis, D., Mulvihill, J. J., Murdock, D. R., Nagy, A., Nakano-Okuno, M., Nath, A., Nelson, S. F., Newman, J. H., Nicholas, S. K., Nickerson, D., Nieves-Rodriguez, S., Novacic, D., Oglesbee, D., Orengo, J. P., Pace, L., Pak, S., Pallais, J. C., Palmer, C. G., Papp, J. C., Parker, N. H., Phillips, J. A., Posey, J. E., Potocki, L., Power, B., Pusey, B. N., Quinlan, A., Raja, A. N., Rao, D. A., Raskind, W., Renteria, G., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Rosenwasser, N., Rossignol, F., Ruzhnikov, M., Sacco, R., Sampson, J. B., Samson, S. L., Saporta, M., Schaechter, J., Schedl, T., Schoch, K., Scott, C. R., Scott, D. A., Shashi, V., Shin, J., Signer, R. H., Silverman, E. K., Sinsheimer, J. S., Sisco, K., Smith, E. C., Smith, K. S., Solem, E., Solnica-Krezel, L., Ben Solomon, S., Spillmann, R. C., Stoler, J. M., Sullivan, J. A., Sullivan, K., Sun, A., Sutton, S., Sweetser, D. A., Sybert, V., Tabor, H. K., Tan, A. L., Tan, Q. K., Tekin, M., Telischi, F., Thorson, W., Thurm, A., Tifft, C. J., Toro, C., Tran, A. A., Tucker, B. M., Urv, T. K., Vanderver, A., Velinder, M., Viskochil, D., Vogel, T. P., Wahl, C. E., Walker, M., Wallace, S., Walley, N. M., Walsh, C. A., Wambach, J., Wan, J., Wang, L., Wangler, M. F., Ward, P. A., Wegner, D., Wener, M., Wenger, T., Perry, K. W., Westerfield, M., Wheeler, M. T., Whitlock, J., Wolfe, L. A., Woods, J. D., Yamamoto, S., Yang, J., Yousef, M., Zastrow, D. B., Zein, W., Zhao, C., Zuchner, S. 2021

    Abstract

    PURPOSE: Genomic sequencing has become an increasingly powerful and relevant tool to be leveraged for the discovery of genetic aberrations underlying rare, Mendelian conditions. Although the computational tools incorporated into diagnostic workflows for this task are continually evolving and improving, we nevertheless sought to investigate commonalities across sequencing processing workflows to reveal consensus and standard practice tools and highlight exploratory analyses where technical and theoretical method improvements would be most impactful.METHODS: We collected details regarding the computational approaches used by a genetic testing laboratory and 11 clinical research sites in the United States participating in the Undiagnosed Diseases Network via meetings with bioinformaticians, online survey forms, and analyses of internal protocols.RESULTS: We found that tools for processing genomic sequencing data can be grouped into four distinct categories. Whereas well-established practices exist for initial variant calling and quality control steps, there is substantial divergence across sites in later stages for variant prioritization and multimodal data integration, demonstrating a diversity of approaches for solving the most mysterious undiagnosed cases.CONCLUSION: The largest differences across diagnostic workflows suggest that advances in structural variant detection, noncoding variant interpretation, and integration of additional biomedical data may be especially promising for solving chronically undiagnosed cases.

    View details for DOI 10.1038/s41436-020-01084-8

    View details for PubMedID 33580225

  • Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay. Genetics in medicine : official journal of the American College of Medical Genetics Melo, U. S., Bonner, D. n., Kent Lloyd, K. C., Moshiri, A. n., Willis, B. n., Lanoue, L. n., Bower, L. n., Leonard, B. C., Martins, D. J., Gomes, F. n., de Souza Leite, F. n., Oliveira, D. n., Kitajima, J. P., Monteiro, F. P., Zatz, M. n., Menck, C. F., Wheeler, M. T., Bernstein, J. A., Dumas, K. n., Spiteri, E. n., Di Donato, N. n., Jahn, A. n., Hashem, M. n., Alsaif, H. S., Chedrawi, A. n., Alkuraya, F. S., Kok, F. n., Byers, H. M. 2021

    Abstract

    To identify novel genes associated with intellectual disability (ID) in four unrelated families.Here, through exome sequencing and international collaboration, we report eight individuals from four unrelated families of diverse geographic origin with biallelic loss-of-function variants in UBE4A.Eight evaluated individuals presented with syndromic intellectual disability and global developmental delay. Other clinical features included hypotonia, short stature, seizures, and behavior disorder. Characteristic features were appreciated in some individuals but not all; in some cases, features became more apparent with age. We demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioral abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals.These data indicate that biallelic loss-of-function variants in UBE4A cause a novel intellectual disability syndrome, suggesting that UBE4A enzyme activity is required for normal development and neurological function.

    View details for DOI 10.1038/s41436-020-01047-z

    View details for PubMedID 33420346

  • Generation of three induced pluripotent stem cell lines from hypertrophic cardiomyopathy patients carrying TNNI3 mutations. Stem cell research Zhao, S. R., Shen, M., Lee, C., Zha, Y., Guevara, J. V., Wheeler, M. T., Wu, J. C. 2021; 57: 102597

    Abstract

    Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with a prevalence of about 0.2%. HCM is typically caused by mutations in genes encoding sarcomere or sarcomere-associated proteins. Here, we characterized induced pluripotent stem cell (iPSC) lines generated from the peripheral blood mononuclear cells of three HCM patients each carrying c.433C > T, c.610C > T, or c.235C > T mutation in the TNNI3 gene by non-integrated Sendai virus. All of the three lines exhibited normal morphology, expression of pluripotent markers, stable karyotype, and the potential of trilineage differentiation. The cardiomyocytes differentiated from these iPSC lines can serve as useful tools to model HCM in vitro.

    View details for DOI 10.1016/j.scr.2021.102597

    View details for PubMedID 34798544

  • Time trajectories in the transcriptomic response to exercise - a meta-analysis. Nature communications Amar, D., Lindholm, M. E., Norrbom, J., Wheeler, M. T., Rivas, M. A., Ashley, E. A. 2021; 12 (1): 3471

    Abstract

    Exercise training prevents multiple diseases, yet the molecular mechanisms that drive exercise adaptation are incompletely understood. To address this, we create a computational framework comprising data from skeletal muscle or blood from 43 studies, including 739 individuals before and after exercise or training. Using linear mixed effects meta-regression, we detect specific time patterns and regulatory modulators of the exercise response. Acute and long-term responses are transcriptionally distinct and we identify SMAD3 as a central regulator of the exercise response. Exercise induces a more pronounced inflammatory response in skeletal muscle of older individuals and our models reveal multiple sex-associated responses. We validate seven of our top genes in a separate human cohort. In this work, we provide a powerful resource ( www.extrameta.org ) that expands the transcriptional landscape of exercise adaptation by extending previously known responses and their regulatory networks, and identifying novel modality-, time-, age-, and sex-associated changes.

    View details for DOI 10.1038/s41467-021-23579-x

    View details for PubMedID 34108459

  • Cardiopulmonary Exercise Testing With Echocardiography to Assess Recovery in Patients With Ventricular Assist Devices. ASAIO journal (American Society for Artificial Internal Organs : 1992) Christle, J. W., Moneghetti, K. J., Duclos, S., Mueller, S., Moayedi, Y., Khush, K. K., Haddad, F., Hiesinger, W., Myers, J., Ashley, E. A., Teuteberg, J. J., Wheeler, M. T., Banerjee, D. 2021; 67 (10): 1134-1138

    Abstract

    The left ventricular assist device (LVAD) is an established treatment for select patients with end-stage heart failure. Some patients recovered and are considered for explantation. Assessing recovery involves exercise testing and echo ramping on full and minimal LVAD support. Combined cardiopulmonary exercise testing with simultaneous echo ramping (CPET-R) has not been well studied. Patients were included if they had CPET within the previous 6 months, were clinically stable, and had an INR >2.0 on the day of examination. Patients had CPET-R on two occasions within 14 days: (a) with LVAD at therapeutic speed and (b) with LVAD at the lowest speed possible. Six patients were between 29 and 75 years (two female). One patient did not complete a turn-down test due to evidence of ischemia on initial CPET-R subsequently confirmed as a significant coronary artery stenosis on angiography. There were no significant differences in CPET or echo metrics between LVAD speeds. Two patients were explanted due to presumed LV recovery and remained event free for 30 and 47 months, respectively. Serial CPET-R seems safe and feasible for the evaluation of LV and global function and may result in improved clinical decision making for LVAD explantation.

    View details for DOI 10.1097/MAT.0000000000001383

    View details for PubMedID 34570726

  • Arrhythmias Other Than Atrial Fibrillation in Those With an Irregular Pulse Detected With a Smartwatch: Findings From the Apple Heart Study. Circulation. Arrhythmia and electrophysiology Perino, A. C., Gummidipundi, S. E., Lee, J., Hedlin, H., Garcia, A., Ferris, T., Balasubramanian, V., Gardner, R. M., Cheung, L., Hung, G., Granger, C. B., Kowey, P., Rumsfeld, J. S., Russo, A. M., True Hills, M., Talati, N., Nag, D., Tsay, D., Desai, S., Desai, M., Mahaffey, K. W., Turakhia, M. P., Perez, M. V. 2021: CIRCEP121010063

    Abstract

    The Apple watch irregular pulse detection algorithm was found to have a positive predictive value of 0.84 for identification of atrial fibrillation (AF). We sought to describe the prevalence of arrhythmias other than AF in those with an irregular pulse detected on a smartwatch.The Apple Heart Study investigated a smartwatch-based irregular pulse notification algorithm to identify AF. For this secondary analysis, we analyzed participants who received an ambulatory ECG patch after index irregular pulse notification. We excluded participants with AF identified on ECG patch and described the prevalence of other arrhythmias on the remaining participant ECG patches. We also reported the proportion of participants self-reporting subsequent AF diagnosis.Among 419 297 participants enrolled in the Apple Heart Study, 450 participant ECG patches were analyzed, with no AF on 297 ECG patches (66%). Non-AF arrhythmias (excluding supraventricular tachycardias <30 beats and pauses <3 seconds) were detected in 119 participants (40.1%) with ECG patches without AF. The most common arrhythmias were frequent PACs (burden ≥1% to <5%, 15.8%; ≥5% to <15%, 8.8%), atrial tachycardia (≥30 beats, 5.4%), frequent PVCs (burden ≥1% to <5%, 6.1%; ≥5% to <15%, 2.7%), and nonsustained ventricular tachycardia (4-7 beats, 6.4%; ≥8 beats, 3.7%). Of 249 participants with no AF detected on ECG patch and patient-reported data available, 76 participants (30.5%) reported subsequent AF diagnosis.In participants with an irregular pulse notification on the Apple Watch and no AF observed on ECG patch, atrial and ventricular arrhythmias, mostly PACs and PVCs, were detected in 40% of participants. Defining optimal care for patients with detection of incidental arrhythmias other than AF is important as AF detection is further investigated, implemented, and refined.

    View details for DOI 10.1161/CIRCEP.121.010063

    View details for PubMedID 34565178

  • Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial. Nature medicine Ho, C. Y., Day, S. M., Axelsson, A., Russell, M. W., Zahka, K., Lever, H. M., Pereira, A. C., Colan, S. D., Margossian, R., Murphy, A. M., Canter, C., Bach, R. G., Wheeler, M. T., Rossano, J. W., Owens, A. T., Bundgaard, H., Benson, L., Mestroni, L., Taylor, M. R., Patel, A. R., Wilmot, I., Thrush, P., Vargas, J. D., Soslow, J. H., Becker, J. R., Seidman, C. E., Lakdawala, N. K., Cirino, A. L., Burns, K. M., McMurray, J. J., MacRae, C. A., Solomon, S. D., Orav, E. J., Braunwald, E. 2021

    Abstract

    Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80-160 mg daily in children) or placebo for 2 years ( NCT01912534 ). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.

    View details for DOI 10.1038/s41591-021-01505-4

    View details for PubMedID 34556856

  • "It seems like COVID-19 now is the only disease present on Earth": living with a rare or undiagnosed disease during the COVID-19 pandemic. Genetics in medicine : official journal of the American College of Medical Genetics Halley, M. C., Stanley, T. n., Maturi, J. n., Goldenberg, A. J., Bernstein, J. A., Wheeler, M. T., Tabor, H. K. 2021

    Abstract

    Patients with rare and undiagnosed diseases (RUDs) face significant health challenges, which may be exacerbated during the COVID-19 pandemic. The goal of this study was to identify specific impacts of the pandemic on RUD patients, and targets for improving support and health-care access.We conducted an online survey of RUD patients and their family members from 21 April to 8 June 2020, recruited from 76 Facebook groups for RUDs. Questions assessed patient characteristics and impacts of the pandemic on RUD diagnosis and management.Respondents (n = 413), including 274 RUD patients and 139 family members, were predominantly female and white, though income varied. Impacts of the pandemic included (1) barriers to accessing essential health care, (2) specific impacts of restrictive COVID-19 visitation policies on ability to advocate in health-care settings, (3) uncertainty and fear regarding COVID-19 risk, (4) exacerbated physical and mental health challenges, (5) magnified impacts of reduced educational and therapeutic services, and (6) unexpected positive changes due to the pandemic.There are specific, serious challenges affecting RUD patients and families during the COVID-19 pandemic. There is an urgent need to develop approaches to mitigate these challenges both during and beyond the pandemic.

    View details for DOI 10.1038/s41436-020-01069-7

    View details for PubMedID 33420343

  • An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids GENETICS IN MEDICINE Ferdinandusse, S., McWalter, K., te Brinke, H., Ijlst, L., Mooijer, P. M., Ruiter, J. N., van Lint, A. M., Pras-Raves, M., Wever, E., Millan, F., Sacoto, M., Begtrup, A., Tarnopolsky, M., Brady, L., Ladda, R. L., Sell, S. L., Nowak, C. B., Douglas, J., Tian, C., Ulm, E., Perlman, S., Drack, A. V., Chong, K., Martin, N., Brault, J., Brokamp, E., Toro, C., Gahl, W. A., Macnamara, E. F., Wolfe, L., Waisfisz, Q., Zwijnenburg, P. G., Ziegler, A., Barth, M., Smith, R., Ellingwood, S., Gaebler-Spira, D., Bakhtiari, S., Kruer, M. C., van Kampen, A. C., Wanders, R. A., Waterham, H. R., Cassiman, D., Vaz, F. M., Undiagnosed Dis Network 2021; 23 (4): 740-750

    Abstract

    In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.

    View details for DOI 10.1038/s41436-020-01027-3

    View details for Web of Science ID 000592640700002

    View details for PubMedID 33239752

    View details for PubMedCentralID PMC8026396

  • DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature MOLECULAR GENETICS & GENOMIC MEDICINE Meissner, L. E., Macnamara, E. F., D'Souza, P., Yang, J., Vezina, G., Ferreira, C. R., Zein, W. M., Tifft, C. J., Adams, D. R., Undiagnosed Diseases Network 2020; 8 (12): e1544

    Abstract

    DYRK1A-Related Intellectual Disability Syndrome is a rare autosomal dominant condition characterized by intellectual disability, speech and language delays, microcephaly, facial dysmorphism, and feeding difficulties. Affected individuals represent simplex cases that result from de novo heterozygous pathogenic variants in DYRK1A (OMIM 614104), or chromosomal structural rearrangements involving the DYRK1A locus. Due to the rarity of DYRK1A-Related Intellectual Disability Syndrome, the spectrum of symptoms associated with this disease has not been completely defined.We present two unrelated cases of DYRK1A-Related Intellectual Disability Syndrome resulting from variants in DYRK1A. Both probands presented to the National Institutes of Health (NIH) with multiple dysmorphic facial features, primary microcephaly, absent or minimal speech, feeding difficulties, and cognitive impairment; features that have been previously reported in individuals with DYRK1A. During NIH evaluation, additional features of enlarged cerebral subarachnoid spaces, retinal vascular tortuosity, and bilateral anomalous large optic discs with increased cup-to-disc ratio were identified in the first proband and multiple ophthalmologic abnormalities and sensorineural hearing loss were identified in the second proband.We recommend that the workup of future of patients include a comprehensive eye exam. Early establishment of physical, occupational, and speech therapy may help in the management of ataxia, hypertonia, and speech impairments common in these patients.

    View details for DOI 10.1002/mgg3.1544

    View details for Web of Science ID 000586993300001

    View details for PubMedID 33159716

    View details for PubMedCentralID PMC7767569

  • Family genetic result communication in rare and undiagnosed disease communities: Understanding the practice JOURNAL OF GENETIC COUNSELING Studwell, C. M., Kelley, E. G., Sinsheimer, J. S., Palmer, C. S., LeBlanc, K., Undiagnosed Dis Network 2021; 30 (2): 439-447

    Abstract

    Genetic results have implications not only for the individual, but also for their family members. Research on family communication of genetic results has primarily focused on families affected by adult-onset, dominant conditions as well as more common genetic conditions such as familial hypercholesterolemia, cardiomyopathies, and genetic hearing loss. This study therefore aimed to characterize genetic result communication in families with rare and undiagnosed conditions and identify factors that influence communication. One hundred and forty-two individuals who received a diagnosis from the Undiagnosed Diseases Network (UDN), a study focused on providing diagnoses to individuals with undiagnosed conditions, were eligible to complete a survey assessing genetic results communication. Survey items assessed if communication was discussed with healthcare providers, with whom participants communicated genetic testing, why they chose to communicate with these family members, and what information they communicated. All respondents (5 adult UDN participants, 38 parents/guardians of UDN participants, and 2 identifying as both) shared genetic results with at least one family member. Individuals who identified as both were considered exclusively adult participants for the purpose of these analyses. Adult participants and parents/guardians of participants reported high levels of understanding (96%), utility (96%), and comfort communicating genetic results (89%). Additionally, parents/guardians were more likely to disclose genetic results due to a general desire to share (60% of parents/guardians vs. 14% adult participants), while adult participants reported that they shared results to communicate risk to family members (86% of adult participants vs. 24% of parents/guardians). Many respondents did not recall discussing with a healthcare provider how (64%) or what (42%) to communicate about results. The results of this study provide insight into the practice of result communication by individuals with rare and previously undiagnosed conditions, which can ideally inform development of more effective counseling strategies and guidelines to aid family communication.

    View details for DOI 10.1002/jgc4.1329

    View details for Web of Science ID 000586287200001

    View details for PubMedID 33108040

    View details for PubMedCentralID PMC8207526

  • Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder BRAIN Schneeberger, P. E., Kortum, F., Korenke, G., Alawi, M., Santer, R., Woidy, M., Buhas, D., Fox, S., Juusola, J., Alfadhel, M., Webb, B. D., Coci, E. G., Abou Jamra, R., Siekmeyer, M., Biskup, S., Heller, C., Maier, E. M., Javaher-Haghighi, P., Bedeschi, M. F., Ajmone, P. F., Iascone, M., Peeters, H., Ballon, K., Jaeken, J., Rodriguez Alonso, A., Palomares-Bralo, M., Santos-Simarro, F., Meuwissen, M. C., Beysen, D., Kooy, R., Houlden, H., Murphy, D., Doosti, M., Karimiani, E., Mojarrad, M., Maroofian, R., Noskova, L., Kmoch, S., Honzik, T., Cope, H., Sanchez-Valle, A., Gelb, B. D., Kurth, I., Hempel, M., Kutsche, K., Undiagnosed Dise Network 2020; 143 (8): 2437-2453

    Abstract

    In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.

    View details for DOI 10.1093/brain/awaa204

    View details for Web of Science ID 000825023900020

    View details for PubMedID 32761064

    View details for PubMedCentralID PMC7447524

  • Cardiopulmonary Differences Between Normal And Overweight Diabetics Christle, J. W., Kobayashi, Y., Moneghetti, K., Wheeler, M., Myers, J., Palaniappan, L., Haddad, F. LIPPINCOTT WILLIAMS & WILKINS. 2020: 131
  • Silencing of MYH7 ameliorates disease phenotypes in human iPSC-Cardiomyocytes. Physiological genomics Dainis, A., Zaleta-Rivera, K., Ribeiro, A., Chang, A. C., Shang, C., Lan, F., Burridge, P. W., Liu, W. R., Wu, J. C., Chang, A. C., Pruitt, B. L., Wheeler, M., Ashley, E. A. 2020

    Abstract

    Allele-specific RNA silencing has been shown to be an effective therapeutic treatment in a number of diseases, including neurodegenerative disorders. Studies of allele-specific silencing in hypertrophic cardiomyopathy (HCM) to date have focused on mouse models of disease. We here examine allele-specific silencing in a human-cell model of HCM. We investigate two methods of silencing, short hairpin RNA (shRNA) and antisense oligonucleotide (ASO) silencing, using a human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model. We used cellular micropatterning devices with traction force microscopy and automated video analysis to examine each strategy's effects on contractile defects underlying disease. We find that shRNA silencing ameliorates contractile phenotypes of disease, reducing disease-associated increases in cardiomyocyte velocity, force, and power. We find that ASO silencing, while better able to target and knockdown a specific disease-associated allele, showed more modest improvements in contractile phenotypes. These findings are the first exploration of allele-specific silencing in a human HCM model and provide a foundation for further exploration of silencing as a therapeutic treatment for MYH7-mutation-associated cardiomyopathy.

    View details for DOI 10.1152/physiolgenomics.00021.2020

    View details for PubMedID 32567507

  • An assessment of the role of vinculin (VCL) loss of function variants in inherited cardiomyopathy. Human mutation Hawley, M. H., Almontashiri, N., Biesecker, L. G., Berger, N., Chung, W. K., Garcia, J., Grebe, T. A., Kelly, M. A., Lebo, M. S., Macaya, D., Mei, H., Platt, J., Richard, G., Ryan, A., Thomson, K. L., Vatta, M., Walsh, R., Ware, J. S., Wheeler, M., Zouk, H., Mason-Suares, H., Funke, B. 2020

    Abstract

    The ACMG/AMP variant classification framework was intended for highly penetrant Mendelian conditions. While it is appreciated that clinically relevant variants exhibit a wide spectrum of penetrance, accurately assessing and expressing the pathogenicity of variants with lower penetrance can be challenging. The vinculin gene (VCL) illustrates these challenges. Model organism data provides evidence that loss of function of VCL may play a role in cardiomyopathy and aggregate case-control studies suggest low penetrance. VCL loss of function variants, however, are rarely identified in affected probands and therefore there is a paucity of family studies clarifying the clinical significance of individual variants. This study, which aggregated data from >18,000 individuals who underwent gene panel or exome testing for inherited cardiomyopathies, identified 32 probands with VCL loss-of-function variants and confirmed enrichment in probands with dilated cardiomyopathy (OR= 9.01; CI=4.93-16.45). Our data revealed that the majority of these individuals (89.5%) had pediatric onset of disease. Family studies demonstrated that heterozygous loss of function of VCL alone is insufficient to cause cardiomyopathy but that these variants do contribute to disease risk. In conclusion, VCL loss-of-function variants should be reported in a diagnostic setting but need to be clearly distinguished as having lower penetrance. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/humu.24061

    View details for PubMedID 32516855

  • Multimodality Imaging for Risk Assessment of Inherited Cardiomyopathies CURRENT CARDIOVASCULAR RISK REPORTS O'Sullivan, J. W., Rhee, J., Hsu, D., Wheeler, M. T., Nieman, K. 2020; 14 (5)
  • Variant Interpretation for Dilated Cardiomyopathy: Refinement of the American College of Medical Genetics and Genomics/ClinGen Guidelines for the DCM Precision Medicine Study. Circulation. Genomic and precision medicine Morales, A., Kinnamon, D. D., Jordan, E., Platt, J., Vatta, M., Dorschner, M. O., Starkey, C. A., Mead, J. O., Ai, T., Burke, W., Gastier-Foster, J., Jarvik, G. P., Rehm, H. L., Nickerson, D. A., Hershberger, R. E., DCM Precision Medicine study of the DCM Consortium, DCM Consortium institutions and personnel participating in this study: Study Principal Investigator and Co-Investigators, D. C., Bowen, D. J., Haas, G., Abraham, W. T., Binkley, P. F., Hasan, A., Host, J., Lampert, B., Smith, S., Huggins, G. S., DeNofrio, D. D., Kiernan, M., Fishbein, D., Cheng, R., Dardas, T., Levy, W., Mahr, C., Masri, S., Stempien-Otero, A., Gottlieb Ste Pl, S. S., Wheeler, M., Ashley, E., Hofmeyer, M., Tang, W. H., Starling, R., Owens, A., Marguilies, K. B., Cappola, T., Goldberg, L. R., McLean, R., Moore, C. K., Long, R. C., Jimenez Carcamo, J., Trachtenberg, B., Ashrith, G., Bhimarahj, A., Sweitzer, N. K., Shah, P., Lowes, B., Stoller, D., Smart, F., Morris, A. A., Wilcox, J., Pan, S., Ewald, G. A., Aaronson, K. D., Wang, J. J., Pamboukian, S., Judge, D. P., Kransdorf, E. P., Garg, S., Desvigne-Nickens, P., Troendle, J., Fu, Y., Hindorff, L. 2020; 13 (2): e002480

    Abstract

    BACKGROUND: The hypothesis of the Dilated Cardiomyopathy Precision Medicine Study is that most dilated cardiomyopathy has a genetic basis. The study returns results to probands and, when indicated, to relatives. While both the American College of Medical Genetics and Genomics/Association for Molecular Pathology and ClinGen's MYH7-cardiomyopathy specifications provide relevant guidance for variant interpretation, further gene- and disease-specific considerations were required for dilated cardiomyopathy. To this end, we tailored the ClinGen MYH7-cardiomyopathy variant interpretation framework; the specifications implemented for the study are presented here.METHODS: Modifications were created and approved by an external Variant Adjudication Oversight Committee. After a pilot using 81 probands, further adjustments were made, resulting in 27 criteria (9 modifications of the ClinGen MYH7 framework and reintroduction of 2 American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria that were deemed not applicable by the ClinGen MYH7 working group).RESULTS: These criteria were applied to 2059 variants in a test set of 97 probands. Variants were classified as benign (n=1702), likely benign (n=33), uncertain significance (n=71), likely pathogenic (likely pathogenic; n=12), and pathogenic (P; n=3). Only 2/15 likely pathogenic/P variants were identified in Non-Hispanic African ancestry probands.CONCLUSIONS: We tailored the ClinGen MYH7 criteria for our study. Our preliminary data show that 15/97 (15.5%) probands have likely pathogenic/P variants, most of which were identified in probands of Non-Hispanic European ancestry. We anticipate continued evolution of our approach, one that will be informed by new insights on variant interpretation and a greater understanding of the genetic architecture of dilated cardiomyopathy.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037632.

    View details for DOI 10.1161/CIRCGEN.119.002480

    View details for PubMedID 32160020

  • De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation. American journal of human genetics Mao, D. n., Reuter, C. M., Ruzhnikov, M. R., Beck, A. E., Farrow, E. G., Emrick, L. T., Rosenfeld, J. A., Mackenzie, K. M., Robak, L. n., Wheeler, M. T., Burrage, L. C., Jain, M. n., Liu, P. n., Calame, D. n., Küry, S. n., Sillesen, M. n., Schmitz-Abe, K. n., Tonduti, D. n., Spaccini, L. n., Iascone, M. n., Genetti, C. A., Koenig, M. K., Graf, M. n., Tran, A. n., Alejandro, M. n., Lee, B. H., Thiffault, I. n., Agrawal, P. B., Bernstein, J. A., Bellen, H. J., Chao, H. T. 2020

    Abstract

    EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.

    View details for DOI 10.1016/j.ajhg.2020.02.016

    View details for PubMedID 32197074

  • Outcomes in Patients With Cardiac Amyloidosis Undergoing Heart Transplantation. JACC. Heart failure Barrett, C. D., Alexander, K. M., Zhao, H. n., Haddad, F. n., Cheng, P. n., Liao, R. n., Wheeler, M. T., Liedtke, M. n., Schrier, S. n., Arai, S. n., Weisshaar, D. n., Witteles, R. M. 2020

    Abstract

    The purpose of this study is to report outcomes after heart transplantation in patients with cardiac amyloidosis based on a large single-center experience.Cardiac amyloidosis causes significant morbidity and mortality, often leading to restrictive cardiomyopathy, progressive heart failure, and death. Historically, heart transplantation outcomes have been worse in patients with cardiac amyloidosis compared with other heart failure populations, in part due to the systemic nature of the disease. However, several case series have suggested that transplantation outcomes may be better in the contemporary era, likely in part due to the availability of more effective light chain suppressive therapies for light chain amyloidosis.This study examined all patients seen between 2004 and 2017, either at the Stanford University Medical Center or the Kaiser Permanente Santa Clara Medical Center, who were diagnosed with cardiac amyloidosis and ultimately underwent heart transplantation. This study examined pre-transplantation characteristics and post-transplantation outcomes in this group compared with the overall transplantation population at our center.During the study period, 31 patients (13 with light chain amyloidosis and 18 with transthyretin [ATTR] amyloidosis) underwent heart transplantation. Patients with ATTR amyloidosis were older, were more likely to be male, had worse baseline renal function, and had longer waitlist times compared with both patients with light chain amyloidosis and the overall transplantation population. Post-transplantation, there were no differences in post-operative bleeding, renal failure, infection, rejection, or malignancy. There was no significant difference in mortality between patients who underwent heart transplantation for amyloid cardiomyopathy and patients who underwent heart transplantation for all other indications.In carefully selected patients with cardiac amyloidosis, heart transplantation can be an effective therapeutic option with outcomes similar to those transplanted for other causes of heart failure.

    View details for DOI 10.1016/j.jchf.2019.12.013

    View details for PubMedID 32387068

  • Accuracy of Smartphone Camera Applications for Detecting Atrial Fibrillation: A Systematic Review and Meta-analysis. JAMA network open O'Sullivan, J. W., Grigg, S. n., Crawford, W. n., Turakhia, M. P., Perez, M. n., Ingelsson, E. n., Wheeler, M. T., Ioannidis, J. P., Ashley, E. A. 2020; 3 (4): e202064

    Abstract

    Atrial fibrillation (AF) affects more than 6 million people in the United States; however, much AF remains undiagnosed. Given that more than 265 million people in the United States own smartphones (>80% of the population), smartphone applications have been proposed for detecting AF, but the accuracy of these applications remains unclear.To determine the accuracy of smartphone camera applications that diagnose AF.MEDLINE and Embase were searched until January 2019 for studies that assessed the accuracy of any smartphone applications that use the smartphone's camera to measure the amplitude and frequency of the user's fingertip pulse to diagnose AF.Bivariate random-effects meta-analyses were constructed to synthesize data. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) of Diagnostic Test Accuracy Studies reporting guideline.Sensitivity and specificity were measured with bivariate random-effects meta-analysis. To simulate the use of these applications as a screening tool, the positive predictive value (PPV) and negative predictive value (NPV) for different population groups (ie, age ≥65 years and age ≥65 years with hypertension) were modeled. Lastly, the association of methodological limitations with outcomes were analyzed with sensitivity analyses and metaregressions.A total of 10 primary diagnostic accuracy studies, with 3852 participants and 4 applications, were included. The oldest studies were published in 2016 (2 studies [20.0%]), while most studies (4 [40.0%]) were published in 2018. The applications analyzed the pulsewave signal for a mean (range) of 2 (1-5) minutes. The meta-analyzed sensitivity and specificity for all applications combined were 94.2% (95% CI, 92.2%-95.7%) and 95.8% (95% CI, 92.4%-97.7%), respectively. The PPV for smartphone camera applications detecting AF in an asymptomatic population aged 65 years and older was between 19.3% (95% CI, 19.2%-19.4%) and 37.5% (95% CI, 37.4%-37.6%), and the NPV was between 99.8% (95% CI, 99.83%-99.84%) and 99.9% (95% CI, 99.94%-99.95%). The PPV and NPV increased for individuals aged 65 years and older with hypertension (PPV, 20.5% [95% CI, 20.4%-20.6%] to 39.2% [95% CI, 39.1%-39.3%]; NPV, 99.8% [95% CI, 99.8%-99.8%] to 99.9% [95% CI, 99.9%-99.9%]). There were methodological limitations in a number of studies that did not appear to be associated with diagnostic performance, but this could not be definitively excluded given the sparsity of the data.In this study, all smartphone camera applications had relatively high sensitivity and specificity. The modeled NPV was high for all analyses, but the PPV was modest, suggesting that using these applications in an asymptomatic population may generate a higher number of false-positive than true-positive results. Future research should address the accuracy of these applications when screening other high-risk population groups, their ability to help monitor chronic AF, and, ultimately, their associations with patient-important outcomes.

    View details for DOI 10.1001/jamanetworkopen.2020.2064

    View details for PubMedID 32242908

  • Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science. Genetics in medicine : official journal of the American College of Medical Genetics Schoch, K. n., Esteves, C. n., Bican, A. n., Spillmann, R. n., Cope, H. n., McConkie-Rosell, A. n., Walley, N. n., Fernandez, L. n., Kohler, J. N., Bonner, D. n., Reuter, C. n., Stong, N. n., Mulvihill, J. J., Novacic, D. n., Wolfe, L. n., Abdelbaki, A. n., Toro, C. n., Tifft, C. n., Malicdan, M. n., Gahl, W. n., Liu, P. n., Newman, J. n., Goldstein, D. B., Hom, J. n., Sampson, J. n., Wheeler, M. T., Cogan, J. n., Bernstein, J. A., Adams, D. R., McCray, A. T., Shashi, V. n. 2020

    Abstract

    The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices.We analyzed retrospective data from four UDN clinical sites, from July 2015 to September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods.Of 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease-gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior nondiagnostic exome sequencing and 45 diagnoses (19%) that were nongenetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants, and collaborative science for functional assays and animal modeling.Investigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries, and delineation of novel disorders represent a model for genomic medicine and science.

    View details for DOI 10.1038/s41436-020-00984-z

    View details for PubMedID 33093671

  • Echocardiographic Assessment of Left Ventricular Remodeling in American Style Footballers. International journal of sports medicine Moneghetti, K. J., Singh, T., Hedman, K., Christle, J. W., Kooreman, Z., Kobayashi, Y., Bouajila, S., Amsallem, M., Wheeler, M., Gerche, A. L., Ashley, E., Haddad, F. 2019

    Abstract

    Several athletic programs incorporate echocardiography during pre-participation screening of American Style Football (ASF) players with great variability in reported echocardiographic values. Pre-participation screening was performed in National Collegiate Athletic Association Division I ASF players from 2008 to 2016 at the Division of Sports Cardiology. The echocardiographic protocol focused on left ventricular (LV) mass, mass-to-volume ratio, sphericity, ejection fraction, and longitudinal Lagrangian strain. LV mass was calculated using the area-length method in end-diastole and end-systole. A total of two hundred and thirty players were included (18±1 years, 57% were Caucasian, body mass index 29±4kg/m2) after four players (2%) were excluded for pathological findings. Although there was no difference in indexed LV mass by race (Caucasian 78±11 vs. African American 81±10g/m2, p=0.089) or sphericity (Caucasian 1.81±0.13 vs. African American 1.78±0.14, p=0.130), the mass-to-volume ratio was higher in African Americans (0.91±0.09 vs. 0.83±0.08, p<0.001). No race-specific differences were noted in LV longitudinal Lagrangian strain. Player position appeared to have a limited role in defining LV remodeling. In conclusion, significant echocardiographic differences were observed in mass-to-volume ratio between African American and Caucasian players. These demographics should be considered as part of pre-participation screening.

    View details for DOI 10.1055/a-1014-2994

    View details for PubMedID 31791086

  • Baseline Characteristics of the VANISH Cohort. Circulation. Heart failure Axelsson Raja, A., Shi, L., Day, S. M., Russell, M., Zahka, K., Lever, H., Colan, S. D., Margossian, R., Hall, E. K., Becker, J., Jefferies, J. L., Patel, A. R., Choudhury, L., Murphy, A. M., Canter, C., Bach, R., Taylor, M., Mestroni, L., Wheeler, M. T., Benson, L., Owens, A. T., Rossano, J., Lin, K. Y., Pahl, E., Pereira, A. C., Bundgaard, H., Lewis, G. D., Vargas, J. D., Cirino, A. L., McMurray, J. J., MacRae, C. A., Solomon, S. D., Orav, E. J., Braunwald, E., Ho, C. Y. 2019; 12 (12): e006231

    Abstract

    BACKGROUND: The VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) targeted young sarcomeric gene mutation carriers with early-stage hypertrophic cardiomyopathy (HCM) to test whether valsartan can modify disease progression. We describe the baseline characteristics of the VANISH cohort and compare to previous trials evaluating angiotensin receptor blockers.METHODS: Applying a randomized, double-blinded, placebo-controlled design, 178 participants with nonobstructive HCM (age, 23.3±10.1 years; 61% men) were randomized in the primary cohort and 34 (age, 16.5±4.9 years; 50% men) in the exploratory cohort of sarcomeric mutation carriers without left ventricular hypertrophy.RESULTS: In the primary cohort, maximal left ventricular wall thickness was 17±4 mm for adults and Z score 7.0±4.5 for children. Nineteen percent had late gadolinium enhancement on cardiac magnetic resonance. Mean peak oxygen consumption was 33 mL/kg per minute, and 92% of participants were New York Heart Association functional class I. New York Heart Association class II was associated with older age, MYH7 variants, and more prominent imaging abnormalities. Six previous trials of angiotensin receptor blockers in HCM enrolled a median of 24 patients (range, 19-133) with mean age of 51.2 years; 42% of patients were in New York Heart Association class ≥II, and sarcomeric mutations were not required.CONCLUSIONS: The VANISH cohort is much larger, younger, less heterogeneous, and has less advanced disease than prior angiotensin receptor blocker trials in HCM. Participants had relatively normal functional capacity and mild HCM features. New York Heart Association functional class II symptoms were associated with older age, more prominent imaging abnormalities, and MYH7 variants, suggesting both phenotype and genotype contribute to disease manifestations.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01912534.

    View details for DOI 10.1161/CIRCHEARTFAILURE.119.006231

    View details for PubMedID 31813281

  • Comparison of the Stanford ECG Left Atrial Criteria With the International ECG Criteria for Sports Screening. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine Hock, J., Wheeler, M., Singh, T., Ha, L. D., Hadley, D., Froelicher, V. 2019

    Abstract

    OBJECTIVE: Because the International left atrial enlargement electrocardiographic (ECG) screening criteria (ECG-LAE) for athletes are rarely fulfilled in young athletes, we compared it with evidence-based criteria from a recent clinical outcome study of ECG left atrial abnormality (ECG-LAA).DESIGN: Retrospective analyses.SETTING: Routine preparticipation ECG screening in California.PARTICIPANTS: Four thousand four hundred thirty-eight young individuals (18.5 ± 5.4 years, 40% women).ASSESSMENT OF RISK FACTORS: The International criteria for ECG-LAE were applied: prolonged P wave duration of ≥120 ms in leads I or II AND negative portion of ≥1 mm in depth in lead V1. This was compared with Stanford criteria for ECG-LAA: prolonged P wave duration of ≥140 ms odds ratio (OR) negative portion in V1 and V2 greater than 1 mm.MAIN OUTCOME MEASURES: Differences in the classification of abnormal ECGs between the 2 criteria applied to the same population of young athletes.RESULTS: Only 33 (0.7%) of our subjects fulfilled the International criteria for ECG-LAE while 110 (2.5%) fulfilled the ECG-LAA criteria. Adding our new ECG-LAA criterion and considering it a major criterion raised the abnormal ECG prevalence and athletes referred for further evaluation from 2.9% to 4.4%.CONCLUSIONS: The Stanford evidence-based criterion for ECG-LAA incorporating V2 and replacing "or" for "and" regarding P wave duration increased the yield of abnormal classification for P waves. Future follow-up studies are needed to confirm that this new criterion should be included in future ECG screening consensus documents.

    View details for DOI 10.1097/JSM.0000000000000766

    View details for PubMedID 31743221

  • The effect of digital physical activity interventions on daily step count: a randomised controlled crossover substudy of the MyHeart Counts Cardiovascular Health Study. The Lancet. Digital health Shcherbina, A., Hershman, S. G., Lazzeroni, L., King, A. C., O'Sullivan, J. W., Hekler, E., Moayedi, Y., Pavlovic, A., Waggott, D., Sharma, A., Yeung, A., Christle, J. W., Wheeler, M. T., McConnell, M. V., Harrington, R. A., Ashley, E. A. 2019; 1 (7): e344-e352

    Abstract

    Smartphone apps might enable interventions to increase physical activity, but few randomised trials testing this hypothesis have been done. The MyHeart Counts Cardiovascular Health Study is a longitudinal smartphone-based study with the aim of elucidating the determinants of cardiovascular health. We aimed to investigate the effect of four different physical activity coaching interventions on daily step count in a substudy of the MyHeart Counts Study.In this randomised, controlled crossover trial, we recruited adults (aged ≥18 years) in the USA with access to an iPhone smartphone (Apple, Cupertino, CA, USA; version 5S or newer) who had downloaded the MyHeart Counts app (version 2.0). After completion of a 1 week baseline period of interaction with the MyHeart Counts app, participants were randomly assigned to receive one of 24 permutations (four combinations of four 7 day interventions) in a crossover design using a random number generator built into the app. Interventions consisted of either daily prompts to complete 10 000 steps, hourly prompts to stand following 1 h of sitting, instructions to read the guidelines from the American Heart Association website, or e-coaching based upon the individual's personal activity patterns from the baseline week of data collection. Participants completed the trial in a free-living setting. Due to the nature of the interventions, participants could not be masked from the intervention. Investigators were not masked to intervention allocation. The primary outcome was change in mean daily step count from baseline for each of the four interventions, assessed in the modified intention-to-treat analysis set, which included all participants who had completed 7 days of baseline monitoring and at least 1 day of one of the four interventions. This trial is registered with ClinicalTrials.gov, NCT03090321.Between Dec 12, 2016, and June 6, 2018, 2783 participants consented to enrol in the coaching study, of whom 1075 completed 7 days of baseline monitoring and at least 1 day of one of the four interventions and thus were included in the modified intention-to-treat analysis set. 493 individuals completed the full set of assigned interventions. All four interventions significantly increased mean daily step count from baseline (mean daily step count 2914 [SE 74]): mean step count increased by 319 steps (75) for participants in the American Heart Association website prompt group (p<0·0001), 267 steps (74) for participants in the hourly stand prompt group (p=0·0003), 254 steps (74) for participants in the cluster-specific prompts group (p=0·0006), and by 226 steps (75) for participants in the 10 000 daily step prompt group (p=0·0026 vs baseline).Four smartphone-based physical activity coaching interventions significantly increased daily physical activity. These findings suggests that digital interventions delivered via a mobile app have the ability to increase short-term physical activity levels in a free-living cohort.Stanford Data Science Initiative.

    View details for DOI 10.1016/S2589-7500(19)30129-3

    View details for PubMedID 33323209

  • The effect of digital physical activity interventions on daily step count: a randomised controlled crossover substudy of the MyHeart Counts Cardiovascular Health Study LANCET DIGITAL HEALTH Shcherbina, A., Hershman, S. G., Lazzeroni, L., King, A. C., O'Sullivan, J. W., Hekler, E., Moayedi, Y., Pavlovic, A., Waggott, D., Sharma, A., Yeung, A., Christle, J. W., Wheeler, M. T., McConnell, M. V., Harrington, R. A., Ashley, E. A. 2019; 1 (7): E344–E352
  • VarSight: prioritizing clinically reported variants with binary classification algorithms. BMC bioinformatics Holt, J. M., Wilk, B., Birch, C. L., Brown, D. M., Gajapathy, M., Moss, A. C., Sosonkina, N., Wilk, M. A., Anderson, J. A., Harris, J. M., Kelly, J. M., Shaterferdosian, F., Uno-Antonison, A. E., Weborg, A., Worthey, E. A. 2019; 20 (1): 496

    Abstract

    When applying genomic medicine to a rare disease patient, the primary goal is to identify one or more genomic variants that may explain the patient's phenotypes. Typically, this is done through annotation, filtering, and then prioritization of variants for manual curation. However, prioritization of variants in rare disease patients remains a challenging task due to the high degree of variability in phenotype presentation and molecular source of disease. Thus, methods that can identify and/or prioritize variants to be clinically reported in the presence of such variability are of critical importance.We tested the application of classification algorithms that ingest variant annotations along with phenotype information for predicting whether a variant will ultimately be clinically reported and returned to a patient. To test the classifiers, we performed a retrospective study on variants that were clinically reported to 237 patients in the Undiagnosed Diseases Network.We treated the classifiers as variant prioritization systems and compared them to four variant prioritization algorithms and two single-measure controls. We showed that the trained classifiers outperformed all other tested methods with the best classifiers ranking 72% of all reported variants and 94% of reported pathogenic variants in the top 20.We demonstrated how freely available binary classification algorithms can be used to prioritize variants even in the presence of real-world variability. Furthermore, these classifiers outperformed all other tested methods, suggesting that they may be well suited for working with real rare disease patient datasets.

    View details for DOI 10.1186/s12859-019-3026-8

    View details for PubMedID 31615419

    View details for PubMedCentralID PMC6792253

  • De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects. American journal of human genetics Accogli, A., Calabretta, S., St-Onge, J., Boudrahem-Addour, N., Dionne-Laporte, A., Joset, P., Azzarello-Burri, S., Rauch, A., Krier, J., Fieg, E., Pallais, J. C., McConkie-Rosell, A., McDonald, M., Freedman, S. F., Rivière, J. B., Lafond-Lapalme, J., Simpson, B. N., Hopkin, R. J., Trimouille, A., Van-Gils, J., Begtrup, A., McWalter, K., Delphine, H., Keren, B., Genevieve, D., Argilli, E., Sherr, E. H., Severino, M., Rouleau, G. A., Yam, P. T., Charron, F., Srour, M. 2019; 105 (4): 854-868

    Abstract

    Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs∗4]; c.2564_2567dupTGTT [p.Leu856Phefs∗5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).

    View details for DOI 10.1016/j.ajhg.2019.09.005

    View details for PubMedID 31585109

    View details for PubMedCentralID PMC6817525

  • Allele-Specific Silencing Ameliorates Restrictive Cardiomyopathy Due to a Human Myosin Regulatory Light Chain Mutation. Circulation Zaleta-Rivera, K., Dainis, A., Ribeiro, A. J., Sanchez Cordero, P., Rubio, G., Shang, C., Liu, J., Finsterbach, T., Parikh, V. N., Sutton, S., Seo, K., Sinha, N., Jain, N., Huang, Y., Hajjar, R. J., Kay, M. A., Szczesna-Cordary, D., Pruitt, B. L., Wheeler, M. T., Ashley, E. A. 2019

    Abstract

    BACKGROUND: Restrictive cardiomyopathy (RCM) is a rare heart disease associated with mutations in sarcomeric genes and with phenotypic overlap with hypertrophic cardiomyopathy. There is no approved therapy. Here, we explore the potential of an interfering RNA (RNAi) therapeutic for a human sarcomeric mutation in MYL2 causative of restrictive cardiomyopathy in a mouse model.METHODS: AAV9-M7.8L shRNA was selected from a pool of RNAi oligonucleotides containing the SNV in different positions to specifically target the mutated allele causative of RCM by FACS screening. Two groups of RLC-N47K transgenic mice were injected with a single dose of AAV9-M7.8L shRNA at 3 days of age and at 60 days of age. Mice were subjected to treadmill exercise and echocardiography after treatment to determine VO2max and left ventricular mass. At the end of treatment, heart, lung, liver and kidney tissue was harvested to determine viral tropism and for transcriptome and proteomic analysis. Cardiomyocytes were isolated for single cell studies.RESULTS: One time injection of AAV9-M7.8L RNAi in 3-day-old humanized RLC mutant transgenic mice silenced the mutated allele (RLC-47K) with minimal effects on the normal allele (RLC-47N) assayed 16 weeks post-injection. AAV9-M7.8L RNAi suppressed the expression of hypertrophic biomarkers, reduced heart weight and attenuated a pathological increase in left ventricular mass (LVM). Single adult cardiac myocytes from mice treated with AAV9-M7.8L showed partial restoration of the maximal contraction velocity with marked reduction in hypercontractility as well as relaxation kinetics and improved time to maximal calcium reuptake velocity. In addition, cardiac stress protein biomarkers, such as calmodulin-dependent protein kinase II (CAMKII) and the transcription activator Brg1 were reduced suggesting recovery towards a healthy myocardium. Transcriptome analyses further revealed no significant changes of argonaute (AGO1, AGO2) and endoribonuclease dicer (DICER1) transcripts while endogenous microRNAs were preserved suggesting the RNAi pathway was not saturated.CONCLUSIONS: Our results show the feasibility, efficacy, and safety of RNAi therapeutics directed at human restrictive cardiomyopathy. This is a promising step towards targeted therapy for a prevalent human disease.

    View details for DOI 10.1161/CIRCULATIONAHA.118.036965

    View details for PubMedID 31315475

  • De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia. American journal of human genetics Kanca, O., Andrews, J. C., Lee, P., Patel, C., Braddock, S. R., Slavotinek, A. M., Cohen, J. S., Gubbels, C. S., Aldinger, K. A., Williams, J., Indaram, M., Fatemi, A., Yu, T. W., Agrawal, P. B., Vezina, G., Simons, C., Crawford, J., Lau, C. C., Undiagnosed Diseases Network, Chung, W. K., Markello, T. C., Dobyns, W. B., Adams, D. R., Gahl, W. A., Wangler, M. F., Yamamoto, S., Bellen, H. J., Malicdan, M. C., Acosta, M. T., Adams, D. R., Agrawal, P., Alejandro, M. E., Allard, P., Alvey, J., Andrews, A., Ashley, E. A., Azamian, M. S., Bacino, C. A., Bademci, G., Baker, E., Balasubramanyam, A., Baldridge, D., Bale, J., Barbouth, D., Batzli, G. F., Bayrak-Toydemir, P., Beggs, A. H., Bejerano, G., Bellen, H. J., Bernstein, J. A., Berry, G. T., Bican, A., Bick, D. P., Birch, C. L., Bivona, S., Bohnsack, J., Bonnenmann, C., Bonner, D., Boone, B. E., Bostwick, B. L., Botto, L., Briere, L. C., Brokamp, E., Brown, D. M., Brush, M., Burke, E. A., Burrage, L. C., Butte, M. J., Carey, J., Carrasquillo, O., Chang, T. C., Chao, H., Clark, G. D., Coakley, T. R., Cobban, L. A., Cogan, J. D., Cole, F. S., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., D'Souza, P., Dasari, S., Davids, M., Dayal, J. G., Dell'Angelica, E. C., Dhar, S. U., Dorrani, N., Dorset, D. C., Douine, E. D., Draper, D. D., Duncan, L., Eckstein, D. J., Emrick, L. T., Eng, C. M., Esteves, C., Estwick, T., Fernandez, L., Ferreira, C., Fieg, E. L., Fisher, P. G., Fogel, B. L., Forghani, I., Fresard, L., Gahl, W. A., Godfrey, R. A., Goldman, A. M., Goldstein, D. B., Gourdine, J. F., Grajewski, A., Groden, C. A., Gropman, A. L., Haendel, M., Hamid, R., Hanchard, N. A., Hayes, N., High, F., Holm, I. A., Hom, J., Huang, A., Huang, Y., Isasi, R., Jamal, F., Jiang, Y., Johnston, J. M., Jones, A. L., Karaviti, L., Kelley, E. G., Kiley, D., Koeller, D. M., Kohane, I. S., Kohler, J. N., Krakow, D., Krasnewich, D. M., Korrick, S., Koziura, M., Krier, J. B., Kyle, J. E., Lalani, S. R., Lam, B., Lanpher, B. C., Lanza, I. R., Lau, C. C., Lazar, J., LeBlanc, K., Lee, B. H., Lee, H., Levitt, R., Levy, S. E., Lewis, R. A., Lincoln, S. A., Liu, P., Liu, X. Z., Longo, N., Loo, S. K., Loscalzo, J., Maas, R. L., Macnamara, E. F., MacRae, C. A., Maduro, V. V., Majcherska, M. M., Malicdan, M. C., Mamounas, L. A., Manolio, T. A., Mao, R., Markello, T. C., Marom, R., Marth, G., Martin, B. A., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., May, T., McCauley, J., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., Metz, T. O., Might, M., Morava-Kozicz, E., Moretti, P. M., Morimoto, M., Mulvihill, J. J., Murdock, D. R., Nath, A., Nelson, S. F., Newberry, J. S., Newman, J. H., Nicholas, S. K., Novacic, D., Oglesbee, D., Orengo, J. P., Pace, L., Pak, S., Pallais, J. C., Palmer, C. G., Papp, J. C., Parker, N. H., Phillips, J. A., Posey, J. E., Postlethwait, J. H., Potocki, L., Pusey, B. N., Quinlan, A., Raja, A. N., Renteria, G., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Rowley, R. K., Ruzhnikov, M., Sacco, R., Sampson, J. B., Samson, S. L., Saporta, M., Schaechter, J., Schedl, T., Schoch, K., Scott, D. A., Shakachite, L., Sharma, P., Shashi, V., Shields, K., Shin, J., Signer, R., Sillari, C. H., Silverman, E. K., Sinsheimer, J. S., Sisco, K., Smith, K. S., Solnica-Krezel, L., Spillmann, R. C., Stoler, J. M., Stong, N., Sullivan, J. A., Sutton, S., Sweetser, D. A., Tabor, H. K., Tamburro, C. P., Tan, Q. K., Tekin, M., Telischi, F., Thorson, W., Tifft, C. J., Toro, C., Tran, A. A., Urv, T. K., Velinder, M., Viskochil, D., Vogel, T. P., Wahl, C. E., Walley, N. M., Walsh, C. A., Walker, M., Wambach, J., Wan, J., Wang, L., Wangler, M. F., Ward, P. A., Waters, K. M., Webb-Robertson, B. M., Wegner, D., Westerfield, M., Wheeler, M. T., Wise, A. L., Wolfe, L. A., Woods, J. D., Worthey, E. A., Yamamoto, S., Yang, J., Yoon, A. J., Yu, G., Zastrow, D. B., Zhao, C., Zuchner, S. 2019

    Abstract

    WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.

    View details for DOI 10.1016/j.ajhg.2019.06.014

    View details for PubMedID 31327508

  • ClinPhen extracts and prioritizes patient phenotypes directly from medical records to expedite genetic disease diagnosis GENETICS IN MEDICINE Deisseroth, C. A., Birgmeier, J., Bodle, E. E., Kohler, J. N., Matalon, D. R., Nazarenko, Y., Genetti, C. A., Brownstein, C. A., Schmitz-Abe, K., Schoch, K., Cope, H., Signer, R., Network, U., Martinez-Agosto, J. A., Shashi, V., Beggs, A. H., Wheeler, M. T., Bernstein, J. A., Bejerano, G. 2019; 21 (7): 1585–93
  • Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling. Biological psychiatry Johnson, B. V., Kumar, R., Oishi, S., Alexander, S., Kasherman, M., Vega, M. S., Ivancevic, A., Gardner, A., Domingo, D., Corbett, M., Parnell, E., Yoon, S., Oh, T., Lines, M., Lefroy, H., Kini, U., Van Allen, M., Grønborg, S., Mercier, S., Küry, S., Bézieau, S., Pasquier, L., Raynaud, M., Afenjar, A., Billette de Villemeur, T., Keren, B., Désir, J., Van Maldergem, L., Marangoni, M., Dikow, N., Koolen, D. A., VanHasselt, P. M., Weiss, M., Zwijnenburg, P., Sa, J., Reis, C. F., López-Otín, C., Santiago-Fernández, O., Fernández-Jaén, A., Rauch, A., Steindl, K., Joset, P., Goldstein, A., Madan-Khetarpal, S., Infante, E., Zackai, E., Mcdougall, C., Narayanan, V., Ramsey, K., Mercimek-Andrews, S., Pena, L., Shashi, V., Schoch, K., Sullivan, J. A., Pinto E Vairo, F., Pichurin, P. N., Ewing, S. A., Barnett, S. S., Klee, E. W., Perry, M. S., Koenig, M. K., Keegan, C. E., Schuette, J. L., Asher, S., Perilla-Young, Y., Smith, L. D., Rosenfeld, J. A., Bhoj, E., Kaplan, P., Li, D., Oegema, R., van Binsbergen, E., van der Zwaag, B., Smeland, M. F., Cutcutache, I., Page, M., Armstrong, M., Lin, A. E., Steeves, M. A., Hollander, N. d., Hoffer, M. J., Reijnders, M. R., Demirdas, S., Koboldt, D. C., Bartholomew, D., Mosher, T. M., Hickey, S. E., Shieh, C., Sanchez-Lara, P. A., Graham, J. M., Tezcan, K., Schaefer, G. B., Danylchuk, N. R., Asamoah, A., Jackson, K. E., Yachelevich, N., Au, M., Pérez-Jurado, L. A., Kleefstra, T., Penzes, P., Wood, S. A., Burne, T., Pierson, T. M., Piper, M., Gécz, J., Jolly, L. A. 2019

    Abstract

    The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function.

    View details for DOI 10.1016/j.biopsych.2019.05.028

    View details for PubMedID 31443933

  • Magnetic Resonance Imaging characteristics in case of TOR1AIP1 muscular dystrophy. Clinical imaging Bhatia, A., Mobley, B. C., Cogan, J., Koziura, M. E., Brokamp, E., Phillips, J., Newman, J., Moore, S. A., Hamid, R. 2019; 58: 108-113

    Abstract

    Mutations in the torsinA-interacting protein 1 (TOR1AIP1) gene result in a severe muscular dystrophy with minimal literature in the pediatric population. We review a case of TOR1AIP1 gene mutation in a 16-year-old Caucasian female with a long history of muscle weakness. Extensive clinical workup was performed and MRI at time of initial presentation demonstrated no significant muscular atrophy with heterogenous STIR hyperintensity of the lower extremity muscles. MRI findings seven years later included extensive atrophy of the lower extremities, with severe progression, including the gluteal muscles, iliopsoas, rectus femoris, and obturator internus. There was also significant atrophy of the rectus abdominis and internal and external oblique muscles, and iliacus muscles. The MRI findings showed more proximal involvement of lower extremities and no atrophy of the tibialis anterior, making TOR1AIP1 the more likely genetic cause. Muscle biopsy findings supported TOR1AIP1 limb-girdle muscular dystrophy. Though rare, TOR1AIP1 gene mutation occurs in pediatric patients and MRI can aid in diagnosis and help differentiate from other types of muscular dystrophy. Genetic and pathology workup is also crucial to accurate diagnosis and possible treatment of these patients.

    View details for DOI 10.1016/j.clinimag.2019.06.010

    View details for PubMedID 31299614

  • Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification. American journal of human genetics Nicoli, E. R., Weston, M. R., Hackbarth, M., Becerril, A., Larson, A., Zein, W. M., Baker, P. R., Burke, J. D., Dorward, H., Davids, M., Huang, Y., Adams, D. R., Zerfas, P. M., Chen, D., Markello, T. C., Toro, C., Wood, T., Elliott, G., Vu, M., Zheng, W., Garrett, L. J., Tifft, C. J., Gahl, W. A., Day-Salvatore, D. L., Mindell, J. A., Malicdan, M. C. 2019; 104 (6): 1127-1138

    Abstract

    Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl-/H+ exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.

    View details for DOI 10.1016/j.ajhg.2019.04.008

    View details for PubMedID 31155284

    View details for PubMedCentralID PMC6562152

  • A Patient with Sjogren's Syndrome and Subsequent Diagnosis of Inclusion Body Myositis and Light-Chain Amyloidosis JOURNAL OF GENERAL INTERNAL MEDICINE Hom, J., Marwaha, S., Postolova, A., Kittle, J., Vasquez, R., Davidson, J., Kohler, J., Dries, A., Fernandez-Betancourt, L., Majcherska, M., Dearlove, J., Raghavan, S., Vogel, H., Bernstein, J. A., Fisher, P., Ashley, E., Sampson, J., Wheeler, M., Undiagnosed Dis Network 2019; 34 (6): 1058–62
  • Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review AMERICAN JOURNAL OF MEDICAL GENETICS PART A Kumar, A., Zastrow, D. B., Kravets, E. J., Beleford, D., Ruzhnikov, M. Z., Grove, M. E., Dries, A. M., Kohler, J. N., Waggott, D. M., Yang, Y., Huang, Y., Mackenzie, K. M., Eng, C. M., Fisher, P. G., Ashley, E. A., Teng, J. M., Stevenson, D. A., Shieh, J. T., Wheeler, M. T., Bernstein, J. A., Adams, D. R., Aday, A., Alejandro, M. E., Allard, P., Azamian, M. S., Bacino, C. A., Baker, E., Balasubramanyam, A., Barseghyan, H., Batzli, G. F., Beggs, A. H., Behnam, B., Bellen, H. J., Bican, A., Bick, D. P., Birch, C. L., Bonner, D., Boone, B. E., Bostwick, B. L., Briere, L. C., Brokamp, E., Brown, D. M., Brush, M., Burke, E. A., Burrage, L. C., Butte, M. J., Chen, S., Clark, G. D., Coakley, T. R., Cogan, J. D., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., D'Souza, P., Davids, M., Davidson, J. M., Dayal, J. G., Dell'Angelica, E. C., Dhar, S. U., Dipple, K. M., Donnell-Fink, L. A., Dorrani, N., Dorset, D. C., Douine, E. D., Draper, D. D., Eckstein, D. J., Emrick, L. T., Enns, G. M., Eskin, A., Esteves, C., Estwick, T., Fairbrother, L., Fernandez, L., Ferreira, C., Fieg, E. L., Fogel, B. L., Friedman, N. D., Gahl, W. A., Glanton, E., Godfrey, R. A., Goldman, A. M., Goldstein, D. B., Gould, S. E., Gourdine, J. F., Groden, C. A., Gropman, A. L., Haendel, M., Hamid, R., Hanchard, N. A., High, F., Holm, I. A., Hom, J., Howerton, E. M., Jamal, F., Jiang, Y., Johnston, J. M., Jones, A. L., Karaviti, L., Koeller, D. M., Kohane, I. S., Krasnewich, D. M., Korrick, S., Koziura, M., Krier, J. B., Kyle, J. E., Lalani, S. R., Lau, C., Lazar, J., LeBlanc, K., Lee, B. H., Lee, H., Levy, S. E., Lewis, R. A., Lincoln, S. A., Loo, S. K., Loscalzo, J., Maas, R. L., Macnamara, E. F., MacRae, C. A., Maduro, V. V., Majcherska, M. M., Malicdan, M., Mamounas, L. A., Manolio, T. A., Markello, T. C., Marom, R., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., May, T., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., Merker, J. D., Metz, T. O., Might, M., Moretti, P. M., Morimoto, M., Mulvihill, J. J., Murdock, D. R., Murphy, J. L., Muzny, D. M., Nehrebecky, M. E., Nelson, S. F., Newberry, J., Newman, J. H., Nicholas, S. K., Novacic, D., Orange, J. S., Orengo, J. P., Pallais, J., Palmer, C. S., Papp, J. C., Parker, N. H., Pena, L. M., Phillips, J. A., Posey, J. E., Postlethwait, J. H., Potocki, L., Pusey, B. N., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Sampson, J. B., Samson, S. L., Schoch, K., Scott, D. A., Shakachite, L., Sharma, P., Shashi, V., Signer, R., Silverman, E. K., Sinsheimer, J. S., Smith, K. S., Spillmann, R. C., Staler, J. M., Stong, N., Sullivan, J. A., Sweetser, D. A., Tan, Q., Tifft, C. J., Toro, C., Tran, A. A., Urv, T. K., Vilain, E., Vogel, T. P., Wahl, C. E., Walley, N. M., Walsh, C. A., Walker, M., Wan, J., Wangler, M. F., Ward, P. A., Waters, K. M., Webb-Robertson, B. M., Westerfield, M., Wise, A. L., Wolfe, L. A., Worthey, E. A., Yamamoto, S., Yang, J., Yoon, A. J., Yu, G., Zhao, C., Zheng, A., Undiagnosed Dis Network 2019; 179 (6): 966–77
  • Targeted Long-Read RNA Sequencing Demonstrates Transcriptional Diversity Driven by Splice-Site Variation in MYBPC3. Circulation. Genomic and precision medicine Dainis, A., Tseng, E., Clark, T. A., Hon, T., Wheeler, M., Ashley, E. 2019; 12 (5): e002464

    View details for DOI 10.1161/CIRCGEN.119.002464

    View details for PubMedID 31112421

  • Athletic Remodeling in Female College Athletes: The "Morganroth Hypothesis" Revisited CLINICAL JOURNAL OF SPORT MEDICINE Kooreman, Z., Giraldeau, G., Finocchiaro, G., Kobayashi, Y., Wheeler, M., Perez, M., Moneghetti, K., Oxborough, D., George, K. P., Myers, J., Ashley, E., Haddad, F. 2019; 29 (3): 224–31
  • IgG4-related disease: Association with a rare gene variant expressed in cytotoxic T cells. Molecular genetics & genomic medicine Newman, J. H., Shaver, A., Sheehan, J. H., Mallal, S., Stone, J. H., Pillai, S., Bastarache, L., Riebau, D., Allard-Chamard, H., Stone, W. M., Perugino, C., Pilkinton, M., Smith, S. A., McDonnell, W. J., Capra, J. A., Meiler, J., Cogan, J., Xing, K., Mahajan, V. S., Mattoo, H., Hamid, R., Phillips, J. A. 2019: e686

    Abstract

    Family screening of a 48-year-old male with recently diagnosed IgG4-related disease (IgG4-RD) revealed unanticipated elevations in plasma IgG4 in his two healthy teenaged sons.We performed gene sequencing, immune cell studies, HLA typing, and analyses of circulating cytotoxic CD4+ T lymphocytes and plasmablasts to seek clues to pathogenesis. DNA from a separate cohort of 99 patients with known IgG4-RD was also sequenced for the presence of genetic variants in a specific gene, FGFBP2.The three share a previously unreported heterozygous single base deletion in fibroblast growth factor binding protein type 2 (FGFBP2), which causes a frameshift in the coding sequence. The FGFBP2 protein is secreted by cytotoxic T-lymphocytes and binds fibroblast growth factor. The variant sequence in the FGFBP2 protein is predicted to form a disordered random coil rather than a helical-turn-helix structure, unable to adopt a stable conformation. The proband and the two sons had 5-10-fold higher numbers of circulating cytotoxic CD4 + T cells and plasmablasts compared to matched controls. The three members also share a homozygous missense common variant in FGFBP2 found in heterozygous form in ~40% of the population. This common variant was found in 73% of an independent, well characterized IgG4-RD cohort, showing enrichment in idiopathic IgG4-RD.The presence of a shared deleterious variant and homozygous common variant in FGFBP2 in the proband and sons strongly implicates this cytotoxic T cell product in the pathophysiology of IgG4-RD. The high prevalence of a common FGFBP2 variant in sporadic IgG4-RD supports the likelihood of participation in disease.

    View details for DOI 10.1002/mgg3.686

    View details for PubMedID 30993913

  • Developing a genomics rotation: Practical training around variant interpretation for genetic counseling students JOURNAL OF GENETIC COUNSELING Grove, M. E., White, S., Fisk, D. G., Rego, S., Dagan-Rosenfeld, O., Kohler, J. N., Reuter, C. M., Bonner, D., Wheeler, M. T., Bernstein, J. A., Ormond, K. E., Hanson-Kahn, A. K., Undiagnosed Dis Network 2019; 28 (2): 466–76

    View details for DOI 10.1002/jgc4.1094

    View details for Web of Science ID 000463993600030

  • A toolkit for genetics providers in follow-up of patients with non-diagnostic exome sequencing JOURNAL OF GENETIC COUNSELING Zastrow, D. B., Kohler, J. N., Bonner, D., Reuter, C. M., Fernandez, L., Grove, M. E., Fisk, D. G., Yang, Y., Eng, C. M., Ward, P. A., Bick, D., Worthey, E. A., Fisher, P. G., Ashley, E. A., Bernstein, J. A., Wheeler, M. T., Adams, D. R., Aday, A., Alejandro, M. E., Allard, P., Ashley, E. A., Azamian, M. S., Bacino, C. A., Baker, E., Balasubramanyam, A., Barseghyan, H., Batzli, G. F., Beggs, A. H., Behnam, B., Bellen, H. J., Bernstein, J. A., Bican, A., Bick, D. P., Birch, C. L., Boone, B. E., Bostwick, B. L., Briere, L. C., Brokamp, E., Brown, D. M., Brush, M., Burke, E. A., Burrage, L. C., Butte, M. J., Chen, S., Clark, G. D., Coakley, T. R., Cogan, J. D., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., D'Souza, P., Davids, M., Dayal, J. G., Dell'Angelica, E. C., Dhar, S. U., Dipple, K. M., Donnell-Fink, L. A., Dorrani, N., Dorset, D. C., Douine, E. D., Draper, D. D., Dries, A. M., Eckstein, D. J., Emrick, L. T., Eng, C. M., Enns, G. M., Eskin, A., Esteves, C., Estwick, T., Fairbrother, L., Ferreira, C., Fieg, E. L., Fisher, P. G., Fogel, B. L., Gahl, W. A., Glanton, E., Godfrey, R. A., Goldman, A. M., Goldstein, D. B., Gould, S. E., Gourdine, J. F., Groden, C. A., Gropman, A. L., Haendel, M., Hamid, R., Hanchard, N. A., High, F., Holm, I. A., Hom, J., Howerton, E. M., Huang, Y., Jamal, F., Jiang, Y., Johnston, J. M., Jones, A. L., Karaviti, L., Koeller, D. M., Kohane, I. S., Krasnewich, D. M., Korrick, S., Koziura, M., Krier, J. B., Kyle, J. E., Lalani, S. R., Lau, C., Lazar, J., LeBlanc, K., Lee, B. H., Lee, H., Levy, S. E., Lewis, R. A., Lincoln, S. A., Loo, S. K., Loscalzo, J., Maas, R. L., Macnamara, E. F., MacRae, C. A., Maduro, V. V., Majcherska, M. M., Malicdan, M. V., Mamounas, L. A., Manolio, T. A., Markello, T. C., Marom, R., Martin, G., Martinez-Agosto, J. A., Marwaha, S., May, T., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., Merker, J. D., Metz, T. O., Might, M., Moretti, P. M., Morimoto, M., Nehrebecky, M. E., Nelson, S. F., Newberry, J., Newman, J. H., Nicholas, S. K., Novacic, D., Orange, J. S., Orengo, J. P., Pallais, J., Palmer, C. S., Papp, J. C., Postlethwait, J. H., Potocki, L., Pusey, B. N., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Sampson, J. B., Samson, S. L., Schoch, K., Scott, D. A., Shakachite, L., Sharma, P., Shashi, V., Signer, R., Silverman, E. K., Sinsheimer, J. S., Smith, K. S., Spillmann, R. C., Stoler, J. M., Stong, N., Sullivan, J. A., Sweetser, D. A., Tan, Q., Tifft, C. J., Toro, C., Tran, A. A., Urv, T. K., Vilain, E., Vogel, T. P., Waggott, D. M., Wahl, C. E., Walley, N. M., Walsh, C. A., Walker, M., Wan, J., Wangler, M. F., Ward, P. A., Waters, K. M., Webb-Robertson, B. M., Westerfield, M., Wheeler, M. T., Wise, A. L., Wolfe, L. A., Worthey, E. A., Yamamoto, S., Yang, J., Yang, Y., Yoon, A. J., Yu, G., Zhao, C., Zheng, A., Undiagnosed Dis Network 2019; 28 (2): 213–28

    View details for DOI 10.1002/jgc4.1119

    View details for Web of Science ID 000463993600005

  • Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy. PloS one Kahn-Kirby, A. H., Amagata, A., Maeder, C. I., Mei, J. J., Sideris, S., Kosaka, Y., Hinman, A., Malone, S. A., Bruegger, J. J., Wang, L., Kim, V., Shrader, W. D., Hoff, K. G., Latham, J. C., Ashley, E. A., Wheeler, M. T., Bertini, E., Carrozzo, R., Martinelli, D., Dionisi-Vici, C., Chapman, K. A., Enns, G. M., Gahl, W., Wolfe, L., Saneto, R. P., Johnson, S. C., Trimmer, J. K., Klein, M. B., Holst, C. R. 2019; 14 (3): e0214250

    Abstract

    Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies.Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured.EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE).These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.

    View details for DOI 10.1371/journal.pone.0214250

    View details for PubMedID 30921410

    View details for PubMedCentralID PMC6438538

  • Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy PLOS ONE Kahn-Kirby, A. H., Amagata, A., Maeder, C. I., Mei, J. J., Sideris, S., Kosaka, Y., Hinman, A., Malone, S. A., Bruegger, J. J., Wang, L., Kim, V., Shrader, W. D., Hoff, K. G., Latham, J. C., Ashley, E. A., Wheeler, M. T., Bertini, E., Carrozzo, R., Martinelli, D., Dionisi-Vici, C., Chapman, K. A., Enns, G. M., Gahl, W., Wolfe, L., Saneto, R. P., Johnson, S. C., Trimmer, J. K., Klein, M. B., Holst, C. R. 2019; 14 (3)
  • Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review. American journal of medical genetics. Part A Kumar, A., Zastrow, D. B., Kravets, E. J., Beleford, D., Ruzhnikov, M. R., Grove, M. E., Dries, A. M., Kohler, J. N., Waggott, D. M., Yang, Y., Huang, Y., Undiagnosed Diseases Network, Mackenzie, K. M., Eng, C. M., Fisher, P. G., Ashley, E. A., Teng, J. M., Stevenson, D. A., Shieh, J. T., Wheeler, M. T., Bernstein, J. A. 2019

    Abstract

    Phacomatosis pigmentovascularis (PPV) comprises a family of rare conditions that feature vascular abnormalities and melanocytic lesions that can be solely cutaneous or multisystem in nature. Recently published work has demonstrated that both vascular and melanocytic abnormalities in PPV of the cesioflammea and cesiomarmorata subtypes can result from identical somatic mosaic activating mutations in the genes GNAQ and GNA11. Here, we present three new cases of PPV with features of the cesioflammea and/or cesiomarmorata subtypes and mosaic mutations in GNAQ or GNA11. To better understand the risk of potentially occult complications faced by such patients we additionally reviewed 176 cases published in the literature. We report the frequency of clinical findings, their patterns of co-occurrence as well as published recommendations for surveillance after diagnosis. Features assessed include: capillary malformation; dermal and ocular melanocytosis; glaucoma; limb asymmetry; venous malformations; and central nervous system (CNS) anomalies, such as ventriculomegaly and calcifications. We found that ocular findings are common in patients with phacomatosis cesioflammea and cesiomarmorata. Facial vascular involvement correlates with a higher risk of seizures (p=.0066). Our genetic results confirm the role of mosaic somatic mutations in GNAQ and GNA11 in phacomatosis cesioflammea and cesiomarmorata. Their clinical and molecular findings place these conditions on a clinical spectrum encompassing other GNAQ and GNA11 related disorders and inform recommendations for their management.

    View details for PubMedID 30920161

  • Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes. American journal of human genetics Burrage, L. C., Reynolds, J. J., Baratang, N. V., Phillips, J. B., Wegner, J., McFarquhar, A., Higgs, M. R., Christiansen, A. E., Lanza, D. G., Seavitt, J. R., Jain, M., Li, X., Parry, D. A., Raman, V., Chitayat, D., Chinn, I. K., Bertuch, A. A., Karaviti, L., Schlesinger, A. E., Earl, D., Bamshad, M., Savarirayan, R., Doddapaneni, H., Muzny, D., Jhangiani, S. N., Eng, C. M., Gibbs, R. A., Bi, W., Emrick, L., Rosenfeld, J. A., Postlethwait, J., Westerfield, M., Dickinson, M. E., Beaudet, A. L., Ranza, E., Huber, C., Cormier-Daire, V., Shen, W., Mao, R., Heaney, J. D., Orange, J. S., Bertola, D., Yamamoto, G. L., Baratela, W. A., Butler, M. G., Ali, A., Adeli, M., Cohn, D. H., Krakow, D., Jackson, A. P., Lees, M., Offiah, A. C., Carlston, C. M., Carey, J. C., Stewart, G. S., Bacino, C. A., Campeau, P. M., Lee, B. 2019; 104 (3): 422-438

    Abstract

    SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

    View details for DOI 10.1016/j.ajhg.2019.01.007

    View details for PubMedID 30773277

    View details for PubMedCentralID PMC6408318

  • Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy CIRCULATION-HEART FAILURE Parikh, V. N., Caleshu, C., Reuter, C., Lazzeroni, L. C., Ingles, J., Garcia, J., McCaleb, K., Adesiyun, T., Sedaghat-Hamedani, F., Kumar, S., Graw, S., Gigli, M., Stolfo, D., Dal Ferro, M., Ing, A. Y., Nussbaum, R., Funke, B., Wheeler, M. T., Hershberger, R. E., Cook, S., Steinmetz, L. M., Lakdawala, N. K., Taylor, M. G., Mestroni, L., Merlo, M., Sinagra, G., Semsarian, C., Meder, B., Judge, D. P., Ashley, E. 2019; 12 (3)
  • Time based versus strain based myocardial performance indices in hypertrophic cardiomyopathy, the merging role of left atrial strain EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING Kobayashi, Y., Moneghetti, K. J., Bouajila, S., Stolfo, D., Finocchiaro, G., Kuznetsova, T., Liang, D., Schnittger, I., Ashley, E., Wheeler, M., Haddad, F. 2019; 20 (3): 334–42
  • A Premature Termination Codon Mutation in MYBPC3 Causes Hypertrophic Cardiomyopathy via Chronic Activation of Nonsense-Mediated Decay CIRCULATION Seeger, T., Shrestha, R., Lam, C., Chen, C., McKeithan, W. L., Lau, E., Wnorowski, A., McMullen, G., Greenhaw, M., Lee, J., Oikonomopoulos, A., Lee, S., Yang, H., Mercola, M., Wheeler, M., Ashley, E. A., Yang, F., Karakikes, I., Wu, J. C. 2019; 139 (6): 799–811
  • Evolving Decisions: Perspectives of Active and Athletic Individuals with Inherited Heart Disease Who Exercise Against Recommendations JOURNAL OF GENETIC COUNSELING Subas, T., Luiten, R., Hanson-Kahn, A., Wheeler, M., Caleshu, C. 2019; 28 (1): 119-129
  • Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources NUCLEIC ACIDS RESEARCH Koehler, S., Carmody, L., Vasilevsky, N., Jacobsen, J. B., Danis, D., Gourdine, J., Gargano, M., Harris, N. L., Matentzoglu, N., McMurry, J. A., Osumi-Sutherland, D., Cipriani, V., Balhoff, J. P., Conlin, T., Blau, H., Baynam, G., Palmer, R., Gratian, D., Dawkins, H., Segal, M., Jansen, A. C., Muaz, A., Chang, W. H., Bergerson, J., Laulederkind, S. F., Yueksel, Z., Beltran, S., Freeman, A. F., Sergouniotis, P. I., Durkin, D., Storm, A. L., Hanauer, M., Brudno, M., Bello, S. M., Sincan, M., Rageth, K., Wheeler, M. T., Oegema, R., Lourghi, H., Della Rocca, M. G., Thompson, R., Castellanos, F., Priest, J., Cunningham-Rundles, C., Hegde, A., Lovering, R. C., Hajek, C., Olry, A., Notarangelo, L., Similuk, M., Zhang, X. A., Gomez-Andres, D., Lochmueller, H., Dollfus, H., Rosenzweig, S., Marwaha, S., Rath, A., Sullivan, K., Smith, C., Milner, J. D., Leroux, D., Boerkoel, C. F., Klion, A., Carter, M. C., Groza, T., Smedley, D., Haendel, M. A., Mungall, C., Robinson, P. N. 2019; 47 (D1): D1018–D1027
  • Approaching Higher Dimension Imaging Data Using Cluster-Based Hierarchical Modeling in Patients with Heart Failure Preserved Ejection Fraction. Scientific reports Kobayashi, Y. n., Tremblay-Gravel, M. n., Boralkar, K. A., Li, X. n., Nishi, T. n., Amsallem, M. n., Moneghetti, K. J., Bouajila, S. n., Selej, M. n., Ozen, M. O., Demirci, U. n., Ashley, E. n., Wheeler, M. n., Knowlton, K. U., Kouznetsova, T. n., Haddad, F. n. 2019; 9 (1): 10431

    Abstract

    Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality, accounting for the majority of heart failure (HF) hospitalization. To identify the most complementary predictors of mortality among clinical, laboratory and echocardiographic data, we used cluster based hierarchical modeling. Using Stanford Translational Research Database, we identified patients hospitalized with HFpEF between 2005 and 2016 in whom echocardiogram and NT-proBNP were both available at the time of admission. Comprehensive echocardiographic assessment including left ventricular longitudinal strain (LVLS), right ventricular function and right ventricular systolic pressure (RVSP) was performed. The outcome was defined as all-cause mortality. Among patients identified, 186 patients with complete echocardiographic assessment were included in the analysis. The cohort included 58% female, with a mean age of 78.7 ± 13.5 years, LVLS of -13.3 ± 2.5%, an estimated RVSP of 38 ± 13 mmHg. Unsupervised cluster analyses identified six clusters including ventricular systolic-function cluster, diastolic-hemodynamic cluster, end-organ function cluster, vital-sign cluster, complete blood count and sodium clusters. Using a stepwise hierarchical selection from each cluster, we identified NT-proBNP (standard hazard ratio [95%CI] = 1.56 [1.17-2.08]) and RVSP (1.37 [1.09-1.78]) as independent correlates of outcome. When adding these parameters to the well validated Get with the Guideline Heart Failure risk score, the Chi-square was significantly improved (p = 0.01). In conclusion, NT-proBNP and RVSP were independently predictive in HFpEF among clinical, imaging, and biomarker parameters. Cluster-based hierarchical modeling may help identify the complementally predictive parameters in small cohorts with higher dimensional clinical data.

    View details for DOI 10.1038/s41598-019-46873-7

    View details for PubMedID 31320698

  • Genomics in medicine: a novel elective rotation for internal medicine residents. Postgraduate medical journal Geng, L. N., Kohler, J. N., Levonian, P. n., Bernstein, J. A., Ford, J. M., Ahuja, N. n., Witteles, R. n., Hom, J. n., Wheeler, M. n. 2019

    Abstract

    It is well recognised that medical training globally and at all levels lacks sufficient incorporation of genetics and genomics education to keep up with the rapid advances and growing application of genomics to clinical care. However, the best strategy to implement these desired changes into postgraduate medical training and engage learners is still unclear. We developed a novel elective rotation in 'Genomic Medicine and Undiagnosed Diseases' for categorical Internal Medicine Residents to address this educational gap and serve as an adaptable model for training that can be applied broadly across different specialties and at other institutions. Key curriculum goals achieved include increased understanding about genetic testing modalities and tools available for diagnosis and risk analysis, the role of genetics-trained allied health professionals, and indications and limitations of genetic and genomic testing in both rare and common conditions.

    View details for DOI 10.1136/postgradmedj-2018-136355

    View details for PubMedID 31439813

  • Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation. The New England journal of medicine Perez, M. V., Mahaffey, K. W., Hedlin, H., Rumsfeld, J. S., Garcia, A., Ferris, T., Balasubramanian, V., Russo, A. M., Rajmane, A., Cheung, L., Hung, G., Lee, J., Kowey, P., Talati, N., Nag, D., Gummidipundi, S. E., Beatty, A., Hills, M. T., Desai, S., Granger, C. B., Desai, M., Turakhia, M. P., Apple Heart Study Investigators, Perez, M. V., Turakhia, M. P., Lhamo, K., Smith, S., Berdichesky, M., Sharma, B., Mahaffey, K., Parizo, J., Olivier, C., Nguyen, M., Tallapalli, S., Kaur, R., Gardner, R., Hung, G., Mitchell, D., Olson, G., Datta, S., Gerenrot, D., Wang, X., McCoy, P., Satpathy, B., Jacobsen, H., Makovey, D., Martin, A., Perino, A., O'Brien, C., Gupta, A., Toruno, C., Waydo, S., Brouse, C., Dorfman, D., Stein, J., Huang, J., Patel, M., Fleischer, S., Doll, E., O'Reilly, M., Dedoshka, K., Chou, M., Daniel, H., Crowley, M., Martin, C., Kirby, T., Brumand, M., McCrystale, K., Haggerty, M., Newberger, J., Keen, D., Antall, P., Holbrook, K., Braly, A., Noone, G., Leathers, B., Montrose, A., Kosowsky, J., Lewis, D., Finkelmeier, J. R., Bemis, K., Mahaffey, K. W., Desai, M., Talati, N., Nag, D., Rajmane, A., Desai, S., Caldbeck, D., Cheung, L., Granger, C., Rumsfeld, J., Kowey, P. R., Hills, M. T., Russo, A., Rockhold, F., Albert, C., Alonso, A., Wruck, L., Friday, K., Wheeler, M., Brodt, C., Park, S., Rogers, A., Jones, R., Ouyang, D., Chang, L., Yen, A., Dong, J., Mamic, P., Cheng, P., Shah, R., Lorvidhaya, P. 2019; 381 (20): 1909–17

    Abstract

    BACKGROUND: Optical sensors on wearable devices can detect irregular pulses. The ability of a smartwatch application (app) to identify atrial fibrillation during typical use is unknown.METHODS: Participants without atrial fibrillation (as reported by the participants themselves) used a smartphone (Apple iPhone) app to consent to monitoring. If a smartwatch-based irregular pulse notification algorithm identified possible atrial fibrillation, a telemedicine visit was initiated and an electrocardiography (ECG) patch was mailed to the participant, to be worn for up to 7 days. Surveys were administered 90 days after notification of the irregular pulse and at the end of the study. The main objectives were to estimate the proportion of notified participants with atrial fibrillation shown on an ECG patch and the positive predictive value of irregular pulse intervals with a targeted confidence interval width of 0.10.RESULTS: We recruited 419,297 participants over 8 months. Over a median of 117 days of monitoring, 2161 participants (0.52%) received notifications of irregular pulse. Among the 450 participants who returned ECG patches containing data that could be analyzed - which had been applied, on average, 13 days after notification - atrial fibrillation was present in 34% (97.5% confidence interval [CI], 29 to 39) overall and in 35% (97.5% CI, 27 to 43) of participants 65 years of age or older. Among participants who were notified of an irregular pulse, the positive predictive value was 0.84 (95% CI, 0.76 to 0.92) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular pulse notification and 0.71 (97.5% CI, 0.69 to 0.74) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular tachogram. Of 1376 notified participants who returned a 90-day survey, 57% contacted health care providers outside the study. There were no reports of serious app-related adverse events.CONCLUSIONS: The probability of receiving an irregular pulse notification was low. Among participants who received notification of an irregular pulse, 34% had atrial fibrillation on subsequent ECG patch readings and 84% of notifications were concordant with atrial fibrillation. This siteless (no on-site visits were required for the participants), pragmatic study design provides a foundation for large-scale pragmatic studies in which outcomes or adherence can be reliably assessed with user-owned devices. (Funded by Apple; Apple Heart Study ClinicalTrials.gov number, NCT03335800.).

    View details for DOI 10.1056/NEJMoa1901183

    View details for PubMedID 31722151

  • Athletic Remodeling in Female College Athletes: The "Morganroth Hypothesis" Revisited. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine Kooreman, Z. n., Giraldeau, G. n., Finocchiaro, G. n., Kobayashi, Y. n., Wheeler, M. n., Perez, M. n., Moneghetti, K. n., Oxborough, D. n., George, K. P., Myers, J. n., Ashley, E. n., Haddad, F. n. 2019; 29 (3): 224–31

    Abstract

    There is limited data regarding ventricular remodeling in college female athletes, especially when appropriate scaling of cardiac dimensions to lean body mass (LBM) is considered. Moreover, it is not well established whether cardiac remodeling in female athletes is a balanced process with proportional increase in left ventricular (LV) mass and volume or the right and LV size.During the preparticipation competitive screening, 72 female college athletes volunteered to undergo dual energy x-ray absorptiometry scan for quantification of LBM and comprehensive 2D echocardiography including assessment of longitudinal myocardial strain. The athletes were divided in 2 groups according to the intensity of the dynamic and static components of their sport categories, ie, a higher intensity dynamic and resistive group (n = 37 participating in rowing, water polo and lacrosse) and a lower intensity group (n = 35, participating in short distance running, sailing, synchronized swimming, and softball). In addition, we recruited a group of 31 age-matched nonathlete controls.The mean age of the study population was 18.7 ± 1.0 years. When scaled to body surface area, the higher intensity group had 17.1 ± 3.6% (P < 0.001) greater LV mass when compared with the lower intensity group and 21.7 ± 4.0% (P < 0.001) greater LV mass than the control group. The differences persisted after scaling to LBM with 14.2 ± 3.2% (P < 0.001) greater LV mass in the higher intensity group. By contrast, there was no difference in any of the relative remodeling indices including the LV mass to volume ratio, right to LV area ratio, or left atrial to LV volume ratio (P > 0.50 for all). In addition, no significant difference was noted among the 3 groups in LV ejection fraction (P = 0.22), LV global longitudinal strain (P = 0.55), LV systolic strain rate (P = 0.62), or right ventricular global longitudinal strain (P = 0.61).Female collegiate athletes participating in higher intensity dynamic and resistive sports have higher indexed LV mass even when scaled to LBM. The remodeling process does however appear to be a balanced process not only at the intraventricular level but also at the interventricular and atrioventricular levels.

    View details for PubMedID 31033616

  • A toolkit for genetics providers in follow-up of patients with non-diagnostic exome sequencing. Journal of genetic counseling Zastrow, D. B., Kohler, J. N., Bonner, D. n., Reuter, C. M., Fernandez, L. n., Grove, M. E., Fisk, D. G., Yang, Y. n., Eng, C. M., Ward, P. A., Bick, D. n., Worthey, E. A., Fisher, P. G., Ashley, E. A., Bernstein, J. A., Wheeler, M. T. 2019; 28 (2): 213–28

    Abstract

    There are approximately 7,000 rare diseases affecting 25-30 million Americans, with 80% estimated to have a genetic basis. This presents a challenge for genetics practitioners to determine appropriate testing, make accurate diagnoses, and conduct up-to-date patient management. Exome sequencing (ES) is a comprehensive diagnostic approach, but only 25%-41% of the patients receive a molecular diagnosis. The remaining three-fifths to three-quarters of patients undergoing ES remain undiagnosed. The Stanford Center for Undiagnosed Diseases (CUD), a clinical site of the Undiagnosed Diseases Network, evaluates patients with undiagnosed and rare diseases using a combination of methods including ES. Frequently these patients have non-diagnostic ES results, but strategic follow-up techniques identify diagnoses in a subset. We present techniques used at the CUD that can be adopted by genetics providers in clinical follow-up of cases where ES is non-diagnostic. Solved case examples illustrate different types of non-diagnostic results and the additional techniques that led to a diagnosis. Frequent approaches include segregation analysis, data reanalysis, genome sequencing, additional variant identification, careful phenotype-disease correlation, confirmatory testing, and case matching. We also discuss prioritization of cases for additional analyses.

    View details for PubMedID 30964584

  • A Patient with Sjogren's Syndrome and Subsequent Diagnosis of Inclusion Body Myositis and Light-Chain Amyloidosis. Journal of general internal medicine Hom, J. n., Marwaha, S. n., Postolova, A. n., Kittle, J. n., Vasquez, R. n., Davidson, J. n., Kohler, J. n., Dries, A. n., Fernandez-Betancourt, L. n., Majcherska, M. n., Dearlove, J. n., Raghavan, S. n., Vogel, H. n., Bernstein, J. A., Fisher, P. n., Ashley, E. n., Sampson, J. n., Wheeler, M. n. 2019

    Abstract

    We discuss a challenging case of a 58-year-old Vietnamese-American woman who presented to her new primary care provider with an 8-year history of slowly progressive dysphagia, hoarseness, muscle weakness with associated frequent falls, and weight loss. She eventually reported dry eyes and dry mouth, and she was diagnosed with Sjogren's syndrome. Subsequently, she was additionally diagnosed with inclusion body myositis and gastric light-chain (AL) amyloidosis. Although inclusion body myositis has been previously associated with Sjogren's syndrome, inclusion body myositis is rare in non-Caucasians, and the trio of Sjogren's syndrome, inclusion body myositis, and AL amyloidosis has not been previously reported. Sjogren's syndrome is a systemic autoimmune condition characterized by ocular and oral dryness. It is one of the most common rheumatologic disorders in the USA and worldwide. Early diagnosis of Sjogren's is particularly important given the frequency and variety of associated autoimmune diseases and extraglandular manifestations. Furthermore, although inclusion body myositis has a low prevalence, it is the most common inflammatory myopathy in older adults and is unfortunately associated with long delays in diagnosis, so knowledge of this disorder is also crucial for practicing internists.

    View details for PubMedID 30887439

  • Improving risk stratification in heart failure with preserved ejection fraction by combining two validated risk scores. Open heart Boralkar, K. A., Kobayashi, Y., Moneghetti, K. J., Pargaonkar, V. S., Tuzovic, M., Krishnan, G., Wheeler, M. T., Banerjee, D., Kuznetsova, T., Horne, B. D., Knowlton, K. U., Heidenreich, P. A., Haddad, F. 2019; 6 (1): e000961

    Abstract

    Introduction: The Intermountain Risk Score (IMRS) was developed and validated to predict short-term and long-term mortality in hospitalised patients using demographics and commonly available laboratory data. In this study, we sought to determine whether the IMRS also predicts all-cause mortality in patients hospitalised with heart failure with preserved ejection fraction (HFpEF) and whether it is complementary to the Get with the Guidelines Heart Failure (GWTG-HF) risk score or N-terminal pro-B-type natriuretic peptide (NT-proBNP).Methods and results: We used the Stanford Translational Research Integrated Database Environment to identify 3847 adult patients with a diagnosis of HFpEF between January 1998 and December 2016. Of these, 580 were hospitalised with a primary diagnosis of acute HFpEF. Mean age was 76±16 years, the majority being female (58%), with a high prevalence of diabetes mellitus (36%) and a history of coronary artery disease (60%). Over a median follow-up of 2.0 years, 140 (24%) patients died. On multivariable analysis, the IMRS and GWTG-HF risk score were independently associated with all-cause mortality (standardised HRs IMRS (1.55 (95% CI 1.27 to 1.93)); GWTG-HF (1.60 (95% CI 1.27 to 2.01))). Combining the two scores, improved the net reclassification over GWTG-HF alone by 36.2%. In patients with available NT-proBNP (n=341), NT-proBNP improved the net reclassification of each score by 46.2% (IMRS) and 36.3% (GWTG-HF).Conclusion: IMRS and GWTG-HF risk scores, along with NT-proBNP, play a complementary role in predicting outcome in patients hospitalised with HFpEF.

    View details for DOI 10.1136/openhrt-2018-000961

    View details for PubMedID 31217994

  • Defining genotype-phenotype relationships in patients with hypertrophic cardiomyopathy using cardiovascular magnetic resonance imaging. PloS one Miller, R. J., Heidary, S. n., Pavlovic, A. n., Schlachter, A. n., Dash, R. n., Fleischmann, D. n., Ashley, E. A., Wheeler, M. T., Yang, P. C. 2019; 14 (6): e0217612

    Abstract

    HCM is the most common inherited cardiomyopathy. Historically, there has been poor correlation between genotype and phenotype. However, CMR has the potential to more accurately assess disease phenotype. We characterized phenotype with CMR in a cohort of patients with confirmed HCM and high prevalence of genetic testing.Patients with a diagnosis of HCM, who had undergone contrast-enhanced CMR were identified. Left ventricular mass index (LVMI) and volumes were measured from steady-state free precession sequences. Late gadolinium enhancement (LGE) was quantified using the full width, half maximum method. All patients were prospectively followed for the development of septal reduction therapy, arrhythmia or death.We included 273 patients, mean age 51.2 ± 15.5, 62.9% male. Of those patients 202 (74.0%) underwent genetic testing with 90 pathogenic, likely pathogenic, or rare variants and 13 variants of uncertain significance identified. Median follow-up was 1138 days. Mean LVMI was 82.7 ± 30.6 and 145 patients had late gadolinium enhancement (LGE). Patients with beta-myosin heavy chain (MYH7) mutations had higher LV ejection fraction (68.8 vs 59.1, p<0.001) than those with cardiac myosin binding protein C (MYBPC3) mutations. Patients with MYBPC3 mutations were more likely to have LVEF < 55% (29.7% vs 4.9%, p = 0.005) or receive a defibrillator than those with MYH7 mutations (54.1% vs 26.8%, p = 0.020).We found that patients with MYBPC3 mutations were more likely to have impaired ventricular function and may be more prone to arrhythmic events. Larger studies using CMR phenotyping may be capable of identifying additional characteristics associated with less frequent genetic causes of HCM.

    View details for DOI 10.1371/journal.pone.0217612

    View details for PubMedID 31199839

  • Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure. Nature communications Cordero, P., Parikh, V. N., Chin, E. T., Erbilgin, A., Gloudemans, M. J., Shang, C., Huang, Y., Chang, A. C., Smith, K. S., Dewey, F., Zaleta, K., Morley, M., Brandimarto, J., Glazer, N., Waggott, D., Pavlovic, A., Zhao, M., Moravec, C. S., Tang, W. H., Skreen, J., Malloy, C., Hannenhalli, S., Li, H., Ritter, S., Li, M., Bernstein, D., Connolly, A., Hakonarson, H., Lusis, A. J., Margulies, K. B., Depaoli-Roach, A. A., Montgomery, S. B., Wheeler, M. T., Cappola, T., Ashley, E. A. 2019; 10 (1): 2760

    Abstract

    Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.

    View details for DOI 10.1038/s41467-019-10591-5

    View details for PubMedID 31235787

  • Developing a genomics rotation: Practical training around variant interpretation for genetic counseling students. Journal of genetic counseling Grove, M. E., White, S. n., Fisk, D. G., Rego, S. n., Dagan-Rosenfeld, O. n., Kohler, J. N., Reuter, C. M., Bonner, D. n., Wheeler, M. T., Bernstein, J. A., Ormond, K. E., Hanson-Kahn, A. K. 2019

    Abstract

    With the wide adoption of next-generation sequencing (NGS)-based genetic tests, genetic counselors require increased familiarity with NGS technology, variant interpretation concepts, and variant assessment tools. The use of exome and genome sequencing in clinical care has expanded the reach and diversity of genetic testing. Regardless of the setting where genetic counselors are performing variant interpretation or reporting, most of them have learned these skills from colleagues, while on the job. Though traditional, lecture-based learning around these topics is important, there has been growing need for the inclusion of case-based, experiential training of genomics and variant interpretation for genetic counseling students, with the goal of creating a strong foundation in variant interpretation for new genetic counselors, regardless of what area of practice they enter. To address this need, we established a genomics and variant interpretation rotation for Stanford's genetic counseling training program. In response to changes in the genomics landscape, this has now evolved into three unique rotation experiences, each focused on variant interpretation in the context of various genomic settings, including clinical laboratory, research laboratory, and healthy genomic analysis studies. Here, we describe the goals and learning objectives that we have developed for these variant interpretation rotations, and illustrate how these concepts are applied in practice.

    View details for PubMedID 30706981

  • The Incremental Value of Right Ventricular Size and Strain in the Risk Assessment of Right Heart Failure Post - Left Ventricular Assist Device Implantation. Journal of cardiac failure Aymami, M., Amsallem, M., Adams, J., Sallam, K., Moneghetti, K., Wheeler, M., Hiesinger, W., Teuteberg, J., Weisshaar, D., Verhoye, J., Woo, Y. J., Ha, R., Haddad, F., Banerjee, D. 2018; 24 (12): 823–32

    Abstract

    BACKGROUND: Right heart failure (RHF) after left ventricular assist device (LVAD) implantation is associated with high morbidity and mortality. Existing risk scores include semiquantitative evaluation of right ventricular (RV) dysfunction. This study aimed to determine whether quantitative evaluation of both RV size and function improve risk stratification for RHF after LVAD implantation beyond validated scores.METHODS AND RESULTS: From 2009 to 2015, 158 patients who underwent implantation of continuous-flow devices who had complete echocardiographic and hemodynamic data were included. Quantitative RV parameters included RV end-diastolic (RVEDAI) and end-systolic area index, RV free-wall longitudinal strain (RVLS), fractional area change, tricuspid annular plane systolic excursion, and right atrial area and pressure. Independent correlates of early RHF (<30 days) were determined with the use of logistic regression analysis. Mean age was 56 ± 13 years, with 79% male; 49% had INTERMACS profiles ≤2. RHF occurred in 60 patients (38%), with 20 (13%) requiring right ventricular assist device. On multivariate analysis, INTERMACS profiles (adjusted odds ratio 2.38 [95% confidence interval [CI] 1.47-3.85]), RVEDAI (1.61 [1.08-2.32]), and RVLS (2.72 [1.65-4.51]) were independent correlates of RHF (all P < .05). Both RVLS and RVEDAI were incremental to validated risk scores (including the EUROMACS score) for early RHF after LVAD (all P < .01).CONCLUSIONS: RV end-diastolic and strain are complementary prognostic markers of RHF after LVAD implantation.

    View details for PubMedID 30539717

  • The Incremental Value of Right Ventricular Size and Strain in the Risk Assessment of Right Heart Failure Post - Left Ventricular Assist Device Implantation JOURNAL OF CARDIAC FAILURE Aymami, M., Amsallem, M., Adams, J., Sallam, K., Moneghetti, K., Wheeler, M., Hiesinger, W., Teuteberg, J., Weisshaar, D., Verhoye, J., Woo, Y., Ha, R., Haddad, F., Banerjee, D. 2018; 24 (12): 823–32
  • Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease NEW ENGLAND JOURNAL OF MEDICINE Splinter, K., Adams, D. R., Bacino, C. A., Bellen, H. J., Bernstein, J. A., Cheatle-Jarvela, A. M., Eng, C. M., Esteves, C., Gahl, W. A., Hamid, R., Jacob, H. J., Kikani, B., Koeller, D. M., Kohane, I. S., Lee, B. H., Loscalzo, J., Luo, X., McCray, A. T., Metz, T. O., Mulvihill, J. J., Nelson, S. F., Palmer, C. S., Phillips, J. A., Pick, L., Postlethwait, J. H., Reuter, C., Shashi, V., Sweetser, D. A., Tifft, C. J., Walley, N. M., Wangler, M. F., Westerfield, M., Wheeler, M. T., Wise, A. L., Worthey, E. A., Yamamoto, S., Ashley, E. A., Undiagnosed Dis Network 2018; 379 (22): 2131–39
  • Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources. Nucleic acids research Kohler, S., Carmody, L., Vasilevsky, N., Jacobsen, J. O., Danis, D., Gourdine, J., Gargano, M., Harris, N. L., Matentzoglu, N., McMurry, J. A., Osumi-Sutherland, D., Cipriani, V., Balhoff, J. P., Conlin, T., Blau, H., Baynam, G., Palmer, R., Gratian, D., Dawkins, H., Segal, M., Jansen, A. C., Muaz, A., Chang, W. H., Bergerson, J., Laulederkind, S. J., Yuksel, Z., Beltran, S., Freeman, A. F., Sergouniotis, P. I., Durkin, D., Storm, A. L., Hanauer, M., Brudno, M., Bello, S. M., Sincan, M., Rageth, K., Wheeler, M. T., Oegema, R., Lourghi, H., Della Rocca, M. G., Thompson, R., Castellanos, F., Priest, J., Cunningham-Rundles, C., Hegde, A., Lovering, R. C., Hajek, C., Olry, A., Notarangelo, L., Similuk, M., Zhang, X. A., Gomez-Andres, D., Lochmuller, H., Dollfus, H., Rosenzweig, S., Marwaha, S., Rath, A., Sullivan, K., Smith, C., Milner, J. D., Leroux, D., Boerkoel, C. F., Klion, A., Carter, M. C., Groza, T., Smedley, D., Haendel, M. A., Mungall, C., Robinson, P. N. 2018

    Abstract

    The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes.

    View details for PubMedID 30476213

  • Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy. Parikh, V. N., Caleshu, C., Reuter, C., Lazzeroni, L., Ingles, J., Kumar, S., Garcia, J., McCaleb, K., Adesiyun, T., Dedaghat-Hamedani, F., Graw, S., Gigli, M., Stolfo, D., Dal Ferro, M., Ing, A., Nussbaum, R., Funke, B., Wheeler, M. T., Hershberger, R. E., Cook, S., Steinmetz, L., Lakdawala, N. K., Taylor, M. R., Mestroni, L., Merlo, M., Sinagra, G., Semsarian, C., Meder, B., Judge, D. P., Ashley, E. A. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Large Q and S waves in lead III on the electrocardiogram distinguish patients with hypertrophic cardiomyopathy from athletes HEART Chen, A. S., Bent, R. E., Wheeler, M., Knowles, J. W., Haddad, F., Froelicher, V., Ashley, E., Perez, M. V. 2018; 104 (22): 1871–77
  • A Premature Termination Codon Mutation in MYBPC3 Causes Hypertrophic Cardiomyopathy via Chronic Activation of Nonsense-Mediated Decay. Circulation Seeger, T., Shrestha, R., Lam, C. K., Chen, C., McKeithan, W. L., Lau, E., Wnorowski, A., McMullen, G., Greenhaw, M., Lee, J., Oikonomopoulos, A., Lee, S., Yang, H., Mercola, M., Wheeler, M., Ashley, E. A., Yang, F., Karakikes, I., Wu, J. C. 2018

    Abstract

    BACKGROUND: Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in myosin binding protein C3 ( MYBPC3) resulting in a premature termination codon (PTC). The underlying mechanisms of how PTC mutations in MYBPC3 lead to the onset and progression of HCM are poorly understood. This study's aim was to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with MYBPC3 PTC mutations by utilizing human isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).METHODS: Isogenic iPSC lines were generated from patients harboring MYBPC3 PTC mutations (p.R943x; p.R1073P_Fsx4) using genome editing and then differentiated into cardiomyocytes. Comprehensive phenotypical and transcriptome analyses were performed.RESULTS: We observed aberrant calcium handling properties with prolonged decay kinetics and elevated diastolic calcium levels in HCM iPSC-CMs compared to isogenic controls without structural abnormalities or contractile dysfunction. The mRNA expression levels of MYBPC3 were significantly reduced in mutant iPSC-CMs, but the protein levels were comparable among isogenic iPSC-CMs, suggesting that haploinsufficiency of MYBPC3 does not contribute to the pathogenesis of HCM in vitro. Furthermore, truncated MYBPC3 peptides were not detected. At the molecular level, the nonsense-mediated decay (NMD) pathway was activated, and a set of genes involved in major cardiac signaling pathways was dysregulated in HCM iPSC-CMs, indicating an HCM gene signature in vitro. Specific inhibition of the NMD pathway in mutant iPSC-CMs resulted in reversal of the molecular phenotype and normalization of calcium handling abnormalities.CONCLUSIONS: iPSC-CMs carrying MYBPC3 PTC mutations displayed aberrant calcium signaling and molecular dysregulations in the absence of significant haploinsufficiency of MYBPC3 protein. Here we provided the first evidence of the direct connection between the chronically activated NMD pathway and HCM disease development.

    View details for PubMedID 30586709

  • Evolving Decisions: Perspectives of Active and Athletic Individuals with Inherited Heart Disease Who Exercise Against Recommendations. Journal of genetic counseling Subas, T., Luiten, R., Hanson-Kahn, A., Wheeler, M., Caleshu, C. 2018

    Abstract

    Individuals with hypertrophic cardiomyopathy (HCM) and long QT syndrome (LQTS) are advised to avoid certain forms of exercise to reduce their risk of sudden death. Cardiovascular genetic counselors facilitate both adaptation to, and decision-making about, these exercise recommendations. This study describes decision-making and experiences of active adults who exercise above physicians' recommendations. Purposive sampling was used to select adults with HCM and LQTS who self-identified as exercising above recommendations. Semi-structured interviews explored participants' decision-making and the psychological impact of exercise recommendations. Fifteen individuals were interviewed (HCM: 10; LQTS: 5; mean age: 40). Transcripts were coded and analyzed for underlying themes. Despite exercising above recommendations, nearly all participants made some modifications to their prior exercise regimen. Often these decisions changed over time, underscoring the importance of shared decision-making conversations beyond the initial evaluation. The importance of exercise was frequently cited as a reason for continued exercise, as were perceptions of sudden death risk as low, acceptable, or modifiable. Many participants reported that family and friends supported their exercise decisions, with a minority having family or friends that expressed significant reservations. Genetic counselors, cardiologists, and nurses can use these data to inform their counseling regarding exercise recommendations.

    View details for PubMedID 30220053

  • Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy NEW ENGLAND JOURNAL OF MEDICINE Maurer, M. S., Schwartz, J. H., Gundapaneni, B., Elliott, P. M., Merlini, G., Waddington-Cruz, M., Kristen, A. V., Grogan, M., Witteles, R., Damy, T., Drachman, B. M., Shah, S. J., Hanna, M., Judge, D. P., Barsdorf, A. I., Huber, P., Patterson, T. A., Riley, S., Schumacher, J., Stewart, M., Sultan, M. B., Rapezzi, C., ATTR-ACT Study Investigators 2018; 379 (11): 1007–16
  • Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. The New England journal of medicine Maurer, M. S., Schwartz, J. H., Gundapaneni, B., Elliott, P. M., Merlini, G., Waddington-Cruz, M., Kristen, A. V., Grogan, M., Witteles, R., Damy, T., Drachman, B. M., Shah, S. J., Hanna, M., Judge, D. P., Barsdorf, A. I., Huber, P., Patterson, T. A., Riley, S., Schumacher, J., Stewart, M., Sultan, M. B., Rapezzi, C., ATTR-ACT Study Investigators 2018

    Abstract

    Background Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis. Methods In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status. Results In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups. Conclusions In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .).

    View details for PubMedID 30145929

  • Characteristics of undiagnosed diseases network applicants: implications for referring providers. BMC health services research Walley, N. M., Pena, L. D., Hooper, S. R., Cope, H., Jiang, Y. H., McConkie-Rosell, A., Sanders, C., Schoch, K., Spillmann, R. C., Strong, K., McCray, A. T., Mazur, P., Esteves, C., LeBlanc, K., Wise, A. L., Shashi, V. 2018; 18 (1): 652

    Abstract

    The majority of undiagnosed diseases manifest with objective findings that warrant further investigation. The Undiagnosed Diseases Network (UDN) receives applications from patients whose symptoms and signs have been intractable to diagnosis; however, many UDN applicants are affected primarily by subjective symptoms such as pain and fatigue. We sought to characterize presenting symptoms, referral sources, and demographic factors of applicants to the UDN to identify factors that may determine application outcome and potentially differentiate between those with undiagnosed diseases (with more objective findings) and those who are less likely to have an undiagnosed disease (more subjective symptoms).We used a systematic retrospective review of 151 consecutive Not Accepted and 50 randomly selected Accepted UDN applications. The primary outcome was whether an applicant was Accepted, or Not Accepted, and, if accepted, whether or not a diagnosis was made. Objective and subjective symptoms and information on prior specialty consultations were collected from provider referral letters. Demographic data and decision data on network acceptance were gathered from the UDN online portal.Fewer objective findings and more subjective symptoms were found in the Not Accepted applications. Not Accepted referrals also were from older individuals, reported a shorter period of illness, and were referred to the UDN by their primary care physicians. All of these differences reached statistical significance in comparison with Accepted applications. The frequency of subspecialty consults for diagnostic purposes prior to UDN application was similar in both groups.The preponderance of subjective and lack of objective findings in the Not Accepted applications distinguish these from applicants that are accepted for evaluation and diagnostic efforts through the UDN. Not Accepted applicants are referred primarily by their primary care providers after multiple specialist consultations fail to yield answers. Distinguishing between patients with undiagnosed diseases with objective findings and those with primarily subjective findings can delineate patients who would benefit from further diagnostic processes from those who may have functional disorders and need alternative pathways for management of their symptoms.clinicaltrials.gov NCT02450851 , posted May 21st 2015.

    View details for DOI 10.1186/s12913-018-3458-2

    View details for PubMedID 30134969

    View details for PubMedCentralID PMC6106923

  • Time based versus strain based myocardial performance indices in hypertrophic cardiomyopathy, the merging role of left atrial strain. European heart journal cardiovascular Imaging Kobayashi, Y., Moneghetti, K. J., Bouajila, S., Stolfo, D., Finocchiaro, G., Kuznetsova, T., Liang, D., Schnittger, I., Ashley, E., Wheeler, M., Haddad, F. 2018

    Abstract

    Aims: The myocardial performance index (MPI) is a time-based index of global myocardial performance. In this study, we sought to compare the prognostic value of the MPI with other strain and remodelling indices in hypertrophic cardiomyopathy (HCM).Methods and results: We enrolled 126 patients with HCM and 50 age- and sex-matched controls. Along with traditional echocardiographic assessment, MPI, left ventricular global longitudinal strain (LVGLS), E/e' ratio, and total left atrial (LA) global strain (LAS) were also measured. Time-based MPI was calculated from flow or tissue-based pulse wave Doppler (PWD and TDI) as the (isovolumic-relaxation and contraction time)/systolic-time. We used hierarchical clustering and network analysis to better visualize the relationship between parameters. The primary endpoint was the composite of all-cause death, heart transplantation, left ventricular assist device implantation, and clinical worsening. Left ventricular outflow tract (LVOT) obstruction was present in 56% of patients. Compared with controls, patients with HCM had worse LVGLS (-14.0±3.4% vs. -19.6±1.5%), higher E/e' (12.9±7.2 vs. 6.1±1.5), LA volume index (LAVI) (36.4±13.8ml/m2 vs. 25.6±6.7ml/m2), and MPI (0.55±0.17 vs. 0.40±0.11 for PWD and 0.59±0.22 vs. 0.46±0.09 for TDI) (all P<0.001). During a median follow-up of 55months, 47 endpoints occurred. PWD or TDI-based MPI was not associated with outcome, while LAVI, LAS, LVGLS, and E/e' were (all P<0.01). On multivariable analysis, LVOT obstruction (P<0.001), LAS (P<0.001), and E/e' (P=0.02) were retained as independent associates. They were in different clusters suggesting complemental relationship between them.Conclusion: Time-based index is less predictive of outcome than strain or tissue Doppler indices. LAS may be a promising prognostic marker in HCM.

    View details for PubMedID 30060097

  • Genome Sequencing in HypertrophicCardiomyopathy. Journal of the American College of Cardiology Ashley, E. A., Reuter, C. M., Wheeler, M. T. 2018; 72 (4): 430–33

    View details for PubMedID 30025579

  • Genome Sequencing in Hypertrophic Cardiomyopathy JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Ashley, E. A., Reuter, C. M., Wheeler, M. T. 2018; 72 (4): 430-433
  • Applying current normative data to prognosis in heart failure: The Fitness Registry and the Importance of Exercise National Database (FRIEND) INTERNATIONAL JOURNAL OF CARDIOLOGY Moneghetti, K. J., Hock, J., Kaminsky, L., Arena, R., Lui, G. K., Haddad, F., Wheeler, M., Froelicher, V., Ashley, E., Myers, J., Christle, J. W. 2018; 263: 75–79

    Abstract

    Percent of predicted peak VO2 (ppVO2) is considered a standard measure for establishing disease severity, however, there are known limitations to traditional normative values. This study sought to compare ppVO2 from the newly derived "Fitness Registry and the Importance of Exercise: a National Database" (FRIEND) registry equation to conventional prediction equations in a clinical cohort of patients undergoing cardiopulmonary exercise testing (CPX).We selected 1094 patients referred for evaluation of heart failure (HF) symptoms who underwent CPX. ppVO2 was calculated using the FRIEND, Wasserman/Hansen and Jones equations. Participants were followed for a median of 4.5 years [Interquartile range 3.5-6.0] for the composite endpoint of death, advanced HF therapy, or acute decompensated HF requiring hospital admission. Mean age was 48 ± 15 years and 62% were female. The FRIEND registry equation predicted the lowest ppVO2 (measured/predicted; 71 ± 31%), compared to the Wasserman/Hansen (74 ± 29%) and Jones equations (83 ± 33%) (p < 0.001). All expressions of peak VO2 were significant as univariate predictors of outcome with no significant differences between equations on pairwise analysis of receiver operating characteristic curves. When compared at a similar threshold of ppVO2 the event rate was significantly lower in the FRIEND registry equation versus the currently used Wasserman and Jones equations.The use of the newly derived FRIEND registry equation predicts HF outcomes; however, it appears to predict a higher predicted VO2; the clinical implication being a lower threshold of percent predicted peak VO2 should be considered when risk stratifying patients with HF.

    View details for PubMedID 29525067

  • Electrocardiographic left atrial abnormalities predict cardiovascular mortality JOURNAL OF ELECTROCARDIOLOGY Ha, L., Grober, A. F., Hock, J., Wheeler, M., Elbadawi, A., Biniwale, N., Baig, B., Froelicher, V. 2018; 51 (4): 652–57

    Abstract

    Clinical utilization of electrocardiography for diagnosis of left atrial abnormalities is hampered by variable P-wave morphologies, multiple empiric criteria, and lack of an imaging "gold standard". Our aim was to determine the prevalence of P-wave patterns and demonstrate which components have associations with cardiovascular death (CVD).This is a retrospective analysis of 20,827 veterans <56 years of age who underwent electrocardiograms at a Veteran's Affairs Medical Center from 1987 to 1999, followed for a median duration of 17.8 years for CVD. Receiver Operating Characteristic, Kaplan-Meier and Cox Hazard analyses were applied, the latter with adjustment for age, gender and electrocardiography abnormalities.The mean age was 43.3 ± 8 years, and 888 CVD (4.3%) occurred. A single positive deflection of the P-wave (Pattern 1) was present in 29% for V1 and 81% for V2. A singular negative P-wave (Pattern 2) was present in 4.6% for V1 and 1.6% in V2. A P-wave with an upward component followed by downward component (Pattern 3) was present in 64.5% for V1 and 17.5% for V2. When the downward component in Patterns 2 and/or 3 is at least -100 μV, a significant association is observed with CVD (adjusted hazard ratios [HRs] 2.9-4.1, P < 0.001). Total P-wave duration ≥140 ms was also associated with CVD (adjusted HR 2.2, P < 0.001).A negative P-wave in V1 or V2 ≤-100 μV, and P-wave with a duration of ≥140 ms, all have independent and significant associations with CVD, with HRs comparable to other electrocardiography abnormalities.

    View details for PubMedID 29997006

  • A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative. Genetics in medicine : official journal of the American College of Medical Genetics Shashi, V., Schoch, K., Spillmann, R., Cope, H., Tan, Q. K., Walley, N., Pena, L., McConkie-Rosell, A., Jiang, Y. H., Stong, N., Need, A. C., Goldstein, D. B. 2018

    Abstract

    Sixty to seventy-five percent of individuals with rare and undiagnosed phenotypes remain undiagnosed after exome sequencing (ES). With standard ES reanalysis resolving 10-15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals.In 38 ES negative patients an individualized genomic-phenotypic approach was employed utilizing (1) phenotyping; (2) reanalyses of FASTQ files, with innovative bioinformatics; (3) targeted molecular testing; (4) genome sequencing (GS); and (5) conferring of clinical diagnoses when pathognomonic clinical findings occurred.Certain and highly likely diagnoses were made in 18/38 (47%) individuals, including identifying two new developmental disorders. The majority of diagnoses (>70%) were due to our bioinformatics, phenotyping, and targeted testing identifying variants that were undetected or not prioritized on prior ES. GS diagnosed 3/18 individuals with structural variants not amenable to ES. Additionally, tentative diagnoses were made in 3 (8%), and in 5 individuals (13%) candidate genes were identified. Overall, diagnoses/potential leads were identified in 26/38 (68%).Our comprehensive approach to ES negatives maximizes the ES and clinical data for both diagnoses and candidate gene identification, without GS in the majority. This iterative approach is cost-effective and is pertinent to the current conundrum of ES negatives.

    View details for DOI 10.1038/s41436-018-0044-2

    View details for PubMedID 29907797

  • Large Q and S waves in lead III on the electrocardiogram distinguish patients with hypertrophic cardiomyopathy from athletes. Heart (British Cardiac Society) Chen, A. S., Bent, R. E., Wheeler, M., Knowles, J. W., Haddad, F., Froelicher, V., Ashley, E., Perez, M. V. 2018

    Abstract

    OBJECTIVE: To identify electrocardiographic findings, especially deep Q and S waves in lead III, that differentiate athletes from patients with hypertrophic cardiomyopathy (HCM).METHODS: Digital ECGs of athletes and patients with HCM followed at the Stanford Center for Inherited Cardiovascular Disease were studied retrospectively. All patients with HCM had an echocardiogram performed. A multivariable logistic regression model was used to calculate ORs for various demographic and ECG characteristics. Linear regression was used to correlate ECG characteristics with echocardiogram findings.RESULTS: We studied 1124 athletes and 240 patients with HCM. The average Q+Swave amplitude in lead III (IIIQ+S) was significantly higher in patients with HCM compared with athletes (0.71±0.69mV vs 0.21±0.17mV, p<0.001). In patients with HCM, IIIQ+S directly correlated with interventricular septal (IVS) thickness on echocardiography (rho=0.45, p<0.001). In a multivariable analysis adjusted for demographic and ECG characteristics, higher IIIQ+S values remained independently associated with HCM compared with athletes (OR=4.2 per 0.5mV, p<0.001). In subgroup analyses of young patients, African-American subjects and subjects without left axis deviation (LAD), IIIQ+S remained associated with HCM. The addition of IIIQ+S>1.0 mV as an abnormal finding to the International Criteria for athletic ECG interpretation improved sensitivity from 64.2% to 70.4%, with a minimal decrease in specificity.CONCLUSION: Large Q and S waves in lead III distinguished athletes from patients with HCM, independent of axis and well-known ECG markers associated with HCM. The correlation between IVS thickness in patients with HCM and IIIQ+S suggests a partial explanation for this association.

    View details for PubMedID 29680808

  • Athletic Remodeling in Female College Athletes, the "Morganroth Hypothesis" Revisited. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine Kooreman, Z. n., Giraldeau, G. n., Finocchiaro, G. n., Kobayashi, Y. n., Wheeler, M. n., Perez, M. n., Moneghetti, K. n., Oxborough, D. n., George, K. P., Myers, J. n., Ashley, E. n., Haddad, F. n. 2018

    Abstract

    There is limited data regarding ventricular remodeling in college female athletes, especially when appropriate scaling of cardiac dimensions to lean body mass (LBM) is considered. Moreover, it is not well established whether cardiac remodeling in female athletes is a balanced process with proportional increase in left ventricular (LV) mass and volume or the right and LV size.During the preparticipation competitive screening, 72 female college athletes volunteered to undergo dual energy x-ray absorptiometry scan for quantification of LBM and comprehensive 2D echocardiography including assessment of longitudinal myocardial strain. The athletes were divided in 2 groups according to the intensity of the dynamic and static components of their sport categories, ie, a higher intensity dynamic and resistive group (n = 37 participating in rowing, water polo and lacrosse) and a lower intensity group (n = 35, participating in short distance running, sailing, synchronized swimming, and softball). In addition, we recruited a group of 31 age-matched nonathlete controls.The mean age of the study population was 18.7 ± 1.0 years. When scaled to body surface area, the higher intensity group had 17.1 ± 3.6% (P < 0.001) greater LV mass when compared with the lower intensity group and 21.7 ± 4.0% (P < 0.001) greater LV mass than the control group. The differences persisted after scaling to LBM with 14.2 ± 3.2% (P < 0.001) greater LV mass in the higher intensity group. By contrast, there was no difference in any of the relative remodeling indices including the LV mass to volume ratio, right to LV area ratio, or left atrial to LV volume ratio (P > 0.50 for all). In addition, no significant difference was noted among the 3 groups in LV ejection fraction (P = 0.22), LV global longitudinal strain (P = 0.55), LV systolic strain rate (P = 0.62), or right ventricular global longitudinal strain (P = 0.61).Female collegiate athletes participating in higher intensity dynamic and resistive sports have higher indexed LV mass even when scaled to LBM. The remodeling process does however appear to be a balanced process not only at the intraventricular level but also at the interventricular and atrioventricular levels.

    View details for PubMedID 29369833

  • Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases. Genetics in medicine : official journal of the American College of Medical Genetics Pena, L. D., Jiang, Y. H., Schoch, K. n., Spillmann, R. C., Walley, N. n., Stong, N. n., Rapisardo Horn, S. n., Sullivan, J. A., McConkie-Rosell, A. n., Kansagra, S. n., Smith, E. C., El-Dairi, M. n., Bellet, J. n., Keels, M. A., Jasien, J. n., Kranz, P. G., Noel, R. n., Nagaraj, S. K., Lark, R. K., Wechsler, D. S., Del Gaudio, D. n., Leung, M. L., Hendon, L. G., Parker, C. C., Jones, K. L., Goldstein, D. B., Shashi, V. n. 2018; 20 (4): 464–69

    Abstract

    PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.

    View details for DOI 10.1038/gim.2017.128

    View details for PubMedID 28914269

    View details for PubMedCentralID PMC5851806

  • ClinPhen extracts and prioritizes patient phenotypes directly from medical records to expedite genetic disease diagnosis. Genetics in medicine : official journal of the American College of Medical Genetics Deisseroth, C. A., Birgmeier, J. n., Bodle, E. E., Kohler, J. N., Matalon, D. R., Nazarenko, Y. n., Genetti, C. A., Brownstein, C. A., Schmitz-Abe, K. n., Schoch, K. n., Cope, H. n., Signer, R. n., Martinez-Agosto, J. A., Shashi, V. n., Beggs, A. H., Wheeler, M. T., Bernstein, J. A., Bejerano, G. n. 2018

    Abstract

    Diagnosing monogenic diseases facilitates optimal care, but can involve the manual evaluation of hundreds of genetic variants per case. Computational tools like Phrank expedite this process by ranking all candidate genes by their ability to explain the patient's phenotypes. To use these tools, busy clinicians must manually encode patient phenotypes from lengthy clinical notes. With 100 million human genomes estimated to be sequenced by 2025, a fast alternative to manual phenotype extraction from clinical notes will become necessary.We introduce ClinPhen, a fast, high-accuracy tool that automatically converts clinical notes into a prioritized list of patient phenotypes using Human Phenotype Ontology (HPO) terms.ClinPhen shows superior accuracy and 20× speedup over existing phenotype extractors, and its novel phenotype prioritization scheme improves the performance of gene-ranking tools.While a dedicated clinician can process 200 patient records in a 40-hour workweek, ClinPhen does the same in 10 minutes. Compared with manual phenotype extraction, ClinPhen saves an additional 3-5 hours per Mendelian disease diagnosis. Providers can now add ClinPhen's output to each summary note attached to a filled testing laboratory request form. ClinPhen makes a substantial contribution to improvements in efficiency critically needed to meet the surging demand for clinical diagnostic sequencing.

    View details for PubMedID 30514889

  • A New Approach to Rare Diseases of Children: The Undiagnosed Diseases Network. The Journal of pediatrics Reuter, C. M., Brimble, E. n., DeFilippo, C. n., Dries, A. M., Enns, G. M., Ashley, E. A., Bernstein, J. A., Fisher, P. G., Wheeler, M. T. 2018

    View details for PubMedID 29331327

  • PHACOMATOSIS PIGMENTOVASCULARIS: A CASE WITH SOMATIC MUTATION IN GNAQ AND ATYPICAL PHENOTYPIC FEATURES Kumar, A., Zastrow, D., Prybol, C., Manning, M., Huang, Y., Fisher, P., Ashley, E., Teng, J., Wheeler, M., Bernstein, J. BMJ PUBLISHING GROUP. 2018: 202
  • Toward Genetics-Driven Early Intervention in Dilated Cardiomyopathy: Design and Implementation of the DCM Precision Medicine Study CIRCULATION-CARDIOVASCULAR GENETICS Kinnamon, D. D., Morales, A., Bowen, D. J., Burke, W., Hershberger, R. E., DCM Consortium 2017; 10 (6)

    Abstract

    The cause of idiopathic dilated cardiomyopathy (DCM) is unknown by definition, but its familial subtype is considered to have a genetic component. We hypothesize that most idiopathic DCM, whether familial or nonfamilial, has a genetic basis, in which case a genetics-driven approach to identifying at-risk family members for clinical screening and early intervention could reduce morbidity and mortality.On the basis of this hypothesis, we have launched the National Heart, Lung, and Blood Institute- and National Human Genome Research Institute-funded DCM Precision Medicine Study, which aims to enroll 1300 individuals (600 non-Hispanic African ancestry, 600 non-Hispanic European ancestry, and 100 Hispanic) who meet rigorous clinical criteria for idiopathic DCM along with 2600 of their relatives. Enrolled relatives will undergo clinical cardiovascular screening to identify asymptomatic disease, and all individuals with idiopathic DCM will undergo exome sequencing to identify relevant variants in genes previously implicated in DCM. Results will be returned by genetic counselors 12 to 14 months after enrollment. The data obtained will be used to describe the prevalence of familial DCM among idiopathic DCM cases and the genetic architecture of idiopathic DCM in multiple ethnicity-ancestry groups. We will also conduct a randomized controlled trial to test the effectiveness of Family Heart Talk, an intervention to aid family communication, for improving uptake of preventive screening and surveillance in at-risk first-degree relatives.We anticipate that this study will demonstrate that idiopathic DCM has a genetic basis and guide best practices for a genetics-driven approach to early intervention in at-risk relatives.URL: http://www.clinicaltrials.gov. Unique identifier: NCT03037632.

    View details for DOI 10.1161/CIRCGENETICS.117.001826

    View details for Web of Science ID 000418461400018

    View details for PubMedID 29237686

    View details for PubMedCentralID PMC5842914

  • Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research GENETICS Wangler, M. F., Yamamoto, S., Chao, H., Posey, J. E., Westerfield, M., Postlethwait, J., Hieter, P., Boycott, K. M., Campeau, P. M., Bellen, H. J., UDN 2017; 207 (1): 9-27

    Abstract

    Efforts to identify the genetic underpinnings of rare undiagnosed diseases increasingly involve the use of next-generation sequencing and comparative genomic hybridization methods. These efforts are limited by a lack of knowledge regarding gene function, and an inability to predict the impact of genetic variation on the encoded protein function. Diagnostic challenges posed by undiagnosed diseases have solutions in model organism research, which provides a wealth of detailed biological information. Model organism geneticists are by necessity experts in particular genes, gene families, specific organs, and biological functions. Here, we review the current state of research into undiagnosed diseases, highlighting large efforts in North America and internationally, including the Undiagnosed Diseases Network (UDN) (Supplemental Material, File S1) and UDN International (UDNI), the Centers for Mendelian Genomics (CMG), and the Canadian Rare Diseases Models and Mechanisms Network (RDMM). We discuss how merging human genetics with model organism research guides experimental studies to solve these medical mysteries, gain new insights into disease pathogenesis, and uncover new therapeutic strategies.

    View details for DOI 10.1534/genetics.117.203067

    View details for Web of Science ID 000409179800002

    View details for PubMedID 28874452

    View details for PubMedCentralID PMC5586389

  • Exercise for Patients With Hypertrophic Cardiomyopathy Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Saberi, S., Wheeler, M., Day, S. M. 2017; 318 (5): 481–82

    View details for PubMedID 28763545

  • Incremental value of right heart metrics and exercise performance to well-validated risk scores in dilated cardiomyopathy. European heart journal cardiovascular Imaging Moneghetti, K. J., Giraldeau, G., Wheeler, M. T., Kobayashi, Y., Vrtovec, B., Boulate, D., Kuznetsova, T., Schnittger, I., Wu, J. C., Myers, J., Ashley, E., Haddad, F. 2017

    Abstract

    Risk stratification in heart failure (HF) relies on several established clinical risk scores, however, myocardial deformation, right heart metrics, and exercise performance have not usually been considered. This study sought to assess the incremental value of advanced echocardiographic and cardiopulmonary exercise testing (CPX) parameters to validated risk scores in HF.The Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) and Metabolic Exercise Test Data Combined with Cardiac and Kidney Indexes (MECKI) scores were applied to 208 ambulatory patients with dilated cardiomyopathy (DCM) who completed echocardiography in conjunction with CPX as part of the Stanford Exercise Testing registry. Patients were followed for the composite end point of death, heart transplant, left ventricular device implantation, and hospitalization for acute HF. Mean age, left ventricular ejection fraction (LVEF), and left ventricular global longitudinal strain (LVGLS) were 47 ± 13 years, 33 ± 13%, and -10.6 ± 4.4%, respectively, while right ventricular free-wall longitudinal strain was -18.8 ± 5.5%. Partial correlation mapping identified strong correlations between LVEF, LVGLS, and LV systolic strain rate, with a moderate correlation between these metrics and peak VO2. Over a median follow up of 5.3 years, the composite end point occurred in 60 patients. Cox proportional hazards identified MAGGIC score [hazard ratio (HR) (2.04 [1.39-3.01], P < 0.01], peak VO2 HR (0.52 [0.28-0.97], P = 0.04), and right atrial volume indexed (RAVI) HR (1.31 [1.07-1.61], P < 0.01) as independent correlates of outcome. RAVI remained an independent correlate when combined with the MECKI score (2.21 [1.59-3.07]), P < 0.01, RAVI, 1.33 [1.06-1.67], P = 0.01).Our study demonstrates that RAVI is complementary to well-validated HF risk scores and highlights the importance of exercise performance in DCM.

    View details for DOI 10.1093/ehjci/jex187

    View details for PubMedID 28977353

  • Repeats and Survival in Myotonic Dystrophy Type 1. Circulation. Cardiovascular genetics Wheeler, M. T. 2017; 10 (3)

    View details for DOI 10.1161/CIRCGENETICS.117.001783

    View details for PubMedID 28611033

  • MARRVEL: Integration of Human and Model Organism Genetic Resources to Facilitate Functional Annotation of the Human Genome. American journal of human genetics Wang, J., Al-Ouran, R., Hu, Y., Kim, S. Y., Wan, Y. W., Wangler, M. F., Yamamoto, S., Chao, H. T., Comjean, A., Mohr, S. E., Perrimon, N., Liu, Z., Bellen, H. J. 2017; 100 (6): 843-853

    Abstract

    One major challenge encountered with interpreting human genetic variants is the limited understanding of the functional impact of genetic alterations on biological processes. Furthermore, there remains an unmet demand for an efficient survey of the wealth of information on human homologs in model organisms across numerous databases. To efficiently assess the large volume of publically available information, it is important to provide a concise summary of the most relevant information in a rapid user-friendly format. To this end, we created MARRVEL (model organism aggregated resources for rare variant exploration). MARRVEL is a publicly available website that integrates information from six human genetic databases and seven model organism databases. For any given variant or gene, MARRVEL displays information from OMIM, ExAC, ClinVar, Geno2MP, DGV, and DECIPHER. Importantly, it curates model organism-specific databases to concurrently display a concise summary regarding the human gene homologs in budding and fission yeast, worm, fly, fish, mouse, and rat on a single webpage. Experiment-based information on tissue expression, protein subcellular localization, biological process, and molecular function for the human gene and homologs in the seven model organisms are arranged into a concise output. Hence, rather than visiting multiple separate databases for variant and gene analysis, users can obtain important information by searching once through MARRVEL. Altogether, MARRVEL dramatically improves efficiency and accessibility to data collection and facilitates analysis of human genes and variants by cross-disciplinary integration of 18 million records available in public databases to facilitate clinical diagnosis and basic research.

    View details for DOI 10.1016/j.ajhg.2017.04.010

    View details for PubMedID 28502612

    View details for PubMedCentralID PMC5670038

  • Accuracy in Wrist-Worn, Sensor-Based Measurements of Heart Rate and Energy Expenditure in a Diverse Cohort JOURNAL OF PERSONALIZED MEDICINE Shcherbina, A., Mattsson, C., Waggott, D., Salisbury, H., Christle, J. W., Hastie, T., Wheeler, M. T., Ashley, E. A. 2017; 7 (2)

    View details for DOI 10.3390/jpm7020003

    View details for Web of Science ID 000457946800001

  • Repeats and Survival in Myotonic Dystrophy Type 1 CIRCULATION-CARDIOVASCULAR GENETICS Wheeler, M. T. 2017; 10 (3)
  • Accuracy in Wrist-Worn, Sensor-Based Measurements of Heart Rate and Energy Expenditure in a Diverse Cohort. Journal of personalized medicine Shcherbina, A., Mattsson, C. M., Waggott, D., Salisbury, H., Christle, J. W., Hastie, T., Wheeler, M. T., Ashley, E. A. 2017; 7 (2)

    Abstract

    The ability to measure physical activity through wrist-worn devices provides an opportunity for cardiovascular medicine. However, the accuracy of commercial devices is largely unknown. The aim of this work is to assess the accuracy of seven commercially available wrist-worn devices in estimating heart rate (HR) and energy expenditure (EE) and to propose a wearable sensor evaluation framework. We evaluated the Apple Watch, Basis Peak, Fitbit Surge, Microsoft Band, Mio Alpha 2, PulseOn, and Samsung Gear S2. Participants wore devices while being simultaneously assessed with continuous telemetry and indirect calorimetry while sitting, walking, running, and cycling. Sixty volunteers (29 male, 31 female, age 38 ± 11 years) of diverse age, height, weight, skin tone, and fitness level were selected. Error in HR and EE was computed for each subject/device/activity combination. Devices reported the lowest error for cycling and the highest for walking. Device error was higher for males, greater body mass index, darker skin tone, and walking. Six of the devices achieved a median error for HR below 5% during cycling. No device achieved an error in EE below 20 percent. The Apple Watch achieved the lowest overall error in both HR and EE, while the Samsung Gear S2 reported the highest. In conclusion, most wrist-worn devices adequately measure HR in laboratory-based activities, but poorly estimate EE, suggesting caution in the use of EE measurements as part of health improvement programs. We propose reference standards for the validation of consumer health devices (http://precision.stanford.edu/).

    View details for DOI 10.3390/jpm7020003

    View details for PubMedID 28538708

  • Left atrial function and phenotypes in asymmetric hypertrophic cardiomyopathy. Echocardiography (Mount Kisco, N.Y.) Kobayashi, Y., Wheeler, M., Finocchiaro, G., Ariyama, M., Kobayashi, Y., Perez, M. V., Liang, D., Kuznetsova, T., Schnittger, I., Ashley, E., Haddad, F. 2017

    Abstract

    Few studies have analyzed changes in left atrial (LA) function associated with different phenotypes of asymmetric hypertrophic cardiomyopathy (HCM). We sought to demonstrate the association of impairments in LA function with disease phenotype in patients with obstructive and nonobstructive HCM.From Stanford Cardiomyopathy Registry, we randomly selected 50 age-/sex-matched healthy controls, 35 patients with nonobstructive HCM (HCM 1), 35 patients with obstructive HCM (HCM 2), and 35 patients with obstructive HCM requiring septal reduction therapy (HCM 3). Echocardiography was performed to evaluate left ventricular (LV) strain as well as LA function including LA emptying fraction and LA strain.The mean age was 51±14 years and 57% were male. LA volume index differed among all four predefined groups (25.6±6.7 mL/m(2) in controls, 32.2±13.3 mL/m(2) in HCM 1, 42.0±12.9 mL/m(2) in HCM 2, 52.4±15.2 mL/m(2) for HCM 3, and P<.05 all between groups). All measurement of LA function was impaired in patients with HCM than controls. Total and passive LA function was further impaired in HCM 2 or 3 compared with HCM 1, while active LA function was not different among the three groups. Among LV strains, only septal longitudinal strain differed among all groups (-18.5±1.9% in controls, -14.5±1.9% in HCM 1, -13.3±1.8% in HCM 2, -11.6±2.3% in HCM 3, and P<.05 all between groups).LA function was impaired in patients with HCM even in minimally symptomatic nonobstructive phenotype. Total and passive LA function was further impaired in patients with obstructive HCM.

    View details for DOI 10.1111/echo.13533

    View details for PubMedID 28370331

  • The Undiagnosed Diseases Network: Accelerating Discovery about Health and Disease AMERICAN JOURNAL OF HUMAN GENETICS Ramoni, R. B., Mulvihill, J. J., Adams, D. R., Allard, P., Ashley, E. A., Bernstein, J. A., Gahl, W. A., Hamid, R., Loscalzo, J., McCray, A. T., Shashi, V., Tifft, C. J., Wise, A. L. 2017; 100 (2): 185-192

    Abstract

    Diagnosis at the edges of our knowledge calls upon clinicians to be data driven, cross-disciplinary, and collaborative in unprecedented ways. Exact disease recognition, an element of the concept of precision in medicine, requires new infrastructure that spans geography, institutional boundaries, and the divide between clinical care and research. The National Institutes of Health (NIH) Common Fund supports the Undiagnosed Diseases Network (UDN) as an exemplar of this model of precise diagnosis. Its goals are to forge a strategy to accelerate the diagnosis of rare or previously unrecognized diseases, to improve recommendations for clinical management, and to advance research, especially into disease mechanisms. The network will achieve these objectives by evaluating patients with undiagnosed diseases, fostering a breadth of expert collaborations, determining best practices for translating the strategy into medical centers nationwide, and sharing findings, data, specimens, and approaches with the scientific and medical communities. Building the UDN has already brought insights to human and medical geneticists. The initial focus has been on data sharing, establishing common protocols for institutional review boards and data sharing, creating protocols for referring and evaluating patients, and providing DNA sequencing, metabolomic analysis, and functional studies in model organisms. By extending this precision diagnostic model nationally, we strive to meld clinical and research objectives, improve patient outcomes, and contribute to medical science.

    View details for DOI 10.1016/j.athg.2017.01.006

    View details for PubMedID 28157539

  • Simultaneous ramp right heart catheterization and echocardiography in a ReliantHeart left ventricular assist device. World journal of cardiology Banerjee, D., Dutt, D., Duclos, S., Sallam, K., Wheeler, M., Ha, R. 2017; 9 (1): 55-59

    Abstract

    Many clinicians caring for patients with continuous flow left ventricular assist devices (CF-LVAD) use ramp right heart catheterization (RHC) studies to optimize pump speed and also to troubleshoot CF-LVAD malfunction. An investigational device, the ReliantHeart Heart Assist 5 (Houston, TX), provides the added benefit of an ultrasonic flow probe on the outflow graft that directly measures flow through the CF-LVAD. We performed a simultaneous ramp RHC and echocardiogram on a patient who received the above CF-LVAD to optimize pump parameters and investigate elevated flow through the CF-LVAD as measured by the flow probe. We found that the patient's hemodynamics were optimized at their baseline pump speed, and that the measured cardiac output via the Fick principle was lower than that measured by the flow probe. Right heart catheterization may be useful to investigate discrepancies between flow measured by a CF-LVAD and a patient's clinical presentation, particularly in investigational devices where little clinical experience exists. More data is needed to elucidate the correlation between the flow measured by an ultrasonic probe and cardiac output as measured by RHC.

    View details for DOI 10.4330/wjc.v9.i1.55

    View details for PubMedID 28163837

    View details for PubMedCentralID PMC5253195

  • A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3. American journal of human genetics Chao, H. T., Davids, M., Burke, E., Pappas, J. G., Rosenfeld, J. A., McCarty, A. J., Davis, T., Wolfe, L., Toro, C., Tifft, C., Xia, F., Stong, N., Johnson, T. K., Warr, C. G., Yamamoto, S., Adams, D. R., Markello, T. C., Gahl, W. A., Bellen, H. J., Wangler, M. F., Malicdan, M. C. 2017; 100 (1): 128-137

    Abstract

    Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations.

    View details for DOI 10.1016/j.ajhg.2016.11.018

    View details for PubMedID 28017372

    View details for PubMedCentralID PMC5223093

  • in a patient with a complex connective tissue phenotype. Cold Spring Harbor molecular case studies Zastrow, D. B., Zornio, P. A., Dries, A., Kohler, J., Fernandez, L., Waggott, D., Walkiewicz, M., Eng, C. M., Manning, M. A., Farrelly, E., Fisher, P. G., Ashley, E. A., Bernstein, J. A., Wheeler, M. T. 2017; 3 (1)

    Abstract

    Here we describe a patient who presented with a history of congenital diaphragmatic hernia, inguinal hernia, and recurrent umbilical hernia. She also has joint laxity, hypotonia, and dysmorphic features. A unifying diagnosis was not identified based on her clinical phenotype. As part of her evaluation through the Undiagnosed Diseases Network, trio whole-exome sequencing was performed. Pathogenic variants in FBN1 and TRPS1 were identified as causing two distinct autosomal dominant conditions, each with de novo inheritance. Fibrillin 1 (FBN1) mutations are associated with Marfan syndrome and a spectrum of similar phenotypes. TRPS1 mutations are associated with trichorhinophalangeal syndrome types I and III. Features of both conditions are evident in the patient reported here. Discrepant features of the conditions (e.g., stature) and the young age of the patient may have made a clinical diagnosis more difficult in the absence of exome-wide genetic testing.

    View details for DOI 10.1101/mcs.a001388

    View details for PubMedID 28050602

  • Exome sequencing identifies de novo pathogenic variants in FBN1 and TRPS1 in a patient with a complex connective tissue phenotype COLD SPRING HARBOR MOLECULAR CASE STUDIES Zastrow, D. B., Zornio, P. A., Dries, A., Kohler, J., Fernandez, L., Waggott, D., Walkiewicz, M., Eng, C. M., Manning, M. A., Farrelly, E., Fisher, P. G., Ashley, E. A., Bernstein, J. A., Wheeler, M. T., Undiagnosed Dis Network 2017; 3 (1)
  • Value of Strain Imaging and Maximal Oxygen Consumption in Patients With Hypertrophic Cardiomyopathy. The American journal of cardiology Moneghetti, K. J., Stolfo, D. n., Christle, J. W., Kobayashi, Y. n., Finocchiaro, G. n., Sinagra, G. n., Myers, J. n., Ashley, E. A., Haddad, F. n., Wheeler, M. T. 2017; 120 (7): 1203–8

    Abstract

    Longitudinal strain (LS) has been shown to be predictive of outcome in hypertrophic cardiomyopathy (HC). Percent predicted peak oxygen uptake (ppVO2), among other cardiopulmonary exercise testing (CPX) metrics, is a strong predictor of prognosis in HC. However, there has been limited investigation into the combination of LS and CPX metrics. This study sought to determine how LS and parameters of exercise performance contribute to prognosis in HC. One hundred and thirty-one consecutive patients with HC who underwent CPX and stress echocardiography were included. Global, septal, and lateral LS were assessed at rest and stress. Eighty matched individuals were used as controls. Patients were followed for the composite end point of death and worsening heart failure. All absolute LS components were lower in patients with HC than in controls (global 14.3 ± 4.0% vs 18.8 ± 2.2%, p <0.001; septal 11.9 ± 4.9% vs 17.9 ± 2.7%, p <0.001; lateral 16.0 ± 4.7% vs 19.4 ± 3.1%, p = 0.001). Global strain reserve was also reduced in patients with HC (13 ± 5% vs 19 ± 8%, p = 0.002). Over a median follow-up of 56 months (interquartile range 14 to 69), the composite end point occurred in 53 patients. Global LS was predictive of outcome on univariate analysis (0.55 [0.41 to 0.74], p <0.001). When combined with CPX metrics, lateral LS was the only strain variable predictive of outcome along with indexed left atrial volume (LAVI) and ppVO2. The worst outcomes were observed for patients with lateral LS <16.1%, LAVI >52 ml/m2, and ppVO2 <80%. The combination of lateral LS, LAVI, and ppVO2 presents a simple model for outcome prediction.

    View details for PubMedID 28802509

  • Autoantibody profiling on a plasmonic nano-gold chip for the early detection of hypertensive heart disease. Proceedings of the National Academy of Sciences of the United States of America Li, X. n., Kuznetsova, T. n., Cauwenberghs, N. n., Wheeler, M. n., Maecker, H. n., Wu, J. C., Haddad, F. n., Dai, H. n. 2017; 114 (27): 7089–94

    Abstract

    The role of autoimmunity in cardiovascular (CV) diseases has been increasingly recognized. Autoimmunity is most commonly examined by the levels of circulating autoantibodies in clinical practices. Measurement of autoantibodies remains, however, challenging because of the deficiency of reproducible, sensitive, and standardized assays. The lack of multiplexed assays also limits the potential to identify a CV-specific autoantibody profile. To overcome these challenges, we developed a nanotechnology-based plasmonic gold chip for autoantibody profiling. This approach allowed simultaneous detection of 10 CV autoantibodies targeting the structural myocardial proteins, the neurohormonal regulatory proteins, the vascular proteins, and the proteins associated with apoptosis and coagulation. Autoantibodies were measured in four groups of participants across the continuum of hypertensive heart diseases. We observed higher levels of all 10 CV autoantibodies in hypertensive subjects (n= 77) compared with healthy participants (n= 30), and the autoantibodies investigated were related to each other, forming a highly linked network. In addition, we established that autoantibodies to troponin I, annexin-A5, and beta 1-adrenegic receptor best discriminated hypertensive subjects with adverse left ventricular (LV) remodeling or dysfunction (n= 49) from hypertensive subjects with normal LV structure and function (n= 28). By further linking these three significant CV autoantibodies to the innate and growth factors, we revealed a positive but weak association between autoantibodies to troponin I and proinflammatory cytokine IL-18. Overall, we demonstrated that this platform can be used to evaluate autoantibody profiles in hypertensive subjects at risk for heart failure.

    View details for PubMedID 28630342

  • Contractile reserve and cardiopulmonary exercise parameters in patients with dilated cardiomyopathy, the two dimensions of exercise testing. Echocardiography (Mount Kisco, N.Y.) Moneghetti, K. J., Kobayashi, Y. n., Christle, J. W., Ariyama, M. n., Vrtovec, B. n., Kouznetsova, T. n., Wilson, A. n., Ashley, E. n., Wheeler, M. T., Myers, J. n., Haddad, F. n. 2017

    Abstract

    Left ventricular (LV) contractile reserve assessed using imaging and cardiopulmonary exercise testing (CPX) has been shown to predict outcome in patients with dilated cardiomyopathy (DCM). Few clinical studies have, however, analyzed the relationship between them.A cohort of 75 ambulatory patients with DCM underwent stress treadmill echocardiography with CPX. LV contractile reserve was calculated as absolute change (ΔLVEF=LVEFpeak -LVEFrest ) and percent change (%LVEF=[(LVEFpeak -LVEFrest )/LVEFpeak) ]×100) in LVEF, circumferential and longitudinal strain (LS). Exercise capacity was measured as peak oxygen uptake (peak VO2 ) and ventilatory efficiency as the slope of minute ventilation to CO2 production (VE/VCO2 slope). Values of contractile reserve were compared to matched controls. We also explored which metric of ventricular response (absolute or percent change) was less dependent on baseline LV function.Patients with DCM had a mean age, rest and peak LVEF of 44±10 years, 42±10% and 50±12%, respectively. Among parameters of contractile reserve, peak cardiac output was the strongest parameter associated with peak VO2 (r=.63, P<.001). Along with age, sex, and BMI, it explained more than 70% of the variance in peak VO2 . In contrast, LVEF and LS were only weakly related to peak VO2 . With regard to ventilatory efficiency, the strongest parameter that emerged was right atrial volume index (r=.36, P<.001). Percent change in LVEF was more independent of baseline function than absolute change.Echocardiographic contractile reserve and CPX provide complementary information. Percent change in contractile reserve was most independent of baseline function, therefore may be preferred when analyzing the ventricular response to exercise.

    View details for PubMedID 28681553

  • Functional Cardiac Recovery and Hematologic Response to Chemotherapy in Patients With Light-Chain Amyloidosis (from the Stanford University Amyloidosis Registry). The American journal of cardiology Tuzovic, M. n., Kobayashi, Y. n., Wheeler, M. n., Barrett, C. n., Liedtke, M. n., Lafayette, R. n., Schrier, S. n., Haddad, F. n., Witteles, R. n. 2017; 120 (8): 1381–86

    Abstract

    Cardiac involvement is common in patients with light-chain (AL) amyloidosis and portends a poor prognosis, although little is known about the changes in cardiac mechanics after chemotherapy. We sought to explore the relation between amyloidosis staging and baseline cardiac mechanics and to investigate short-term changes in cardiac mechanics after chemotherapy. We identified 41 consecutive patients from the Stanford Amyloid Center who had echocardiograms and free light-chain values before and after chemotherapy, along with 40 age- and gender-matched controls. Echocardiographic assessment included left ventricular global longitudinal strain, E/e' ratio, and left atrial (LA) stiffness. Hematologic response to chemotherapy was defined as ≥50% reduction in the difference between the involved and the uninvolved free light chain (dFLC). The mean age was 66.9 ± 8.4 years and 66% were men. Before chemotherapy, global longitudinal strain, E/e' ratio, and LA stiffness were impaired in patients with amyloidosis compared with controls, and the severity of impairment worsened with advanced staging. After chemotherapy, hematologic response was observed in 30 (73%) patients. There was a significant association between the change in dFLC and cardiac function (E/e' ratio: r = -0.43, p = 0.01; LA stiffness: r = -0.35, p = 0.05). There was no significant improvement in cardiac mechanics in patients without a hematologic response to chemotherapy. In conclusion, amyloidosis stage correlated with noninvasive measurements of cardiac mechanics, and improvement in dFLC correlated with cardiac improvement on short-term follow-up echocardiography.

    View details for PubMedID 28844519

  • Incremental value of right heart metrics and exercise performance to well-validated risk scores in dilated cardiomyopathy European Heart Journal - Cardiovascular Imaging Moneghetti , K. J., Giraldeau, G., Wheeler, M. T., Kobayashi , Y., Vrtovec, B., Boulate, D., Kuznetsova, T., Schnittger, I., Wu, J. C., Myers, J., Ashely, E., Haddad , F. 2017

    View details for DOI 10.1093/ehjci/jex187

  • Long-read genome sequencing identifies causal structural variation in a Mendelian disease. Genetics in medicine : official journal of the American College of Medical Genetics Merker, J. D., Wenger, A. M., Sneddon, T. n., Grove, M. n., Zappala, Z. n., Fresard, L. n., Waggott, D. n., Utiramerur, S. n., Hou, Y. n., Smith, K. S., Montgomery, S. B., Wheeler, M. n., Buchan, J. G., Lambert, C. C., Eng, K. S., Hickey, L. n., Korlach, J. n., Ford, J. n., Ashley, E. A. 2017

    Abstract

    PurposeCurrent clinical genomics assays primarily utilize short-read sequencing (SRS), but SRS has limited ability to evaluate repetitive regions and structural variants. Long-read sequencing (LRS) has complementary strengths, and we aimed to determine whether LRS could offer a means to identify overlooked genetic variation in patients undiagnosed by SRS.MethodsWe performed low-coverage genome LRS to identify structural variants in a patient who presented with multiple neoplasia and cardiac myxomata, in whom the results of targeted clinical testing and genome SRS were negative.ResultsThis LRS approach yielded 6,971 deletions and 6,821 insertions > 50 bp. Filtering for variants that are absent in an unrelated control and overlap a disease gene coding exon identified three deletions and three insertions. One of these, a heterozygous 2,184 bp deletion, overlaps the first coding exon of PRKAR1A, which is implicated in autosomal dominant Carney complex. RNA sequencing demonstrated decreased PRKAR1A expression. The deletion was classified as pathogenic based on guidelines for interpretation of sequence variants.ConclusionThis first successful application of genome LRS to identify a pathogenic variant in a patient suggests that LRS has significant potential for the identification of disease-causing structural variation. Larger studies will ultimately be required to evaluate the potential clinical utility of LRS.GENETICS in MEDICINE advance online publication, 22 June 2017; doi:10.1038/gim.2017.86.

    View details for PubMedID 28640241

  • De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype. American journal of human genetics Shashi, V., Pena, L. D., Kim, K., Burton, B., Hempel, M., Schoch, K., Walkiewicz, M., McLaughlin, H. M., Cho, M., Stong, N., Hickey, S. E., Shuss, C. M., Freemark, M. S., Bellet, J. S., Keels, M. A., Bonner, M. J., El-Dairi, M., Butler, M., Kranz, P. G., Stumpel, C. T., Klinkenberg, S., Oberndorff, K., Alawi, M., Santer, R., Petrovski, S., Kuismin, O., Korpi-Heikkilä, S., Pietilainen, O., Aarno, P., Kurki, M. I., Hoischen, A., Need, A. C., Goldstein, D. B., Kortüm, F. 2016; 99 (4): 991-999

    Abstract

    The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder. In this study, we performed whole-exome sequencing in six unrelated probands with developmental delay, macrocephaly, and dysmorphic features. All six had de novo truncating variants in ASXL2. A careful review enabled the recognition of a specific phenotype consisting of macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, hypotonia, and developmental disabilities. Although overlapping features with Bohring-Opitz and Bainbridge-Ropers syndromes exist, features that distinguish the ASXL2-associated condition from ASXL1- and ASXL3-related disorders are macrocephaly, absence of growth retardation, and more variability in the degree of intellectual disabilities. We were also able to demonstrate with mRNA studies that these variants are likely to exert a dominant-negative effect, given that both alleles are expressed in blood and the mutated ASXL2 transcripts escape nonsense-mediated decay. In conclusion, de novo truncating variants in ASXL2 underlie a neurodevelopmental syndrome with a clinically recognizable phenotype. This report expands the germline disorders that are linked to the ASXL genes.

    View details for DOI 10.1016/j.ajhg.2016.08.017

    View details for PubMedID 27693232

    View details for PubMedCentralID PMC5065681

  • Exercise restrictions trigger psychological difficulty in active and athletic adults with hypertrophic cardiomyopathy OPEN HEART Luiten, R. C., Ormond, K., Post, L., Asif, I. M., Wheeler, M. T., Caleshu, C. 2016; 3 (2)
  • Sports genetics moving forward: lessons learned from medical research. Physiological genomics Mattsson, C. M., Wheeler, M. T., Waggott, D., Caleshu, C., Ashley, E. A. 2016; 48 (3): 175-182

    Abstract

    Sports genetics can take advantage of lessons learned from human disease genetics. By righting past mistakes and increasing scientific rigor, we can magnify the breadth and depth of knowledge in the field. We present an outline of challenges facing sports genetics in the light of experiences from medical research. Sports performance is complex, resulting from a combination of a wide variety of different traits and attributes. Improving sports genetics will foremost require analyses based on detailed phenotyping. To find widely valid, reproducible common variants associated with athletic phenotypes, study sample sizes must be dramatically increased. One paradox is that in order to confirm relevance, replications in specific populations must be undertaken. Family studies of athletes may facilitate the discovery of rare variants with large effects on athletic phenotypes. The complexity of the human genome, combined with the complexity of athletic phenotypes, will require additional metadata and biological validation to identify a comprehensive set of genes involved. Analysis of personal genetic and multiomic profiles contribute to our conceptualization of precision medicine; the same will be the case in precision sports science. In the refinement of sports genetics it is essential to evaluate similarities and differences between sexes and among ethnicities. Sports genetics to date have been hampered by small sample sizes and biased methodology, which can lead to erroneous associations and overestimation of effect sizes. Consequently, currently available genetic tests based on these inherently limited data cannot predict athletic performance with any accuracy.

    View details for DOI 10.1152/physiolgenomics.00109.2015

    View details for PubMedID 26757801

  • Athlome Project Consortium: a concerted effort to discover genomic and other "omic" markers of athletic performance. Physiological genomics Pitsiladis, Y. P., Tanaka, M., Eynon, N., Bouchard, C., North, K. N., Williams, A. G., Collins, M., Moran, C. N., Britton, S. L., Fuku, N., Ashley, E. A., Klissouras, V., Lucia, A., Ahmetov, I. I., de Geus, E., Alsayrafi, M. 2016; 48 (3): 183-190

    Abstract

    Despite numerous attempts to discover genetic variants associated with elite athletic performance, injury predisposition, and elite/world-class athletic status, there has been limited progress to date. Past reliance on candidate gene studies predominantly focusing on genotyping a limited number of single nucleotide polymorphisms or the insertion/deletion variants in small, often heterogeneous cohorts (i.e., made up of athletes of quite different sport specialties) have not generated the kind of results that could offer solid opportunities to bridge the gap between basic research in exercise sciences and deliverables in biomedicine. A retrospective view of genetic association studies with complex disease traits indicates that transition to hypothesis-free genome-wide approaches will be more fruitful. In studies of complex disease, it is well recognized that the magnitude of genetic association is often smaller than initially anticipated, and, as such, large sample sizes are required to identify the gene effects robustly. A symposium was held in Athens and on the Greek island of Santorini from 14-17 May 2015 to review the main findings in exercise genetics and genomics and to explore promising trends and possibilities. The symposium also offered a forum for the development of a position stand (the Santorini Declaration). Among the participants, many were involved in ongoing collaborative studies (e.g., ELITE, GAMES, Gene SMART, GENESIS, and POWERGENE). A consensus emerged among participants that it would be advantageous to bring together all current studies and those recently launched into one new large collaborative initiative, which was subsequently named the Athlome Project Consortium.

    View details for DOI 10.1152/physiolgenomics.00105.2015

    View details for PubMedID 26715623

    View details for PubMedCentralID PMC4773890

  • Medical implications of technical accuracy in genome sequencing. Genome medicine Goldfeder, R. L., Priest, J. R., Zook, J. M., Grove, M. E., Waggott, D., Wheeler, M. T., Salit, M., Ashley, E. A. 2016; 8 (1): 24-?

    Abstract

    As whole exome sequencing (WES) and whole genome sequencing (WGS) transition from research tools to clinical diagnostic tests, it is increasingly critical for sequencing methods and analysis pipelines to be technically accurate. The Genome in a Bottle Consortium has recently published a set of benchmark SNV, indel, and homozygous reference genotypes for the pilot whole genome NIST Reference Material based on the NA12878 genome.We examine the relationship between human genome complexity and genes/variants reported to be associated with human disease. Specifically, we map regions of medical relevance to benchmark regions of high or low confidence. We use benchmark data to assess the sensitivity and positive predictive value of two representative sequencing pipelines for specific classes of variation.We observe that the accuracy of a variant call depends on the genomic region, variant type, and read depth, and varies by analytical pipeline. We find that most false negative WGS calls result from filtering while most false negative WES variants relate to poor coverage. We find that only 74.6% of the exonic bases in ClinVar and OMIM genes and 82.1% of the exonic bases in ACMG-reportable genes are found in high-confidence regions. Only 990 genes in the genome are found entirely within high-confidence regions while 593 of 3,300 ClinVar/OMIM genes have less than 50% of their total exonic base pairs in high-confidence regions. We find greater than 77 % of the pathogenic or likely pathogenic SNVs currently in ClinVar fall within high-confidence regions. We identify sites that are prone to sequencing errors, including thousands present in publicly available variant databases. Finally, we examine the clinical impact of mandatory reporting of secondary findings, highlighting a false positive variant found in BRCA2.Together, these data illustrate the importance of appropriate use and continued improvement of technical benchmarks to ensure accurate and judicious interpretation of next-generation DNA sequencing results in the clinical setting.

    View details for DOI 10.1186/s13073-016-0269-0

    View details for PubMedID 26932475

    View details for PubMedCentralID PMC4774017

  • Systems Genomics Identifies a Key Role for Hypocretin/Orexin Receptor-2 in Human Heart Failure JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Perez, M. V., Pavlovic, A., Shang, C., Wheeler, M. T., Miller, C. L., Liu, J., Dewey, F. E., Pan, S., Thanaporn, P. K., Absher, D., Brandimarto, J., Salisbury, H., Chan, K., Mukherjee, R., Konadhode, R. P., Myers, R. M., Sedehi, D., Scammell, T. E., Quertermous, T., Cappola, T., Ashley, E. A. 2015; 66 (22): 2522-2533

    Abstract

    The genetic determinants of heart failure (HF) and response to medical therapy remain unknown. We hypothesized that identifying genetic variants of HF that associate with response to medical therapy would elucidate the genetic basis of cardiac function.This study sought to identify genetic variations associated with response to HF therapy.This study compared extremes of response to medical therapy in 866 HF patients using a genome-wide approach that informed the systems-based design of a customized single nucleotide variant array. The effect of genotype on gene expression was measured using allele-specific luciferase reporter assays. Candidate gene transcription-deficient mice underwent echocardiography and treadmill exercise. The ability of the target gene agonist to rescue mice from chemically-induced HF was assessed with echocardiography.Of 866 HF patients, 136 had an ejection fraction improvement of 20% attributed to resynchronization (n = 83), revascularization (n = 7), tachycardia resolution (n = 2), alcohol cessation (n = 1), or medications (n = 43). Those with the minor allele for rs7767652, upstream of hypocretin (orexin) receptor-2 (HCRTR2), were less likely to have improved left ventricular function (odds ratio: 0.40 per minor allele; p = 3.29 × 10(-5)). In a replication cohort of 798 patients, those with a minor allele for rs7767652 had a lower prevalence of ejection fraction >35% (odds ratio: 0.769 per minor allele; p = 0.021). In an HF model, HCRTR2-deficient mice exhibited poorer cardiac function, worse treadmill exercise capacity, and greater myocardial scarring. Orexin, an HCRTR2 agonist, rescued function in this HF mouse model.A systems approach identified a novel genetic contribution to human HF and a promising therapeutic agent efficacious in an HF model.

    View details for DOI 10.1016/j.jacc.2015.09.061

    View details for Web of Science ID 000366094500009

    View details for PubMedID 26653627

  • Gender Differences in Ventricular Remodeling and Function in College Athletes, Insights from Lean Body Mass Scaling and Deformation Imaging AMERICAN JOURNAL OF CARDIOLOGY Giraldeau, G., Kobayashi, Y., Finocchiaro, G., Wheeler, M., Perez, M., Kuznetsova, T., Lord, R., George, K. P., Oxborough, D., Schnittger, T., Froelicher, V., Liang, D., Ashley, E., Haddad, F. 2015; 116 (10): 1610-1616

    Abstract

    Several studies suggest gender differences in ventricular dimensions in athletes. Few studies have, however, made comparisons of data indexed for lean body mass (LBM) using allometry. Ninety Caucasian college athletes (mixed sports) who were matched for age, ethnicity, and sport total cardiovascular demands underwent dual-energy x-ray absorptiometry scan for quantification of LBM. Athletes underwent comprehensive assessment of left and right ventricular and atrial structure and function using 2-dimensional echocardiography and deformation imaging using the TomTec analysis system. The mean age of the study population was 18.9 ± 1.9 years. Female athletes (n = 45) had a greater fat free percentage (19.4 ± 3.7%) compared to male athletes (11.5 ± 3.7%). When scaled to body surface area, male had on average 19 ± 3% (p <0.001) greater left ventricular (LV) mass; in contrast, when scaled to LBM, there was no significant difference in indexed LV mass -1.4 ± 3.0% (p = 0.63). Similarly, when allometrically scaled to LBM, there was no significant gender-based difference in LV or left atrial volumes. Although female athletes had mildly higher LV ejection fraction and LV global longitudinal strain in absolute value, systolic strain rate and allometrically indexed stroke volume were not different between genders (1.5 ± 3.6% [p = 0.63] and 0.0 ± 3.7% [p = 0.93], respectively). There were no differences in any of the functional atrial indexes including strain or strain rate parameters. In conclusion, gender-related differences in ventricular dimensions or function (stroke volume) appear less marked, if not absent, when indexing using LBM allometrically.

    View details for DOI 10.1016/j.amjcard.2015.08.026

    View details for PubMedID 26456207

  • Limitations of Current AHA Guidelines and Proposal of New Guidelines for the Preparticipation Examination of Athletes CLINICAL JOURNAL OF SPORT MEDICINE Dunn, T. P., Pickham, D., Aggarwal, S., Saini, D., Kumar, N., Wheeler, M. T., Perez, M., Ashley, E., Froelicher, V. F. 2015; 25 (6): 472-477

    Abstract

    To examine the prevalence of athletes who screen positive with the preparticipation examination guidelines from the American Heart Association, the AHA 12-elements, in combination with 3 screening electrocardiogram (ECG) criteria.Observational cross-sectional study.Stanford University Sports Medicine Clinic.Total of 1596 participants, including 297 (167 male; mean age, 16.2 years) high school athletes, 1016 (541 male; mean age, 18.8 years) collegiate athletes, and 283 (mean age, 26.3 years) male professional athletes.Athletes were screened using the 8 personal and family history questions from the AHA 12-elements. Electrocardiograms were obtained for all participants and interpreted using Seattle criteria, Stanford criteria, and European Society of Cardiology (ESC) recommendations.Approximately one-quarter of all athletes (23.8%) had at least 1 positive response to the AHA personal and family history elements. High school and college athletes had similar rates of having at least 1 positive response (25.9% vs 27.4%), whereas professional athletes had a significantly lower rate of having at least 1 positive response (8.8%, P < 0.05). Females reported more episodes of unexplained syncope (11.4% vs 7.5%, P = 0.017) and excessive exertional dyspnea with exercise (11.1% vs 6.1%, P = 0.001) than males. High school athletes had more positive responses to the family history elements when compared with college athletes (P < 0.05). The percentage of athletes who had an abnormal ECG varied between Seattle criteria (6.0%), Stanford criteria (8.8%), and ESC recommendations (26.8%).Many athletes screen positive under current screening recommendations, and ECG results vary widely by interpretation criteria.In a patient population without any adverse cardiovascular events, the currently recommended AHA 12-elements have an unacceptably high rate of false positives. Newer screening guidelines are needed, with fewer false positives and evidence-based updates.

    View details for Web of Science ID 000364310700003

    View details for PubMedID 25915146

  • Letter by Wheeler et al Regarding Article, "Recognition and Significance of Pathological T-Wave Inversions in Athletes" CIRCULATION Wheeler, M. T., Adelfattah, R., Froelicher, V. F. 2015; 132 (14): E180

    View details for PubMedID 26438774

  • Sequence to Medical Phenotypes: A Framework for Interpretation of Human Whole Genome DNA Sequence Data PLOS GENETICS Dewey, F. E., Grove, M. E., Priest, J. R., Waggott, D., Batra, P., Miller, C. L., Wheeler, M., Zia, A., Pan, C., Karzcewski, K. J., Miyake, C., Whirl-Carrillo, M., Klein, T. E., Datta, S., Altman, R. B., Snyder, M., Quertermous, T., Ashley, E. A. 2015; 11 (10)

    Abstract

    High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, prompting predictions of a revolution in medicine via genetic personalization of diagnostic and therapeutic strategies. There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed. Here, we present a series of methods for identification of genetic variants and genotypes with clinical associations, phasing genetic data and using Mendelian inheritance for quality control, and providing predictive genetic information about risk for rare disease phenotypes and response to pharmacological therapy in single individuals and father-mother-child trios. We demonstrate application of these methods for disease and drug response prognostication in whole genome sequence data from twelve unrelated adults, and for disease gene discovery in one father-mother-child trio with apparently simplex congenital ventricular arrhythmia. In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals. We also nominate a new candidate gene in congenital arrhythmia, ATP2B4, and provide experimental evidence of a regulatory role for variants discovered using this framework.

    View details for DOI 10.1371/journal.pgen.1005496

    View details for Web of Science ID 000364401600008

    View details for PubMedID 26448358

    View details for PubMedCentralID PMC4598191

  • Data Sharing in the Undiagnosed Diseases Network HUMAN MUTATION Brownstein, C. A., Holm, I. A., Ramoni, R., Goldstein, D. B., Undiag Dis Network 2015; 36 (10): 985-988

    Abstract

    The Undiagnosed Diseases Network (UDN) builds on the successes of the Undiagnosed Diseases Program at the National Institutes of Health (NIH UDP). Through support from the NIH Common Fund, a coordinating center, six additional clinical sites, and two sequencing cores comprise the UDN. The objectives of the UDN are to: (1) improve the level of diagnosis and care for patients with undiagnosed diseases through the development of common protocols designed by an enlarged community of investigators across the network; (2) facilitate research into the etiology of undiagnosed diseases, by collecting and sharing standardized, high-quality clinical and laboratory data including genotyping, phenotyping, and environmental exposure data; and (3) create an integrated and collaborative research community across multiple clinical sites, and among laboratory and clinical investigators, to investigate the pathophysiology of these rare diseases and to identify options for patient management. Broad-based data sharing is at the core of achieving these objectives, and the UDN is establishing the policies and governance structure to support broad data sharing.

    View details for DOI 10.1002/humu.22840

    View details for Web of Science ID 000362989500010

    View details for PubMedID 26220576

    View details for PubMedCentralID PMC4706173

  • Systematic Comparison of Digital Electrocardiograms From Healthy Athletes and Patients With Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology Bent, R. E., Wheeler, M. T., Hadley, D., Knowles, J. W., Pavlovic, A., Finocchiaro, G., Haddad, F., Salisbury, H., Race, S., Shmargad, Y., Matheson, G. O., Kumar, N., Saini, D., Froelicher, V., Ashley, E., Perez, M. V. 2015; 65 (22): 2462-2463

    View details for DOI 10.1016/j.jacc.2015.03.559

    View details for PubMedID 26046742

  • Examining QRS amplitude criteria for electrocardiographic left ventricular hypertrophy in recommendations for screening criteria in athletes. Journal of electrocardiology Singla, V., Jindal, A., Pargaonkar, V., Soofi, M., Wheeler, M., Froelicher, V. 2015; 48 (3): 368-372

    Abstract

    Current guidelines for interpretation of the ECGs of athletes recommend that isolated R and S wave amplitudes that exceed traditional criteria for left ventricular hypertrophy be accepted as a physiological response to exercise training. This is based on training and echocardiographic studies but not on long term follow up. Demonstration of the prognostic characteristics of the amplitude criteria in a non-athletic population could support the current guidelines.To evaluate the prognostic value of the R and S wave voltage criteria for electrocardiographic left ventricular hypertrophy (ECG-LVH) in an ambulatory clinical population.The target population consisted of 20,903 ambulatory subjects who had ECGs recorded between 1987 and 1999 and were followed for cardiovascular death until 2013. During the mean follow up of 17years, there were 881 cardiovascular deaths.The mean age was 43±10, 91% were male and 16% were African American. Of the 2482 (12%) subjects who met the Sokolow-Lyon criteria, 241 (1.2%) subjects with left ventricular (LV) strain had an HR of 5.4 (95% CI 4.1-7.2, p<0.001), while 2241 (11%) subjects without strain had an HR of 1.4 (95% CI 1.2-1.8, p<0.001). Of the 4836 (23%) subjects who met the Framingham voltage criteria, 350 (2%) subjects with LV strain had an HR of 5.1 (95% CI 4.0-6.5, p<0.001), while 4486 (22%) subjects without strain had an HR of 1.1 (95% CI 0.9-1.3, p=0.26). The individual components of the Romhilt-Estes had HRs ranging from 1.4 to 3.6, with only the voltage component not being significant (HR 1.1, 95% CI 0.9-1.5, p=0.35).This study demonstrates that the R and S wave voltage criteria components of most of the original classification schema for electrocardiographic left ventricular hypertrophy are not predictive of CV mortality. Our findings support the current guidelines for electrocardiographic screening of athletes.

    View details for DOI 10.1016/j.jelectrocard.2014.12.012

    View details for PubMedID 25661864

  • Computerized Q wave dimensions in athletes and hypertrophic cardiomyopathy patients JOURNAL OF ELECTROCARDIOLOGY Bent, R. E., Wheeler, M. T., Hadley, D., Froelicher, V., Ashley, E., Perez, M. V. 2015; 48 (3): 362-367

    Abstract

    There is controversy regarding Q wave criteria for assessing risk for hypertrophic cardiomyopathy (HCM) in young athletes.The 12-lead ECGs from Preparticipation screening in healthy athletes and patients with HCM were studied retrospectively. All 12 leads were measured using the same automated ECG analysis program.There were a total of 225 HCM patients and 1124 athletes with 12-lead electrocardiograms available for analysis. Athletes were on average 20 years of age, 65% were male and 24% were African-American. Patients with HCM were on average 51 years of age, 56% were male and 5.8% were African-American. Q waves by either amplitude, duration or area criteria were more prevalent in males than females, in lateral leads than inferior and in HCM patients than athletes. The most striking difference in Q waves between the groups was in Limb lead I and in the females. Tall, skinny Q waves were rare in athletes and had the highest prevalence of only 3.7% in male HCM patients.Q waves are more common in males compared to females and in patients with HCM compared to athletes. Q waves of 30 ms or more in limb lead I appear to offer the greatest discriminatory value for separating patients with HCM from athletes.

    View details for DOI 10.1016/j.jelectrocard.2015.01.009

    View details for PubMedID 25732098

  • Outcomes after heart transplantation for amyloid cardiomyopathy in the modern era. American journal of transplantation Davis, M. K., Kale, P., Liedtke, M., Schrier, S., Arai, S., Wheeler, M., Lafayette, R., Coakley, T., Witteles, R. M. 2015; 15 (3): 650-658

    Abstract

    We conducted a review of patients undergoing heart transplantation (HT) at our institution for amyloid cardiomyopathy (ACM) between 2008 and 2013. Complete follow-up was available for all patients. Nineteen patients with ACM underwent HT during the study period, accounting for 9.4% of all HT performed at our institution during this period. Amyloid subtype was light chain (AL) in 9 patients and transthyretin (ATTR) in 10 (2 wild-type, 7 familial, 1 unknown). Eight of nine patients with AL amyloidosis began chemotherapy prior to HT, six have resumed chemotherapy since HT, and five have undergone autologous stem cell transplantation. Most recent free light chain levels in AL patients decreased by a median of 85% from peak values. Only one patient developed recurrent graft amyloidosis, occurring at 3.5 years post-HT and asymptomatic. After a median follow-up of 380 days, 17 (89.5%) patients are alive. To our knowledge, this is the largest single-center series reported of ACM patients undergoing HT in the modern era. Our results suggest that acceptable outcomes following HT can be achieved in the short-to-intermediate term and that this is a feasible option for end-stage ACM with careful patient selection and aggressive control of amyloidogenic light chains in AL patients.

    View details for DOI 10.1111/ajt.13025

    View details for PubMedID 25648766

  • Hypertrophic cardiomyopathy: can the horse be put back in the barn? Journal of the American College of Cardiology Wheeler, M. T., Ashley, E. A. 2015; 65 (6): 570-572

    View details for DOI 10.1016/j.jacc.2014.12.004

    View details for PubMedID 25677316

  • Personalized preventive medicine: genetics and the response to regular exercise in preventive interventions. Progress in cardiovascular diseases Bouchard, C., Antunes-Correa, L. M., Ashley, E. A., Franklin, N., Hwang, P. M., Mattsson, C. M., Negrao, C. E., Phillips, S. A., Sarzynski, M. A., Wang, P., Wheeler, M. T. 2015; 57 (4): 337-346

    Abstract

    Regular exercise and a physically active lifestyle have favorable effects on health. Several issues related to this theme are addressed in this report. A comment on the requirements of personalized exercise medicine and in-depth biological profiling along with the opportunities that they offer is presented. This is followed by a brief overview of the evidence for the contributions of genetic differences to the ability to benefit from regular exercise. Subsequently, studies showing that mutations in TP53 influence exercise capacity in mice and humans are succinctly described. The evidence for effects of exercise on endothelial function in health and disease also is covered. Finally, changes in cardiac and skeletal muscle in response to exercise and their implications for patients with cardiac disease are summarized. Innovative research strategies are needed to define the molecular mechanisms involved in adaptation to exercise and to translate them into useful clinical and public health applications.

    View details for DOI 10.1016/j.pcad.2014.08.005

    View details for PubMedID 25559061

  • BEST IN PHYSICS (THERAPY) - Stereotactic Radiotherapy for Renal Sympathetic Ablation for the Treatment of Refractory Hypertension Maxim, P., Wheeler, M., Maguire, P., Loo, B. WILEY. 2014: 503–4
  • Clinical interpretation and implications of whole-genome sequencing. JAMA Dewey, F. E., Grove, M. E., Pan, C., Goldstein, B. A., Bernstein, J. A., Chaib, H., Merker, J. D., Goldfeder, R. L., Enns, G. M., David, S. P., Pakdaman, N., Ormond, K. E., Caleshu, C., Kingham, K., Klein, T. E., Whirl-Carrillo, M., Sakamoto, K., Wheeler, M. T., Butte, A. J., Ford, J. M., Boxer, L., Ioannidis, J. P., Yeung, A. C., Altman, R. B., Assimes, T. L., Snyder, M., Ashley, E. A., Quertermous, T. 2014; 311 (10): 1035-1045

    Abstract

    Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001).In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

    View details for DOI 10.1001/jama.2014.1717

    View details for PubMedID 24618965

  • Genetic Variation Near HCRTR2 Associates With Dramatic Improvement of Heart Function in Patients With Heart Failure Perez, M. V., Pavlovic, A., Wheeler, M. T., Miller, C. L., Thanaporn, P., Dewey, F. E., Pan, S., Absher, D., Cretti, E., Southwick, A., Heidenreich, P., Sedehi, D., Brandimarto, J., Kao, D., Salisbury, H., Chan, K., Rosenthal, D., Bernstein, D., Fowler, M. B., Robbins, R. C., Meyers, R., Meyers, R., Quertermous, T., Cappola, T., Ashley, E. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Physical Activity and Other Health Behaviors in Adults With Hypertrophic Cardiomyopathy AMERICAN JOURNAL OF CARDIOLOGY Reineck, E., Rolston, B., Bragg-Gresham, J. L., Salberg, L., Baty, L., Kumar, S., Wheeler, M. T., Ashley, E., Saberi, S., Day, S. M. 2013; 111 (7): 1034-1039

    Abstract

    The clinical expression of hypertrophic cardiomyopathy (HC) is undoubtedly influenced by modifying genetic and environmental factors. Lifestyle practices such as tobacco and alcohol use, poor nutritional intake, and physical inactivity are strongly associated with adverse cardiovascular outcomes and increased mortality in the general population. Before addressing the direct effect of such modifiable factors on the natural history of HC, it is critical to define their prevalence in this population. A voluntary survey, drawing questions in part from the 2007 to 2008 National Health and Nutrition Examination Survey (NHANES), was posted on the HC Association website and administered to patients with HC at the University of Michigan. Propensity score matching to NHANES participants was used. Dichotomous and continuous health behaviors were analyzed using logistic and linear regression, respectively, and adjusted for body mass index and propensity score quintile. Compared to the matched NHANES participants, the patients with HC reported significantly less alcohol and tobacco use but also less time engaged in physical activity at work and for leisure. Time spent participating in vigorous or moderate activity was a strong predictor of self-reported exercise capacity. The body mass index was greater in the HC cohort than in the NHANES cohort. Exercise restrictions negatively affected emotional well-being in most surveyed subjects. In conclusion, patients with HC are less active than the general United States population. The well-established relation of inactivity, obesity, and cardiovascular mortality might be exaggerated in patients with HC. More data are needed on exercise in those with HC to strike a balance between acute risks and the long-term health benefits of exercise.

    View details for DOI 10.1016/j.amjcard.2012.12.018

    View details for Web of Science ID 000316923700018

    View details for PubMedID 23340032

  • Abnormal Calcium Handling Properties Underlie Familial Hypertrophic Cardiomyopathy Pathology in Patient-Specific Induced Pluripotent Stem Cells CELL STEM CELL Lan, F., Lee, A. S., Liang, P., Sanchez-Freire, V., Nguyen, P. K., Wang, L., Han, L., Yen, M., Wang, Y., Sun, N., Abilez, O. J., Hu, S., Ebert, A. D., Navarrete, E. G., Simmons, C. S., Wheeler, M., Pruitt, B., Lewis, R., Yamaguchi, Y., Ashley, E. A., Bers, D. M., Robbins, R. C., Longaker, M. T., Wu, J. C. 2013; 12 (1): 101-113

    Abstract

    Familial hypertrophic cardiomyopathy (HCM) is a prevalent hereditary cardiac disorder linked to arrhythmia and sudden cardiac death. While the causes of HCM have been identified as genetic mutations in the cardiac sarcomere, the pathways by which sarcomeric mutations engender myocyte hypertrophy and electrophysiological abnormalities are not understood. To elucidate the mechanisms underlying HCM development, we generated patient-specific induced pluripotent stem cell cardiomyocytes (iPSC-CMs) from a ten-member family cohort carrying a hereditary HCM missense mutation (Arg663His) in the MYH7 gene. Diseased iPSC-CMs recapitulated numerous aspects of the HCM phenotype including cellular enlargement and contractile arrhythmia at the single-cell level. Calcium (Ca(2+)) imaging indicated dysregulation of Ca(2+) cycling and elevation in intracellular Ca(2+) ([Ca(2+)](i)) are central mechanisms for disease pathogenesis. Pharmacological restoration of Ca(2+) homeostasis prevented development of hypertrophy and electrophysiological irregularities. We anticipate that these findings will help elucidate the mechanisms underlying HCM development and identify novel therapies for the disease.

    View details for DOI 10.1016/j.stem.2012.10.010

    View details for Web of Science ID 000313839500014

    View details for PubMedID 23290139

    View details for PubMedCentralID PMC3638033

  • A public resource facilitating clinical use of genomes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ball, M. P., Thakuria, J. V., Zaranek, A. W., Clegg, T., Rosenbaum, A. M., Wu, X., Angrist, M., Bhak, J., Bobe, J., Callow, M. J., Cano, C., Chou, M. F., Chung, W. K., Douglas, S. M., Estep, P. W., Gore, A., Hulick, P., Labarga, A., Lee, J., Lunshof, J. E., Kim, B. C., Kim, J., Li, Z., Murray, M. F., Nilsen, G. B., Peters, B. A., Raman, A. M., Rienhoff, H. Y., Robasky, K., Wheeler, M. T., Vandewege, W., Vorhaus, D. B., Yang, J. L., Yang, L., Aach, J., Ashley, E. A., Drmanac, R., Kim, S., Li, J. B., Peshkin, L., Seidman, C. E., Seo, J., Zhang, K., Rehm, H. L., Church, G. M. 2012; 109 (30): 11920-11927

    Abstract

    Rapid advances in DNA sequencing promise to enable new diagnostics and individualized therapies. Achieving personalized medicine, however, will require extensive research on highly reidentifiable, integrated datasets of genomic and health information. To assist with this, participants in the Personal Genome Project choose to forgo privacy via our institutional review board- approved "open consent" process. The contribution of public data and samples facilitates both scientific discovery and standardization of methods. We present our findings after enrollment of more than 1,800 participants, including whole-genome sequencing of 10 pilot participant genomes (the PGP-10). We introduce the Genome-Environment-Trait Evidence (GET-Evidence) system. This tool automatically processes genomes and prioritizes both published and novel variants for interpretation. In the process of reviewing the presumed healthy PGP-10 genomes, we find numerous literature references implying serious disease. Although it is sometimes impossible to rule out a late-onset effect, stringent evidence requirements can address the high rate of incidental findings. To that end we develop a peer production system for recording and organizing variant evaluations according to standard evidence guidelines, creating a public forum for reaching consensus on interpretation of clinically relevant variants. Genome analysis becomes a two-step process: using a prioritized list to record variant evaluations, then automatically sorting reviewed variants using these annotations. Genome data, health and trait information, participant samples, and variant interpretations are all shared in the public domain-we invite others to review our results using our participant samples and contribute to our interpretations. We offer our public resource and methods to further personalized medical research.

    View details for DOI 10.1073/pnas.1201904109

    View details for Web of Science ID 000306992700018

    View details for PubMedID 22797899

    View details for PubMedCentralID PMC3409785

  • DNA Sequencing Clinical Applications of New DNA Sequencing Technologies CIRCULATION Dewey, F. E., Pan, S., Wheeler, M. T., Quake, S. R., Ashley, E. A. 2012; 125 (7): 931-944
  • Cardiovascular Magnetic Resonance Imaging Elucidates Genotype-Phenotype Relationships in Patients with Hypertrophic Cardiomyopathy Scientific Sessions of the American-Heart-Association/Resuscitation Science Symposium Heidary, S., Wheeler, M. T., Bennett, M. V., Chung, J., Pavlovic, A., Parent, M., Dash, R., McConnell, M. V., Ashley, E. A., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2011
  • Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence PLOS GENETICS Dewey, F. E., Chen, R., Cordero, S. P., Ormond, K. E., Caleshu, C., Karczewski, K. J., Whirl-Carrillo, M., Wheeler, M. T., Dudley, J. T., Byrnes, J. K., Cornejo, O. E., Knowles, J. W., Woon, M., Sangkuhl, K., Gong, L., Thorn, C. F., Hebert, J. M., Capriotti, E., David, S. P., Pavlovic, A., West, A., Thakuria, J. V., Ball, M. P., Zaranek, A. W., Rehm, H. L., Church, G. M., West, J. S., Bustamante, C. D., Snyder, M., Altman, R. B., Klein, T. E., Butte, A. J., Ashley, E. A. 2011; 7 (9)

    Abstract

    Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date (< 1,000 base pairs). We use family inheritance state analysis to control sequencing error and inform family-wide haplotype phasing, allowing quantification of genome-wide compound heterozygosity. We develop a sequence-based methodology for Human Leukocyte Antigen typing that contributes to disease risk prediction. Finally, we advance methods for analysis of disease and pharmacogenomic risk across the coding and non-coding genome that incorporate phased variant data. We show these methods are capable of identifying multigenic risk for inherited thrombophilia and informing the appropriate pharmacological therapy. These ethnicity-specific, family-based approaches to interpretation of genetic variation are emblematic of the next generation of genetic risk assessment using whole-genome sequencing.

    View details for DOI 10.1371/journal.pgen.1002280

    View details for PubMedID 21935354

  • Interpretation of the Electrocardiogram of Young Athletes CIRCULATION Uberoi, A., Stein, R., Perez, M. V., Freeman, J., Wheeler, M., Dewey, F., Peidro, R., Hadley, D., Drezner, J., Sharma, S., Pelliccia, A., Corrado, D., Niebauer, J., Estes, M., Ashley, E., Froelicher, V. 2011; 124 (6): 746-757

    View details for DOI 10.1161/CIRCULATIONAHA.110.013078

    View details for PubMedID 21824936

  • Systems biology of heart failure, challenges and hopes CURRENT OPINION IN CARDIOLOGY Dewey, F. E., Wheeler, M. T., Ashley, E. A. 2011; 26 (4): 314-321

    Abstract

    Heart failure remains a leading cause of morbidity and mortality in developed nations. Our current understanding of molecular pathways involved in heart failure reveals little of the multiscale biological systems at work. Here we consider recent advances in understanding the integrative multiscale biology, or systems biology, of heart failure and present a framework for future work in the area.Multiplexed assays of gene expression and the complex dynamics of protein-protein interactions in heart failure have illuminated key pathways important to myocardial adaptation. Modeling of complex systems has advanced to incorporate these dynamic data sources into networks that capture fundamental interactions on different biological scales. The complex syndrome of heart failure, like other complex disease syndromes, can be viewed as an emergent property of these multiscale systems.A comprehensive understanding of adaptive mechanisms in heart failure requires integration of multiple data sources on several biological scales. A combination of holistic systems biology approaches and traditional reductionist experimentation will be required for a nuanced understanding of this multifaceted disease process.

    View details for DOI 10.1097/HCO.0b013e328346597d

    View details for Web of Science ID 000291424400007

    View details for PubMedID 21478745

  • Gene Coexpression Network Topology of Cardiac Development, Hypertrophy, and Failure CIRCULATION-CARDIOVASCULAR GENETICS Dewey, F. E., Perez, M. V., Wheeler, M. T., Watt, C., Spin, J., Langfelder, P., Horvath, S., Hannenhalli, S., Cappola, T. P., Ashley, E. A. 2011; 4 (1): 26-U129

    Abstract

    Network analysis techniques allow a more accurate reflection of underlying systems biology to be realized than traditional unidimensional molecular biology approaches. Using gene coexpression network analysis, we define the gene expression network topology of cardiac hypertrophy and failure and the extent of recapitulation of fetal gene expression programs in failing and hypertrophied adult myocardium.We assembled all myocardial transcript data in the Gene Expression Omnibus (n=1617). Because hierarchical analysis revealed species had primacy over disease clustering, we focused this analysis on the most complete (murine) dataset (n=478). Using gene coexpression network analysis, we derived functional modules, regulatory mediators, and higher-order topological relationships between genes and identified 50 gene coexpression modules in developing myocardium that were not present in normal adult tissue. We found that known gene expression markers of myocardial adaptation were members of upregulated modules but not hub genes. We identified ZIC2 as a novel transcription factor associated with coexpression modules common to developing and failing myocardium. Of 50 fetal gene coexpression modules, 3 (6%) were reproduced in hypertrophied myocardium and 7 (14%) were reproduced in failing myocardium. One fetal module was common to both failing and hypertrophied myocardium.Network modeling allows systems analysis of cardiovascular development and disease. Although we did not find evidence for a global coordinated program of fetal gene expression in adult myocardial adaptation, our analysis revealed specific gene expression modules active during both development and disease and specific candidates for their regulation.

    View details for DOI 10.1161/CIRCGENETICS.110.941757

    View details for PubMedID 21127201

  • Extremely elevated lipoprotein(a), combined hyperlipidemia, and premature atherosclerosis in a Chinese family JOURNAL OF CLINICAL LIPIDOLOGY deGoma, E. M., Wheeler, M. T., Marcovina, S. M., Ashley, E. A. 2010; 4 (6): 543–47

    View details for DOI 10.1016/j.jacl.2010.09.002

    View details for Web of Science ID 000285702800013

    View details for PubMedID 21122702

  • Addition of the Electrocardiogram to the Preparticipation Examination of College Athletes (vol 20, pg 98, 2010) CLINICAL JOURNAL OF SPORT MEDICINE Le, V., Wheeler, M. T., Mandic, S. 2010; 20 (4): 332
  • Effect of Gender on Computerized Electrocardiogram Measurements in College Athletes PHYSICIAN AND SPORTSMEDICINE Mandic, S., Fonda, H., Dewey, F., Vy-van Le, Stein, R., Wheeler, M., Ashley, E. A., Myers, J., Froelicher, V. F. 2010; 38 (2): 156-164

    Abstract

    Background Broad criteria for classifying an electrocardiogram (ECG) as abnormal and requiring additional testing prior to participating in competitive athletics have been recommended for the preparticipation examination (PPE) of athletes. Because these criteria have not considered gender differences, we examined the effect of gender on the computerized ECG measurements obtained on Stanford student athletes. Currently available computer programs require a basis for "normal" in athletes of both genders to provide reliable interpretation. Methods During the 2007 PPE, computerized ECGs were recorded and analyzed on 658 athletes (54% male; mean age, 19 +/- 1 years) representing 22 sports. Electrocardiogram measurements included intervals and durations in all 12 leads to calculate 12-lead voltage sums, QRS amplitude and QRS area, spatial vector length (SVL), and the sum of the R wave in V5 and S wave in V2 (RSsum). Results By computer analysis, male athletes had significantly greater QRS duration, PR interval, Q-wave duration, J-point amplitude, and T-wave amplitude, and shorter QTc interval compared with female athletes (all P < 0.05). All ECG indicators of left ventricular electrical activity were significantly greater in males. Although gender was consistently associated with indices of atrial and ventricular electrical activity in multivariable analysis, ECG measurements correlated poorly with body dimensions. Conclusion Significant gender differences exist in ECG measurements of college athletes that are not explained by differences in body size. Our tables of "normal" computerized gender-specific measurements can facilitate the development of automated ECG interpretation for screening young athletes.

    View details for Web of Science ID 000290808000025

    View details for PubMedID 20631475

  • Challenges in the clinical application of whole-genome sequencing LANCET Ormond, K. E., Wheeler, M. T., Hudgins, L., Klein, T. E., Butte, A. J., Altman, R. B., Ashley, E. A., Greely, H. T. 2010; 375 (9727): 1749-1751
  • Clinical assessment incorporating a personal genome LANCET Ashley, E. A., Butte, A. J., Wheeler, M. T., Chen, R., Klein, T. E., Dewey, F. E., Dudley, J. T., Ormond, K. E., Pavlovic, A., Morgan, A. A., Pushkarev, D., Neff, N. F., Hudgins, L., Gong, L., Hodges, L. M., Berlin, D. S., Thorn, C. F., Sangkuhl, K., Hebert, J. M., Woon, M., Sagreiya, H., Whaley, R., Knowles, J. W., Chou, M. F., Thakuria, J. V., Rosenbaum, A. M., Zaranek, A. W., Church, G. M., Greely, H. T., Quake, S. R., Altman, R. B. 2010; 375 (9725): 1525-1535

    Abstract

    The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context.We assessed a patient with a family history of vascular disease and early sudden death. Clinical assessment included analysis of this patient's full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome and clinical risk. Disease and risk analysis focused on prediction of genetic risk of variants associated with mendelian disease, recognised drug responses, and pathogenicity for novel variants. We queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. We estimated post-test probabilities of disease by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sex-appropriate pre-test probabilities. We also accounted for gene-environment interactions and conditionally dependent risks.Analysis of 2.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death-TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported.Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients.National Institute of General Medical Sciences; National Heart, Lung And Blood Institute; National Human Genome Research Institute; Howard Hughes Medical Institute; National Library of Medicine, Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; Breetwor Family Foundation.

    View details for Web of Science ID 000277655100025

    View details for PubMedID 20435227

  • Cost-Effectiveness of Preparticipation Screening for Prevention of Sudden Cardiac Death in Young Athletes ANNALS OF INTERNAL MEDICINE Wheeler, M. T., Heidenreich, P. A., Froelicher, V. F., Hlatky, M. A., Ashley, E. A. 2010; 152 (5): 276-W91

    Abstract

    Inclusion of 12-lead electrocardiography (ECG) in preparticipation screening of young athletes is controversial because of concerns about cost-effectiveness.To evaluate the cost-effectiveness of ECG plus cardiovascular-focused history and physical examination compared with cardiovascular-focused history and physical examination alone for preparticipation screening.Decision-analysis, cost-effectiveness model.Published epidemiologic and preparticipation screening data, vital statistics, and other publicly available data.Competitive athletes in high school and college aged 14 to 22 years.Lifetime.Societal.Nonparticipation in competitive athletic activity and disease-specific treatment for identified athletes with heart disease.Incremental health care cost per life-year gained.Addition of ECG to preparticipation screening saves 2.06 life-years per 1000 athletes at an incremental total cost of $89 per athlete and yields a cost-effectiveness ratio of $42 900 per life-year saved (95% CI, $21 200 to $71 300 per life-year saved) compared with cardiovascular-focused history and physical examination alone. Compared with no screening, ECG plus cardiovascular-focused history and physical examination saves 2.6 life-years per 1000 athletes screened and costs $199 per athlete, yielding a cost-effectiveness ratio of $76 100 per life-year saved ($62 400 to $130 000).Results are sensitive to the relative risk reduction associated with nonparticipation and the cost of initial screening.Effectiveness data are derived from 1 major European study. Patterns of causes of sudden death may vary among countries.Screening young athletes with 12-lead ECG plus cardiovascular-focused history and physical examination may be cost-effective.Stanford Cardiovascular Institute and the Breetwor Foundation.

    View details for PubMedID 20194233

  • Addition of the Electrocardiogram to the Preparticipation Examination of College Athletes CLINICAL JOURNAL OF SPORT MEDICINE Le, V., Wheeler, M. T., Mandic, S., Dewey, F., Fonda, H., Perez, M., Sungar, G., Garza, D., Ashley, E. A., Matheson, G., Froelicher, V. 2010; 20 (2): 98-105

    Abstract

    Although the use of standardized cardiovascular (CV) system-focused history and physical examination is recommended for the preparticipation examination (PPE) of athletes, the addition of the electrocardiogram (ECG) has been controversial. Because the impact of ECG screening on college athletes has rarely been reported, we analyzed the findings of adding the ECG to the PPE of Stanford athletes.For the past 15 years, the Stanford Sports Medicine program has mandated a PPE questionnaire and physical examination by Stanford physicians for participation in intercollegiate athletics. In 2007, computerized ECGs with digital measurements were recorded on athletes and entered into a database.Although the use of standardized CV-focused history and physical examination are recommended for the PPE of athletes, the addition of the ECG has been controversial. Because the feasibility and outcomes of ECG screening on college athletes have rarely been reported, we present findings derived from the addition of the ECG to the PPE of Stanford athletes. For the past 15 years, the Stanford Sports Medicine program has mandated a PPE questionnaire and physical examination by Stanford physicians for participation in intercollegiate athletics. In 2007, computerized ECGs with digital measurements were recorded on athletes and entered into a database.Six hundred fifty-eight recordings were obtained (54% men, 10% African-American, mean age 20 years) representing 24 sports. Although 68% of the women had normal ECGs, only 38% of the men did so. Incomplete right bundle branch block (RBBB) (13%), right axis deviation (RAD) (10%), and atrial abnormalities (3%) were the 3 most common minor abnormalities. Sokolow-Lyon criteria for left ventricular hypertrophy (LVH) were found in 49%; however, only 27% had a Romhilt-Estes score of >or=4. T-wave inversion in V2 to V3 occurred in 7%, and only 5 men had abnormal Q-waves. Sixty-three athletes (10%) were judged to have distinctly abnormal ECG findings possibly associated with conditions including hypertrophic cardiomyopathy or arrhythmogenic right ventricular dysplasia/cardiomyopathy. These athletes were offered further testing but this was not mandated according to the research protocol.Six hundred fifty-three recordings were obtained (54% men, 7% African American, mean age 20 years), representing 24 sports. Although 68% of the women had normal ECGs, only 38% of the men did so. Incomplete RBBB (13%), RAD (10%), and atrial abnormalities (3%) were the 3 most common minor abnormalities. Sokolow-Lyon criteria for LVH were found in 49%; however, only 27% had a Romhilt-Estes score of >or=4. T-wave inversion in V2 to V3 occurred in 7% and only 5 men had abnormal Q-waves. Sixty-five athletes (10%) were judged to have distinctly abnormal ECG findings suggestive of arrhythmogenic right ventricular dysplasia, hypertrophic cardiomyopathy, and/or biventricular hypertrophy. These athletes will be submitted to further testing.Mass ECG screening is achievable within the collegiate setting by using volunteers when the appropriate equipment is available. However, the rate of secondary testing suggests the need for an evaluation of cost-effectiveness for mass screening and the development of new athlete-specific ECG interpretation algorithms.

    View details for DOI 10.1097/JSM.0b013e3181d44705

    View details for PubMedID 20215891

  • A New Era in Clinical Genetic Testing for Hypertrophic Cardiomyopathy JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH Wheeler, M., Pavlovic, A., deGoma, E., Salisbury, H., Brown, C., Ashley, E. A. 2009; 2 (4): 381-391

    Abstract

    Building on seminal studies of the last 20 years, genetic testing for hypertrophic cardiomyopathy (HCM) has become a clinical reality in the form of targeted exonic sequencing of known disease-causing genes. This has been driven primarily by the decreasing cost of sequencing, but the high profile of genome-wide association studies, the launch of direct-to-consumer genetic testing, and new legislative protection have also played important roles. In the clinical management of hypertrophic cardiomyopathy, genetic testing is primarily used for family screening. An increasing role is recognized, however, in diagnostic settings: in the differential diagnosis of HCM; in the differentiation of HCM from hypertensive or athlete's heart; and more rarely in preimplantation genetic diagnosis. Aside from diagnostic clarification and family screening, use of the genetic test for guiding therapy remains controversial, with data currently too limited to derive a reliable mutation risk prediction from within the phenotypic noise of different modifying genomes. Meanwhile, the power of genetic testing derives from the confidence with which a mutation can be called present or absent in a given individual. This confidence contrasts with our more limited ability to judge the significance of mutations for which co-segregation has not been demonstrated. These variants of "unknown" significance represent the greatest challenge to the wider adoption of genetic testing in HCM. Looking forward, next-generation sequencing technologies promise to revolutionize the current approach as whole genome sequencing will soon be available for the cost of today's targeted panel. In summary, our future will be characterized not by lack of genetic information but by our ability to effectively parse it.

    View details for DOI 10.1007/s12265-009-9139-0

    View details for Web of Science ID 000284691000005

    View details for PubMedID 20559996

  • Mechanisms of exercise intolerance in patients with hypertrophic cardiomyopathy AMERICAN HEART JOURNAL Le, V., Perez, M. V., Wheeler, M. T., Myers, J., Schnittger, I., Ashley, E. A. 2009; 158 (3): E27-E34

    Abstract

    To determine the relation between echocardiogram findings and exercise capacity in hypertrophic cardiomyopathy (HCM).Sixty-three patients (48 +/- 15 years) were referred for cardiopulmonary testing and exercise echocardiography. They were classified by morphology: proximal (n = 11), reverse curvature (n = 32), apical (n = 7), and concentric HCM (n = 13). There were more women in proximal and reverse curvature groups. Proximal HCM patients were older. Maximal left ventricular thickness was highest in reverse curvature group. At peak exercise, concentric HCM achieved the lowest percent predicted maximal Vo2. Excluding apical group, no significant differences in gradient were noted between groups. Overall, no statistically significant correlation was found between peak Vo2, wall thickness, and gradient. Significant correlations were noted between peak Vo2 and indexed left atrial (LA) volume (r = -0.52), lateral E' (r = 0.50), and lateral E/E' ratio (r = -0.46). A multivariate model including age, lateral E', indexed LA volume, and mitral A wave explained 46% of the variance in peak Vo2 (P = .01).Lateral E' and indexed LA volume are negatively correlated with functional capacity. Although patients with concentric morphology achieved the lowest peak Vo2, wall thickness and gradient did not predict exercise capacity.

    View details for DOI 10.1016/j.ahj.2009.06.006

    View details for Web of Science ID 000269641200027

    View details for PubMedID 19699847

  • Genetics of Arrhythmia: Disease Pathways Beyond Ion Channels JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH Perez, M. V., Wheeler, M., Ho, M., Pavlovic, A., Wang, P., Ashley, E. A. 2008; 1 (2): 155-165

    Abstract

    Diseases of the electrical conduction system that lead to irregularities in cardiac rhythm can have morbid and often lethal clinical outcomes. Linkage analysis has been the principal tool used to discover the genetic mutations responsible for Mendelian arrhythmic disease. Although the majority of arrhythmias can be accounted for by mutations in genes encoding ion channels, linkage analysis has also uncovered the role of other gene families such as those encoding members of the desmosome. With a list of candidates in mind, mutational analysis has helped confirm the suspicion that proteins found in caveolae or gap junctions also play a role in arrhythmogenesis. Atrial fibrillation and sudden cardiac death are relatively common arrhythmias that may be caused by multiple factors including common genetic variants. Genome-wide association studies are already revealing the important and poorly understood role of intergenic regions in atrial fibrillation. Despite the great advancements that have been made in our understanding of the genetics of these diseases, we are still far from able to routinely use genomic data to make clinical management decisions. There remain several hurdles in the study of genetics of arrhythmia, including the costs of genotyping, the need to find large affected families for linkage analysis, or to recruit large numbers of patients for genome-wide studies. Novel techniques that incorporate epigenetic information, such as known gene-gene interactions, biologic pathways, and experimental gene expression, will need to be developed to better interpret the large amount of genetic data that can now be generated. The study of arrhythmia genetics will continue to elucidate the pathophysiology of disease, help identify novel therapies, and ultimately allow us to deliver the individualized medical therapy that has long been anticipated.

    View details for DOI 10.1007/s12265-008-9030-4

    View details for Web of Science ID 000207734800012

    View details for PubMedID 20559910

  • Pharmacogenetics of Heart Failure: Evidence, Opportunities, and Challenges for Cardiovascular Pharmacogenomics JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH Wheeler, M. T., Ho, M., Knowles, J. W., Pavlovic, A., Ashley, E. A. 2008; 1 (1): 25-36

    Abstract

    Heart failure is a significant medical problem affecting more than five million people in the USA alone. Although clinical trials of pharmacological agents have demonstrated significant reductions in the relative risk of mortality across populations, absolute mortality remains high. In addition, individual variation in response is great. Some of this variation may be explained by genetic polymorphism. In this paper, we review the key studies to date in heart failure pharmacogenetics, setting this against a background of recent progress in the genetics of warfarin metabolism. Several polymorphisms that have supporting molecular and clinical data in the heart failure literature are reviewed, among them the beta1-adrenergic receptor variant Arg389Gly and the angiotensin converting enzyme gene insertion/deletion polymorphism. These variants and others are responsible for a fraction of the total variation seen in the treatment response to heart failure. With the dawn of the genomic age, further pharmacogenetic and new pharmacogenomic studies will advance our ability to tailor the treatment of heart failure.

    View details for DOI 10.1007/s12265-007-9007-8

    View details for Web of Science ID 000207734400008

    View details for PubMedID 20559955

  • Angiotensin-converting enzyme genotype predicts cardiac and autonomic responses to prolonged exercise JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Ashley, E. A., Kardos, A., Jack, E. S., Habenbacher, W., Wheeler, M., Kim, Y. M., Froning, J., Myers, J., Whyte, G., Froelicher, V., Douglas, P. 2006; 48 (3): 523-531

    Abstract

    The purpose of this study was to investigate the phenomenon of left ventricular (LV) dysfunction after ultraendurance exercise.Subclinical LV dysfunction in response to endurance exercise up to 24 h duration has been described, but its mechanism remains elusive.We tested 86 athletes before and after the Adrenalin Rush Adventure Race using echocardiography, impedance cardiography, and plasma immunoassay.At baseline, athletes demonstrated physiology characteristic of extreme endurance training. After 90 to 120 h of almost-continuous exercise, LV systolic and diastolic function declined (fractional shortening before the race, 39.6 +/- 0.65%; after, 32.2 +/- 0.84%, p < 0.001; mitral inflow E-wave deceleration time before the race, 133 +/- 5 ms; after, 160 +/- 5 ms, n = 48, p < 0.001) without change in loading conditions as defined by LV end-diastolic dimension and total peripheral resistance estimated by thoracic impedance. There was a compensatory increase in heart rate (before, 55 +/- 1.3 beats/min; after, 59 +/- 1.5 beats/min, p = 0.05), which left cardiac output unchanged, as well as significant-but-subclinical increases in brain natriuretic peptide and troponin I. In addition, we found that athletes who were homozygous for the intron-16 insertion polymorphism of the angiotensin-converting enzyme (ACE) gene exhibited a significantly greater decrease in fractional shortening than athletes who were homozygous for the deletion allele. Heterozygotes showed an intermediate phenotype. In addition, the deletion group manifest an enhanced sympathovagal balance after the race, as evidenced by greater power in the low-frequency component of blood pressure variability.The ACE genotype predicts the extent of reversible subclinical LV dysfunction after prolonged exercise and is associated with a differential postactivity augmentation of sympathetic nervous system function that may explain it.

    View details for DOI 10.1016/j.jacc.2006.02.071

    View details for PubMedID 16875979

  • The interaction of coronary tone and cardiac fibrosis. Current atherosclerosis reports Wheeler, M. T., McNally, E. M. 2005; 7 (3): 219-226

    Abstract

    Regulation of coronary vascular tone is critical for proper perfusion and function of the myocardium. Many disease processes result in compromised regulation of coronary vascular tone and impaired myocardial perfusion. A common result of coronary vascular dysfunction is the development of areas of replacement fibrosis within the myocardium and surrounding the vasculature. Both intravascular processes, such as coronary atherosclerosis and endothelial dysfunction, and extravascular processes, including compromised myocardial metabolism, hormone excesses, and altered local signaling, may result in coronary vascular dysregulation. Coronary occlusion events, in turn, lead to myocardial damage and the activation of inflammatory cells and fibroblasts. The role of fibroblasts in regulating myocardial fibrosis and the contribution of myofibroblasts, cells that have limited contractile potential while retaining many of the extracellular matrix regulating processes of the fibroblast, may also contribute to the development of myocardial disease. In this review we examine the recent literature on myocardial fibrosis and myofibroblast activity, highlighting the effects of several classes of cardiovascular agents on the remodeling process.

    View details for PubMedID 15811257

  • The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses NATURE IMMUNOLOGY Boone, D. L., Turer, E. E., Lee, E. G., Ahmad, R. C., Wheeler, M. T., Tsui, C., Hurley, P., Chien, M., Chai, S., Hitotsumatsu, O., McNally, E., Pickart, C., Ma, A. 2004; 5 (10): 1052-1060

    Abstract

    A20 is a cytoplasmic protein required for the termination of tumor necrosis factor (TNF)-induced signals. We show here that mice doubly deficient in either A20 and TNF or A20 and TNF receptor 1 developed spontaneous inflammation, indicating that A20 is also critical for the regulation of TNF-independent signals in vivo. A20 was required for the termination of Toll-like receptor-induced activity of the transcription factor NF-kappaB and proinflammatory gene expression in macrophages, and this function protected mice from endotoxic shock. A20 accomplished this biochemically by directly removing ubiquitin moieties from the signaling molecule TRAF6. The critical function of this deubiquitinating enzyme in the restriction of TLR signals emphasizes the importance of the regulation of ubiquitin conjugation in innate immune cells.

    View details for DOI 10.1038/ni1110

    View details for Web of Science ID 000224156600029

    View details for PubMedID 15334086

  • Secondary coronary artery vasospasm promotes cardiomyopathy progression AMERICAN JOURNAL OF PATHOLOGY Wheeler, M. T., Korcarz, C. E., Collins, K. A., Lapidos, K. A., Hack, A. A., Lyons, M. R., Zarnegar, S., Earley, J. U., Lang, R. M., McNally, E. M. 2004; 164 (3): 1063-1071

    Abstract

    Genetic defects in the plasma membrane-associated sarcoglycan complex produce cardiomyopathy characterized by focal degeneration. The infarct-like pattern of cardiac degeneration has led to the hypothesis that coronary artery vasospasm underlies cardiomyopathy in this disorder. We evaluated the coronary vasculature of gamma-sarcoglycan mutant mice and found microvascular filling defects consistent with arterial vasospasm. However, the vascular smooth muscle sarcoglycan complex was intact in the coronary arteries of gamma-sarcoglycan hearts with perturbation of the sarcoglycan complex only within the adjacent myocytes. Thus, in this model, coronary artery vasospasm derives from a vascular smooth muscle-cell extrinsic process. To reduce this secondary vasospasm, we treated gamma-sarcoglycan-deficient mice with the calcium channel antagonist verapamil. Verapamil treatment eliminated evidence of vasospasm and ameliorated histological and functional evidence of cardiomyopathic progression. Echocardiography of verapamil-treated, gamma-sarcoglycan-null mice showed an improvement in left ventricular fractional shortening (44.3 +/- 13.3% treated versus 37.4 +/- 15.3% untreated), maximal velocity at the aortic outflow tract (114.9 +/- 27.9 cm/second versus 92.8 +/- 22.7 cm/second), and cardiac index (1.06 +/- 0.30 ml/minute/g versus 0.67 +/- 0.16 ml/minute/g, P < 0.05). These data indicate that secondary vasospasm contributes to the development of cardiomyopathy and is an important therapeutic target to limit cardiomyopathy progression.

    View details for Web of Science ID 000189164300031

    View details for PubMedID 14982859

    View details for PubMedCentralID PMC1614719

  • Smooth muscle cell-extrinsic vascular spasm arises from cardiomyocyte degeneration in sarcoglycan-deficient cardiomyopathy JOURNAL OF CLINICAL INVESTIGATION Wheeler, M. T., Allikian, M. J., Heydemann, A., Hadhazy, M., Zarnegar, S., McNally, E. M. 2004; 113 (5): 668-675

    Abstract

    Vascular spasm is a poorly understood but critical biomedical process because it can acutely reduce blood supply and tissue oxygenation. Cardiomyopathy in mice lacking gamma-sarcoglycan or delta-sarcoglycan is characterized by focal damage. In the heart, sarcoglycan gene mutations produce regional defects in membrane permeability and focal degeneration, and it was hypothesized that vascular spasm was responsible for this focal necrosis. Supporting this notion, vascular spasm was noted in coronary arteries, and disruption of the sarcoglycan complex was observed in vascular smooth muscle providing a molecular mechanism for spasm. Using a transgene rescue strategy in the background of sarcoglycan-null mice, we replaced cardiomyocyte sarcoglycan expression. Cardiomyocyte-specific sarcoglycan expression was sufficient to correct cardiac focal degeneration. Intriguingly, successful restoration of the cardiomyocyte sarcoglycan complex also eliminated coronary artery vascular spasm, while restoration of smooth muscle sarcoglycan in the background of sarcoglycan-null alleles did not. This mechanism, whereby tissue damage leads to vascular spasm, can be partially corrected by NO synthase inhibitors. Therefore, we propose that cytokine release from damaged cardiomyocytes can feed back to produce vascular spasm. Moreover, vascular spasm feeds forward to produce additional cardiac damage.

    View details for DOI 10.1172/JCI200420410

    View details for Web of Science ID 000189379500008

    View details for PubMedID 14991064

    View details for PubMedCentralID PMC351323

  • Functional nitric oxide synthase mislocalization in cardiomyopathy JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Heydemann, A., Huber, J. M., Kakkar, R., Wheeler, M. T., McNally, E. M. 2004; 36 (2): 213-223

    Abstract

    Mutations in the dystrophin glycoprotein complex, and in particular the sarcoglycan subcomplex, lead to cardiomyopathy and muscular dystrophy. Mice with mutations in gamma-sarcoglycan or delta-sarcoglycan develop cardiomyopathy that is characterized by focal regions of tissue damage. These focally damaged regions constitute 0-5% of cardiac tissue. In cardiomyopathy arising from sarcoglycan mutations, we found that endothelial nitric oxide synthase (eNOS) was significantly increased in focally damaged cardiac myocytes. In addition, we noted that nitric oxide (NO) was also increased in regions of tissue damage and altered membrane permeability. In sarcoglycan mutant mice, regionally increased cardiac NO was associated with hypersensitivity to carbachol and decreased sensitivity to adrenergic stimulation. Inhibition of NO production in sarcoglycan mutant mice was associated with improved recovery after carbachol and isoproterenol infusion. These data provide a mechanism where regional, focal cardiac damage creates pathologic gradients of NO. Moreover, inhibition of nitric oxide synthase corrects defects that arise from pathologic NO gradients.

    View details for DOI 10.1016/j.yjmcc.2003.09.020

    View details for Web of Science ID 000189264800007

    View details for PubMedID 14871549

  • Sarcoglycans in vascular smooth and striated muscle TRENDS IN CARDIOVASCULAR MEDICINE Wheeler, M. T., McNally, E. M. 2003; 13 (6): 238-243

    Abstract

    Sarcoglycans are transmembrane proteins important in the maintenance of proper muscle function. Together, the sarcoglycans form a heteromeric complex that interacts with dystrophin, dystroglycan, and filamin C to form a mechanosignaling complex. Mutations in the genes encoding sarcoglycan can produce cardiomyopathy and muscular dystrophy. Studies of patients and animal models have emphasized the variability in penetrance and severity of cardiomyopathy. In animal models of sarcoglycan mutations, muscular dystrophy develops owing to loss of the sarcoglycan complex at the membrane of skeletal myocytes. Cardiomyopathy similarly develops with evidence of focal areas of degeneration and necrosis, as well as loss of sarcoglycan at the cardiomyocyte membrane. Vascular spasm has been noted as a feature of sarcoglycan-mediated cardiomyopathy. Recent evidence suggests that disruption of the smooth muscle sarcoglycan complex is not required for the development of vascular spasm and that vascular spasm arises from a vascular smooth muscle cell-extrinsic process.

    View details for Web of Science ID 000184950300005

    View details for PubMedID 12922020

  • Cytoskeletal defects in cardiomyopathy JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY McNally, E., Allikian, M., Wheeler, M. T., Mislow, J. M., Heydemann, A. 2003; 35 (3): 231-241

    Abstract

    Genetic studies of cardiomyopathy and muscular dystrophy have emphasized the importance of the striated myocyte cytoskeleton. Cytoskeletal defects produce myopathies through a combination of structural and signaling mechanisms. Broadly, the cytoskeletal proteins defective in these myopathic syndromes can be classified into categories based on their intracellular locations. The first category includes proteins of the plasma membrane that interact with both subsarcolemmal and extracellular matrix proteins. The second category, generally associated with hypertrophic cardiomyopathies, includes proteins of the sarcomere. The last, newly emerging, category includes proteins of the inner nuclear membrane. In this review, we will examine the genetic defects that lead to cardiomyopathy and the potential means by which these varied proteins normally maintain the structural integrity of myocytes.

    View details for DOI 10.1016/S0022-2828(03)00018-X

    View details for Web of Science ID 000182212600002

    View details for PubMedID 12676538

  • zeta-Sarcoglycan, a novel component of the sarcoglycan complex, is reduced in muscular dystrophy HUMAN MOLECULAR GENETICS Wheeler, M. T., Zarnegar, S., McNally, E. M. 2002; 11 (18): 2147-2154

    Abstract

    The dystrophin glycoprotein complex (DGC) is found at the plasma membrane of muscle cells, where it provides a link between the cytoskeleton and the extracellular matrix. A subcomplex within the DGC, the sarcoglycan complex, associates with dystrophin and mediates muscle membrane stability. Mutations in sarcoglycan genes lead to muscular dystrophy and cardiomyopathy in both humans and mice. In invertebrates, there are three sarcoglycan genes, while in mammals there are additional sarcoglycan genes that probably arose from gene duplication events. We identified a novel mammalian sarcoglycan, zeta-sarcoglycan, that is highly related to gamma-sarcoglycan and delta-sarcoglycan. We generated a zeta-sarcoglycan-specific antibody and found that zeta-sarcoglycan associated with other members of the sarcoglycan complex at the plasma membrane. Additionally, zeta-sarcoglycan was reduced at the membrane in muscular dystrophy, consistent with a role in mediating membrane stability. zeta-Sarcoglycan was also found as a component of the vascular smooth muscle sarcoglycan complex. Together, these data demonstrate that zeta-sarcoglycan is an integral component of the sarcoglycan complex and, as such, is important in the pathogenesis of muscular dystrophy.

    View details for Web of Science ID 000177590700008

    View details for PubMedID 12189167

  • Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K-ATP channels JOURNAL OF CLINICAL INVESTIGATION Chutkow, W. A., Pu, J. L., Wheeler, M. T., Wada, T., Makielski, J. C., Burant, C. F., McNally, E. M. 2002; 110 (2): 203-208

    Abstract

    K(ATP) channels couple the intracellular energy state to membrane excitability and regulate a wide array of biologic activities. K(ATP) channels contain a pore-forming inwardly rectifying potassium channel and a sulfonylurea receptor regulatory subunit (SUR1 or SUR2). To clarify the role of K(ATP) channels in vascular smooth muscle, we studied Sur2 gene-targeted mice (Sur2(-/-)) and found significantly elevated resting blood pressures and sudden death. Using in vivo monitoring, we detected transient, repeated episodes of coronary artery vasospasm in Sur2(-/-) mice. Focal narrowings in the coronary arteries were present in Sur2(-/-) mice consistent with vascular spasm. We treated Sur2(-/-) mice with a calcium channel antagonist and successfully reduced vasospastic episodes. The intermittent coronary artery vasospasm seen in Sur2(-/-) mice provides a model for the human disorder Prinzmetal variant angina and demonstrates that the SUR2 K(ATP) channel is a critical regulator of episodic vasomotor activity.

    View details for DOI 10.1172/JCI200215672

    View details for Web of Science ID 000176872600011

    View details for PubMedID 12122112

    View details for PubMedCentralID PMC151064

  • Cardiomyopathy is independent of skeletal muscle disease in muscular dystrophy. FASEB journal Zhu, X., Wheeler, M. T., Hadhazy, M., Lam, M. J., McNally, E. M. 2002; 16 (9): 1096-1098

    Abstract

    Dystrophin and its associated proteins, the sarcoglycans, are normally expressed in heart and skeletal muscle. Mutations that alter the expression of these membrane-associated proteins lead to muscular dystrophy (MD) and cardiomyopathy in humans. Because of the timing and nature of the accompanying cardiomyopathy, it has been suggested that cardiomyopathy develops as a secondary consequence of skeletal muscle dysfunction in the muscular dystrophies. To determine whether skeletal muscle dystrophy contributes to the development of sarcoglycan-mediated cardiomyopathy, we used mice lacking gamma-sarcoglycan and inserted a transgene that "rescued" gamma-sarcoglycan expression only in skeletal muscle. Gamma-sarcoglycan was expressed in skeletal muscle under the control of the skeletal muscle-specific myosin light chain 1/3 promoter. Gamma-sarcoglycan-null mice expressing this transgene fully restore gamma-sarcoglycan expression. Furthermore, the transgene-rescued mice lack the focal necrosis and membrane permeability defects that are a hallmark of MD. Despite correction of the skeletal muscle disease, focal degeneration and membrane permeability abnormalities persisted in cardiac muscle, and notably persisted in the right ventricle. Therefore, heart and skeletal muscle defects are independent processes in sarcoglycan-mediated muscular dystrophies and, as such, therapy should target both skeletal and cardiac muscle correction to prevent sudden death due to cardiomyopathy in the muscular dystrophies.

    View details for PubMedID 12039854

  • Cardiomyopathy is independent of skeletal muscle disease in muscular dystrophy FASEB JOURNAL Zhu, X. L., Wheeler, M. T., Hadhazy, M., Lam, M. Y., McNally, E. M. 2002; 16 (7): 1096-?

    Abstract

    Dystrophin and its associated proteins, the sarcoglycans, are normally expressed in heart and skeletal muscle. Mutations that alter the expression of these membrane-associated proteins lead to muscular dystrophy (MD) and cardiomyopathy in humans. Because of the timing and nature of the accompanying cardiomyopathy, it has been suggested that cardiomyopathy develops as a secondary consequence of skeletal muscle dysfunction in the muscular dystrophies. To determine whether skeletal muscle dystrophy contributes to the development of sarcoglycan-mediated cardiomyopathy, we used mice lacking gamma-sarcoglycan and inserted a transgene that "rescued" gamma-sarcoglycan expression only in skeletal muscle. Gamma-sarcoglycan was expressed in skeletal muscle under the control of the skeletal muscle-specific myosin light chain 1/3 promoter. Gamma-sarcoglycan-null mice expressing this transgene fully restore gamma-sarcoglycan expression. Furthermore, the transgene-rescued mice lack the focal necrosis and membrane permeability defects that are a hallmark of MD. Despite correction of the skeletal muscle disease, focal degeneration and membrane permeability abnormalities persisted in cardiac muscle, and notably persisted in the right ventricle. Therefore, heart and skeletal muscle defects are independent processes in sarcoglycan-mediated muscular dystrophies and, as such, therapy should target both skeletal and cardiac muscle correction to prevent sudden death due to cardiomyopathy in the muscular dystrophies.

    View details for DOI 10.1096/fj.01-0954fje

    View details for Web of Science ID 000175973900014

  • The sarcoglycan complex in striated and vascular smooth muscle Cold Spring Harbor Symposium on Quantitative Biology Wheeler, M. T., Allikian, M. J., Heydemann, A., McNally, E. M. COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. 2002: 389–397

    View details for Web of Science ID 000183780700049

    View details for PubMedID 12858564

  • Overexpression of gamma-sarcoglycan induces severe muscular dystrophy - Implications for the regulation of sarcoglycan assembly JOURNAL OF BIOLOGICAL CHEMISTRY Zhu, X. L., Hadhazy, M., Groh, M. E., Wheeler, M. T., Wollmann, R., McNally, E. M. 2001; 276 (24): 21785-21790

    Abstract

    The sarcoglycan complex is found normally at the plasma membrane of muscle. Disruption of the sarcoglycan complex, through primary gene mutations in dystrophin or sarcoglycan subunits, produces membrane instability and muscular dystrophy. Restoration of the sarcoglycan complex at the plasma membrane requires reintroduction of the mutant sarcoglycan subunit in a manner that will permit normal assembly of the entire sarcoglycan complex. To study sarcoglycan gene replacement, we introduced transgenes expressing murine gamma-sarcoglycan into muscle of normal mice. Mice expressing high levels of gamma-sarcoglycan, under the control of the muscle-specific creatine kinase promoter, developed a severe muscular dystrophy with greatly reduced muscle mass and early lethality. Marked gamma-sarcoglycan overexpression produced cytoplasmic aggregates that interfered with normal membrane targeting of gamma-sarcoglycan. Overexpression of gamma-sarcoglycan lead to the up-regulation of alpha- and beta-sarcoglycan. These data suggest that increased gamma-sarcoglycan and/or mislocalization of gamma-sarcoglycan to the cytoplasm is sufficient to induce muscle damage and provides a new model of muscular dystrophy that highlights the importance of this protein in the assembly, function, and downstream signaling of the sarcoglycan complex. Most importantly, gene dosage and promoter strength should be given serious consideration in replacement gene therapy to ensure safety in human clinical trials.

    View details for Web of Science ID 000169297900129

    View details for PubMedID 11287429

  • Cardiomyopathy in animal models of muscular dystrophy CURRENT OPINION IN CARDIOLOGY Heydemann, A., Wheeler, M. T., McNally, E. M. 2001; 16 (3): 211-217

    Abstract

    Arrhythmia and cardiomyopathy frequently accompany muscular dystrophy. In the last year, the cardiovascular consequences of muscular dystrophy gene mutations have been established through studies of murine models. These models have highlighted the potential role of primary defects in cardiac muscle as well as those secondary cardiovascular outcomes that arise from severe muscle disease. This review focuses on three areas. Recent studies using mouse models have shown that the dystrophin-associated proteins, the sarcoglycans and alpha-dystrobrevin, are critical for both cardiac and skeletal muscle membrane function, yet may exert their roles by different molecular mechanisms. New findings have shown that cytoskeletal proteins at the nuclear membrane, such as emerin and lamin AC, cause muscular dystrophy and cardiomyopathy with cardiac conduction system disease. Finally, the mechanism of cardiac and muscle degeneration in myotonic dystrophy has been re-evaluated through a series of studies using murine models. Implications for human therapy are considered in light of these new findings.

    View details for Web of Science ID 000169006500009

    View details for PubMedID 11357018

  • An E-box within the MHC IIB gene is bound by MyoD and is required for gene expression in fast muscle AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY Wheeler, M. T., Snyder, E. C., Patterson, M. N., Swoap, S. J. 1999; 276 (5): C1069-C1078

    Abstract

    The myosin heavy chain (MHC) IIB gene is selectively expressed in skeletal muscles, imparting fast contractile kinetics. Why the MHC IIB gene product is expressed in muscles like the tibialis anterior (TA) and not expressed in muscles like the soleus is currently unclear. It is shown here that the mutation of an E-box within the MHC IIB promoter decreased reporter gene activity in the fast-twitch TA muscle 90-fold as compared with the wild-type promoter. Reporter gene expression within the TA required this E-box for activation of a heterologous construct containing upstream regulatory regions of the MHC IIB promoter linked to the basal 70-kDa heat shock protein TATA promoter. Electrophoretic mobility shift assays demonstrated that mutation of the E-box prevented the binding of both MyoD and myogenin to this element. In cotransfected C2C12 myotubes and Hep G2 cells, MyoD preferentially activated the MHC IIB promoter in an E-box-dependent manner, whereas myogenin activated the MHC IIB promoter to a lesser extent, and in an E-box-independent manner. A time course analysis of hindlimb suspension demonstrated that the unweighted soleus muscle activated expression of MyoD mRNA before the de novo expression of MHC IIB mRNA. These data suggest a possible causative role for MyoD in the observed upregulation of MHC IIB in the unweighted soleus muscle.

    View details for Web of Science ID 000080245000009

    View details for PubMedID 10329954

  • Regulation of IIB MyHC expression by MyoD Wheeler, M., Swoap, S. FEDERATION AMER SOC EXP BIOL. 1998: A728