- Clinical Genetics
Clinical Assistant Professor, Pediatrics - Medical Genetics
Boards, Advisory Committees, Professional Organizations
Trainee member, American College of Medical Genetics and Genomics (ACMG) (2017 - Present)
Residency: Stanford University Division of Medical Genetics (2023) CA
Internship: Stanford University Pediatric Residency at Lucile Packard Children's Hospital (2021) CA
Medical Education: Medical University of South Carolina Registrar (2020) SC
Clinicopathologic Features of IDEDNIK (MEDNIK) Syndrome in a Term Infant: Histopathologic Features of the Gastrointestinal Tract and Report of a Novel AP1S1 Variant.
Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society
Inherited syndromes of congenital enteropathy are rare, with many genetic causes described. Mutations of the AP1S1 gene results in the syndrome of intellectual disability, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (IDEDNIK, formerly in the medical literature as MEDNIK). The clinicopathologic features of the enteropathy in IDEDNIK syndrome have not been fully explored. We describe a female infant who presented with metabolic acidosis, lethargy, and 14 watery stools per day. In the intensive care unit she required parenteral nutrition. She was found to have a novel homozygous pathogenic variant in the AP1S1 gene c.186T>G (p.Y62*). Esophagogastroduodenoscopy and colonoscopy at 6months of age were grossly normal. However, histologic sections of the duodenum showed mild villous blunting and enterocytes with cytoplasmic vacuoles. CD10 immunostaining highlighted the disrupted brush border. MOC31 immunostaining was wild-type with a membranous pattern of expression. Electron microscopy of the duodenum showed scattered enterocytes cells with shortened and disrupted apical microvilli. Although there is a mixed gap diarrhea and disrupted brush border, there are no significant inclusions typical of microvillus inclusion disease, nor tufted enterocytes typical of tufting enteropathy, making the clinical and histopathologic features for this syndrome unique.
View details for DOI 10.1177/10935266231177402
View details for PubMedID 37278357
A homozygous Gly470Ala variant in PEX6 causes severe Zellweger spectrum disorder.
American journal of medical genetics. Part A
Zellweger spectrum disorder (ZSD) is a group of autosomal recessive disorders caused by biallelic pathogenic variants in any one of the 13 PEX genes essential for peroxisomal biogenesis. We report a cohort of nine infants who presented at birth with severe neonatal features suggestive of ZSD and found to be homozygous for a variant in PEX6 (NM_000287.4:c.1409G > C[p.Gly470Ala]). All were of Mixtec ancestry and identified by the California Newborn Screening (NBS) Program to have elevated C26:0-lysophosphatidylcholine but no reportable variants in ABCD1. The clinical and biochemical features of this cohort are described within. Gly470Ala may represent a founder variant in the Mixtec population of Central California. ZSD should be considered in patients who present at birth with severe hypotonia and enlarged fontanelles, especially in the setting of an abnormal NBS, Mixtec ancestry, or family history of infant death. There is a need to further characterize the natural history of ZSD, the Gly470Ala variant, and expand upon possible genotype-phenotype correlations.
View details for DOI 10.1002/ajmg.a.63234
View details for PubMedID 37144748
Neonatal lupus is a novel cause of positive newborn screening for X-linked adrenoleukodystrophy.
American journal of medical genetics. Part A
We report three unrelated individuals, each exposed to maternal autoantibodies during gestation and found to have elevated very long-chain fatty acids (VLCFAs) in the newborn period after screening positive by California newborn screening (NBS) for X-linked adrenoleukodystrophy (ALD). Two probands presented with clinical and laboratory features of neonatal lupus erythematosus (NLE); the third had features suggestive of NLE and a known maternal history of Sjogren's syndrome and rheumatoid arthritis. In all three individuals, subsequent biochemical and molecular evaluation for primary and secondary peroxisomal disorders was nondiagnostic with normalization of VLCFAs by 15months of age. These cases add to the expanding differential diagnosis to consider in newborns who screen positive for ALD via elevated C26:0-lysophosphatidylcholine. Though the pathophysiology of how transplacental maternal anti-Ro antibodies damage fetal tissue is not well-understood, we postulate that the VLCFA elevations reflect a systemic inflammatory response and secondary peroxisomal dysfunction that improves once maternal autoantibodies wane after birth. Additional evaluation of this phenomenon is warranted to better understand the intricate biochemical, clinical, and possible therapeutic overlap between autoimmunity, inflammation, peroxisomal dysfunction, and human disease.
View details for DOI 10.1002/ajmg.a.63144
View details for PubMedID 36863699
Phenotypic variability in RERE-related disorders and the first report of an inherited variant.
American journal of medical genetics. Part A
RERE-related disorders, also known as Neurodevelopmental Disorders with or without Anomalies of the Brain, Eye, or Heart (NEDBEH), are caused by heterozygous pathogenic variants in the arginine-glutamic acid dipeptide repeats gene (RERE). Up-to-date, 20 cases have been reported with the core characteristics of developmental delay, intellectual disability, and/or autism spectrum disorder. Here, we describe three additional cases. In the first case, the patient was found to have a previously reported de novo missense variant; her clinical findings of global developmental delay, intellectual disability, autism spectrum disorder, vision abnormalities, musculoskeletal anomalies, dysmorphic facial features, and a congenital heart defect strengthen existing genotype-phenotype correlations. We also describe the first inherited variant in RERE, found in a patient (case 2) with developmental delay, autism, and hyperopia and his mother (case 3) with ADHD, myopia, and history of mild speech delay. Lastly, by summarizing the clinical features presented in the 23 cases now reported, we provide an updated review of the literature.
View details for DOI 10.1002/ajmg.a.62952
View details for PubMedID 36053530
A survey of program directors for combined pediatrics and medical genetics and genomics residency programs: Perspectives when evaluating applicants.
American journal of medical genetics. Part A
While combined pediatrics and medical genetics and genomics residency programs are growing in number and applicants, there are still workforce shortages within the medical genetics field. Medical students would benefit from additional information on the training pathways and insight into the application process itself. Program Directors of combined pediatrics and medical genetics and genomics residency programs were surveyed to characterize factors that influence interview selection and rank list decisions, application logistics, recruitment, and training pathways. When evaluating applicants, representatives from both pediatrics and medical genetics are involved in the screening process. Additionally, both groups value prior research experience, but do not have a clear preference for a particular subcategory or domain of research. Most program directors think that all currently-available training pathways can provide optimal training. Further action is needed to provide medical students with the knowledge to make more informed decisions about their career and medical school advisors with objective data to counsel students. There was support among program directors to initiate consideration of creating a pathway for medical students to match directly into a medical genetics and genomics residency.
View details for DOI 10.1002/ajmg.a.62846
View details for PubMedID 35633299
- A survey assessing adoption of the ACMG-AMP guidelines for interpreting sequence variants and identification of areas for continued improvement GENETICS IN MEDICINE 2019; 21 (8): 1699-1701
Development of Clinical Domain Working Groups for the Clinical Genome Resource (ClinGen): lessons learned and plans for the future
GENETICS IN MEDICINE
2019; 21 (4): 987-993
The Clinical Genome Resource (ClinGen) is supported by the National Institutes of Health (NIH) to develop expertly curated and freely accessible resources defining the clinical relevance of genes and variants for use in precision medicine and research. To facilitate expert input, ClinGen has formed Clinical Domain Working Groups (CDWGs) to leverage the collective knowledge of clinicians, laboratory diagnosticians, and researchers. In the initial phase of ClinGen, CDWGs were launched in the cardiovascular, hereditary cancer, and inborn errors of metabolism clinical fields. These early CDWGs established the infrastructure necessary to implement standardized processes developed or adopted by ClinGen working groups for the interpretation of gene-disease associations and variant pathogenicity, and provided a sustainable model for the formation of future disease-focused curation groups. The establishment of CDWGs requires recruitment of international experts to broadly represent the interests of their field and ensure that assertions made are reliable and widely accepted. Building on the successes, challenges, and trade-offs made in establishing the original CDWGs, ClinGen has developed standard operating procedures for the development of CDWGs in new clinical domains, while maximizing efforts to scale up curation and facilitate involvement of external groups who wish to utilize ClinGen methods and infrastructure for expert curation.
View details for DOI 10.1038/s41436-018-0267-2
View details for Web of Science ID 000463167300027
View details for PubMedID 30181607
View details for PubMedCentralID PMC6401338
Development of a consent resource for genomic data sharing in the clinical setting
GENETICS IN MEDICINE
2019; 21 (1): 81-88
Data sharing between clinicians, laboratories, and patients is essential for improvements in genomic medicine, but obtaining consent for individual-level data sharing is often hindered by a lack of time and resources. To address this issue, the Clinical Genome Resource (ClinGen) developed tools to facilitate consent, including a one-page consent form and online supplemental video with information on key topics, such as risks and benefits of data sharing.To determine whether the consent form and video accurately conveyed key data sharing concepts, we surveyed 5,162 members of the general public. We measured comprehension at baseline, after reading the form and watching the video. Additionally, we assessed participants' attitudes toward genomic data sharing.Participants' performance on comprehension questions significantly improved over baseline after reading the form and continued to improve after watching the video.Results suggest reading the form alone provided participants with important knowledge regarding broad data sharing, and watching the video allowed for broader comprehension. These materials are now available at http://www.clinicalgenome.org/share . These resources will provide patients a straightforward way to share their genetic and health information, and improve the scientific community's access to data generated through routine healthcare.
View details for DOI 10.1038/s41436-018-0017-5
View details for Web of Science ID 000455403400012
View details for PubMedID 29899502
View details for PubMedCentralID PMC6292744
Points to consider for sharing variant-level information from clinical genetic testing with ClinVar
COLD SPRING HARBOR MOLECULAR CASE STUDIES
2018; 4 (1)
Data sharing between laboratories, clinicians, researchers, and patients is essential for improvements and standardization in genomic medicine; encouraging genomic data sharing (GDS) is a key activity of the National Institutes of Health (NIH)-funded Clinical Genome Resource (ClinGen). The ClinGen initiative is dedicated to evaluating the clinical relevance of genes and variants for use in precision medicine and research. Currently, data originating from each of the aforementioned stakeholder groups is represented in ClinVar, a publicly available repository of genomic variation, and its relationship to human health hosted by the National Center for Biotechnology Information at the NIH. Although policies such as the 2014 NIH GDS policy are clear regarding the mandate for informed consent for broad data sharing from research participants, no clear guidance exists on the level of consent appropriate for the sharing of information obtained through clinical testing to advance knowledge. ClinGen has collaborated with ClinVar and the National Human Genome Research Institute to develop points to consider for clinical laboratories on sharing de-identified variant-level data in light of both the NIH GDS policy and the recent updates to the Common Rule. We propose specific data elements from interpreted genomic variants that are appropriate for submission to ClinVar when direct patient consent was not sought and describe situations in which obtaining informed consent is recommended.
View details for DOI 10.1101/mcs.a002345
View details for Web of Science ID 000449982700002
View details for PubMedID 29437798
View details for PubMedCentralID PMC5793773
A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation
GENETICS IN MEDICINE
2016; 18 (12): 1258-1268
Genome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder enables clinical interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource of information regarding the clinical relevance of genomic variation for use in precision medicine and research.We developed a practical, standardized protocol to identify available evidence and generate qualitative summary reports of actionability for disorders and associated genes. We applied a semiquantitative metric to score actionability.We generated summary reports and actionability scores for the 56 genes and associated disorders recommended by the American College of Medical Genetics and Genomics for return as secondary findings from clinical genome-scale sequencing. We also describe the challenges that arose during the development of the protocol that highlight important issues in characterizing actionability across a range of disorders.The ClinGen framework for actionability assessment will assist research and clinical communities in making clear, efficient, and consistent determinations of actionability based on transparent criteria to guide analysis and reporting of findings from clinical genome-scale sequencing.Genet Med 18 12, 1258-1268.
View details for DOI 10.1038/gim.2016.40
View details for Web of Science ID 000389563700014
View details for PubMedID 27124788
View details for PubMedCentralID PMC5085884
Using ClinVar as a Resource to Support Variant Interpretation.
Current protocols in human genetics
2016; 89: 8.16.1-8.16.23
ClinVar is a freely accessible, public archive of reports of the relationships among genomic variants and phenotypes. To facilitate evaluation of the clinical significance of each variant, ClinVar aggregates submissions of the same variant, displays supporting data from each submission, and determines if the submitted clinical interpretations are conflicting or concordant. The unit describes how to (1) identify sequence and structural variants of interest in ClinVar by multiple searching approaches, including Variation Viewer and (2) understand the display of submissions to ClinVar and the evidence supporting each interpretation. By following this protocol, ClinVar users will be able to learn how to incorporate the wealth of resources and knowledge in ClinVar into variant curation and interpretation.
View details for DOI 10.1002/0471142905.hg0816s89
View details for PubMedID 27037489
View details for PubMedCentralID PMC4832236
Providing Access to Genomic Variant Knowledge in a Healthcare Setting: A Vision for the ClinGen Electronic Health Records Workgroup.
Clinical pharmacology and therapeutics
2016; 99 (2): 157–60
The Clinical Genome Resource (ClinGen) is a National Institutes of Health (NIH)-funded collaborative program that brings together a variety of projects designed to provide high-quality, curated information on clinically relevant genes and variants. ClinGen's EHR (Electronic Health Record) Workgroup aims to ensure that ClinGen is accessible to providers and patients through EHR and related systems. This article describes the current scope of these efforts and progress to date. The ClinGen public portal can be accessed at www.clinicalgenome.org.
View details for PubMedID 26418054
After Myriad: Genetic Testing in the Wake of Recent Supreme Court Decisions about Gene Patents.
Current genetic medicine reports
2014; 2 (4): 223-241
Genetic testing is becoming more common and more powerful by the day. The costs of the underlying DNA sequencing technology are plummeting, making it likely that tests based on it will become even more pervasive. The use of tests to determine DNA sequence to help make clinical decisions is here to stay. DNA sequencing is also finding new uses in forensics, determination of ancestry, understanding the history and genetic lineages of human populations and many other applications.
View details for DOI 10.1007/s40142-014-0055-5
View details for PubMedID 25401053
View details for PubMedCentralID PMC4225052