James Priest

All Publications

• Adults With Mild-to-Moderate Congenital Heart Disease Demonstrate Measurable Neurocognitive Deficits. Journal of the American Heart Association Perrotta, M. L., Saha, P. n., Zawadzki, R. n., Beidelman, M. n., Ingelsson, E. n., Lui, G. K., Priest, J. R. 2020: e015379

  Abstract

  Background Neurocognitive impairment is a common complication of congenital heart disease (CHD) as well as acquired cardiovascular disease. Data are limited on neurocognitive function in adults with CHD (ACHD). Methods and Results A total of 1020 individuals with mild-to-moderate ACHD and 497 987 individuals without ACHD from the volunteer-based UK Biobank study underwent neurocognitive tests for fluid intelligence, reaction time, numeric memory, symbol-digit substitution, and trail making at enrollment and follow-up. Performance scores were compared before and after exclusion of preexisting stroke or coronary artery disease as measures of cerebro- and cardiovascular disease. Individuals with ACHD had significantly poorer performance on alpha-numeric trail making, a measure of visual attention and cognitive flexibility, spending 6.4 seconds longer on alpha-numeric trail making (95% CI, 3.0-9.9 seconds, P=0.002) and 2.5 seconds longer on numeric trail making (95% CI, 0.5-4.6 seconds, P=0.034), a measure of visual attention and processing speed. The ACHD cohort had modestly lower performance on symbol-digit substitution, a measure of processing speed, with 0.9 fewer correct substitutions (95% CI, - 1.5 to - 0.2 substitutions, P=0.021). After excluding preexisting stroke or coronary artery disease, individuals with ACHD continued to show poorer performance in all 6 domains (P=NS). Conclusions Individuals with mild-to-moderate ACHD had poorer neurocognitive performance, most significantly in tests of cognitive flexibility, analogous to deficits in children with CHD. These differences appear to be driven by increased burden of cerebro- and cardiovascular disease among individuals with ACHD.

  View details for DOI 10.1161/JAHA.119.015379

  View details for PubMedID 32981450

• Association of congenital cardiovascular malformation and neuropsychiatric phenotypes with 15q11.2 (BP1-BP2) deletion in the UK Biobank. European journal of human genetics : EJHG Williams, S. G., Nakev, A. n., Guo, H. n., Frain, S. n., Tenin, G. n., Liakhovitskaia, A. n., Saha, P. n., Priest, J. R., Hentges, K. E., Keavney, B. D. 2020

  Abstract

  Deletion of a non-imprinted 500kb genomic region at chromosome 15q11.2, between breakpoints 1 and 2 of the Prader-Willi/Angelman locus (BP1-BP2 deletion), has been associated in previous studies with phenotypes including congenital cardiovascular malformations (CVM). Previous studies investigating association between BP1-BP2 deletion and CVM have tended to recruit cases with rarer and more severe CVM phenotypes; the impact of CVM on relatively unselected population cohorts, anticipated to contain chiefly less severe but commoner CHD phenotypes, is relatively unexplored. More precisely defining the impact of BP1-BP2 deletion on CVM risk could be useful to guide genetic counselling, since the deletion is frequently identified in the neurodevelopmental clinic. Using the UK Biobank (UKB) cohort of ~500,000 individuals, we identified individuals with CVM and investigated the association with deletions at the BP1-BP2 locus. In addition, we assessed the association of BP1-BP2 deletions with neuropsychiatric diagnoses, cognitive function and academic achievement. Cases of CVM had an increased prevalence of the deletion compared with controls (0.64%; OR = 1.73 [95% CI 1.08-2.75]; p = 0.03), as did those with neuropsychiatric diagnoses (0.68%; OR = 1.84 [95% CI 1.23-2.75]; p = 0.004). We conclude that BP1-BP2 deletion moderately increases the risk of the generally milder, but commoner, CVM phenotypes seen in this unselected population, in addition to its previously demonstrated association in case/control studies ascertained for CVM.

  View details for DOI 10.1038/s41431-020-0626-8

  View details for PubMedID 32327713

• Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade. Proceedings of the National Academy of Sciences of the United States of America Wang, Y. n., Nanda, V. n., Direnzo, D. n., Ye, J. n., Xiao, S. n., Kojima, Y. n., Howe, K. L., Jarr, K. U., Flores, A. M., Tsantilas, P. n., Tsao, N. n., Rao, A. n., Newman, A. A., Eberhard, A. V., Priest, J. R., Ruusalepp, A. n., Pasterkamp, G. n., Maegdefessel, L. n., Miller, C. L., Lind, L. n., Koplev, S. n., Björkegren, J. L., Owens, G. K., Ingelsson, E. n., Weissman, I. L., Leeper, N. J. 2020

  Abstract

  Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of "dedifferentiated" vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsonin-sensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don't eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.

  View details for DOI 10.1073/pnas.2006348117

  View details for PubMedID 32541024

• Maternal Obesity and Diabetes Mellitus as Risk Factors for Congenital Heart Disease in the Offspring. Journal of the American Heart Association Helle, E. n., Priest, J. R. 2020: e011541

  Abstract

  Congenital heart disease (CHD) is the most common anatomical malformation occurring live-born infants and an increasing cause of morbidity and mortality across the lifespan and throughout the world. Population-based observations have long described associations between maternal cardiometabolic disorders and the risk of CHD in the offspring. Here we review the epidemiological evidence and clinical observations relating maternal obesity and diabetes mellitus to the risk of CHD offspring with particular attention to mechanistic models of maternal-fetal risk transmission and first trimester disturbances of fetal cardiac development. A deeper understanding of maternal risk factors holds the potential to improve both prenatal detection of CHD by identifying at-risk pregnancies, along with primary prevention of disease by improving preconception and prenatal treatment of at-risk mothers.

  View details for DOI 10.1161/JAHA.119.011541

  View details for PubMedID 32308111

• Exome-Based Case-Control Analysis Highlights the Pathogenic Role of Ciliary Genes in Transposition of the Great Arteries. Circulation research Liu, X. n., Chen, W. n., Li, W. n., Priest, J. R., Fu, Y. n., Pang, K. J., Ma, B. n., Han, B. n., Liu, X. n., Hu, S. n., Zhou, Z. n. 2020

  Abstract

  Rationale: Transposition of the great arteries (TGA) is one of the most severe types of congenital heart diseases (CHD). Understanding the clinical characteristics and pathogenesis of TGA is therefore urgently needed for patient management of this severe disease. However, the clinical characteristics and genetic etiology underlying TGA remain largely unexplored. Objective: We sought to systematically examine the clinical characteristics and genetic etiology for isolated nonsyndromic TGA. Methods and Results: We recruited 249 TGA patients (66 family trios) and performed whole-exome sequencing. The incidence of patent ductus arteriosus in dextro-TGA (52.7%) and dextrocardia/mesocardia in congenitally corrected TGA (32.8%) were significantly higher than that in other subtypes. A high prevalence of bicuspid pulmonic valve (9.6%) was observed in TGA patients. Similar results were observed in a replication group of TGA (n=132). Through a series of bioinformatics filtering steps, we obtained 82 candidate genes harboring potentially damaging de novo, loss of function, compound heterozygous or X-linked recessive variants. Established CHD-causing genes, such as FOXH1, were found among the list of candidate genes. A total of 19 ciliary genes harboring rare potentially damaging variants were also found; for example, DYNC2LI1 with a de novo putatively damaging variant. The enrichment of ciliary genes supports the roles of cilia in the pathogenesis of TGA. In total, 33% of the TGA probands had more than one candidate gene hit by putatively deleterious variants, suggesting that a portion of the TGA cases were probably affected by oligogenic or polygenic inheritance. Conclusions: The findings of clinical characteristic analyses have important implications for TGA patient stratification. The results of genetic analyses highlight the pathogenic role of ciliary genes and a complex genetic architecture underlying TGA.

  View details for DOI 10.1161/CIRCRESAHA.119.315821

  View details for PubMedID 32078439

• Ivy: Instrumental Variable Synthesis for Causal Inference Kuangy, Z., Sala, F., Sohoni, N., Wu, S., Cordova-Palomera, A., Dunnmon, J., Priest, J., Re, C., Chiappa, S., Calandra, R. ADDISON-WESLEY PUBL CO. 2020: 398–409

  View details for Web of Science ID 000559931301087

• Association between the 4p16 genomic locus and different types of congenital heart disease: results from adult survivors in the UK Biobank. Scientific reports Cordova-Palomera, A., Priest, J. R. 2019; 9 (1): 16515

  Abstract

  Congenital heart disease is the most common birth defect in newborns and the leading cause of death in infancy, affecting nearly 1% of live births. A locus in chromosome 4p16, adjacent to MSX1 and STX18, has been associated with atrial septal defects (ASD) in multiple European and Chinese cohorts. Here, genotyping data from the UK Biobank was used to test for associations between this locus and congenital heart disease in adult survivors of left ventricular outflow tract obstruction (n=164) and ASD (n=223), with a control sample of 332,788 individuals, and a meta-analysis of the new and existing ASD data was performed. The results show an association between the previously reported markers at 4p16 and risk for either ASD or left ventricular outflow tract obstruction, with effect sizes similar to the published data (OR between 1.27-1.45; all p<0.05). Differences in allele frequencies remained constant through the studied age range (40-70 years), indicating that the variants themselves do not drive lethal genetic defects. Meta-analysis shows an OR of 1.35 (95% CI: 1.25-1.46; p<10-4) for the association with ASD. The findings show that the genetic associations with ASD can be generalized to adult survivors of both ASD and left ventricular lesions. Although the 4p16 associations are statistically compelling, the mentioned alleles confer only a small risk for disease and their frequencies in this adult sample are the same as in children, likely limiting their clinical significance. Further epidemiological and functional studies may elicit factors triggering disease in interaction with the risk alleles.

  View details for DOI 10.1038/s41598-019-52969-x

  View details for PubMedID 31712678

• Phenome-wide Burden of Copy-Number Variation in the UK Biobank. American journal of human genetics Aguirre, M., Rivas, M. A., Priest, J. 2019

  Abstract

  Copy-number variations (CNVs) represent a significant proportion of the genetic differences between individuals and many CNVs associate causally with syndromic disease and clinical outcomes. Here, we characterize the landscape of copy-number variation and their phenome-wide effects in a sample of 472,228 array-genotyped individuals from the UK Biobank. In addition to population-level selection effects against genic loci conferring high mortality, we describe genetic burden from potentially pathogenic and previously uncharacterized CNV loci across more than 3,000 quantitative and dichotomous traits, with separate analyses for common and rare classes of variation. Specifically, we highlight the effects of CNVs at two well-known syndromic loci 16p11.2 and 22q11.2, previously uncharacterized variation at 9p23, and several genic associations in the context of acute coronary artery disease and high body mass index. Our data constitute a deeply contextualized portrait of population-wide burden of copy-number variation, as well as a series of dosage-mediated genic associations across the medical phenome.

  View details for DOI 10.1016/j.ajhg.2019.07.001

  View details for PubMedID 31353025

• Risk factors associated with the development of double-inlet ventricle congenital heart disease BIRTH DEFECTS RESEARCH Paige, S. L., Yang, W., Priest, J. R., Botto, L. D., Shaw, G. M., Collins, R., Natl Birth Defects Prevention 2019; 111 (11): 640–48

  View details for DOI 10.1002/bdr2.1501

  View details for Web of Science ID 000473561000003

• Substantial Cardiovascular Morbidity in Adults With Lower-Complexity Congenital Heart Disease CIRCULATION Saha, P., Potiny, P., Rigdon, J., Morello, M., Tcheandjieu, C., Romfh, A., Fernandes, S. M., McElhinney, D. B., Bernstein, D., Lui, G. K., Shaw, G. M., Ingelsson, E., Priest, J. R. 2019; 139 (16): 1889–99

  View details for DOI 10.1161/CIRCULATIONAHA.118.037064

  View details for Web of Science ID 000469321500006

• Risk factors associated with the development of double-inlet ventricle congenital heart disease. Birth defects research Paige, S. L., Yang, W., Priest, J. R., Botto, L. D., Shaw, G. M., Collins, R. T., National Birth Defects Prevention Study 2019

  Abstract

  BACKGROUND: Congenital heart disease (CHD) is the most common birth defect group and a significant contributor to neonatal and infant death. CHD with single ventricle anatomy, including hypoplastic left heart syndrome (HLHS), tricuspid atresia (TA), and various double-inlet ventricle (DIV) malformations, is the most complex with the highest mortality. Prenatal risk factors associated with HLHS have been studied, but such data for DIV are lacking.METHODS: We analyzed DIV cases and nonmalformed controls in the National Birth Defects Prevention Study, a case-control, multicenter population-based study of birth defects. Random forest analysis identified potential predictor variables for DIV, which were included in multivariable models to estimate effect magnitude and directionality.RESULTS: Random forest analysis identified pre-pregnancy diabetes, history of maternal insulin use, maternal total lipid intake, paternal race, and intake of several foods and nutrients as potential predictors of DIV. Logistic regression confirmed pre-pregnancy diabetes, maternal insulin use, and paternal race as risk factors for having a child with DIV. Additionally, higher maternal total fat intake was associated with a reduced risk.CONCLUSIONS: Maternal pre-pregnancy diabetes and history of insulin use were associated with an increased risk of having an infant with DIV, while maternal lipid intake had an inverse association. These novel data provide multiple metabolic pathways for investigation to identify better the developmental etiologies of DIV and suggest that public health interventions targeting diabetes prevention and management in women of childbearing age could reduce CHD risk.

  View details for PubMedID 30920163

• NEUROCOGNITIVE DEFICITS IN ADULT CONGENITAL HEART DISEASE: DOES CORONARY ARTERY DISEASE ADD INSULT TO INJURY? Morello, M. L., Beidelman, M., Saha, P., Ingelsson, E., Shaw, G., Lui, G., Priest, J. ELSEVIER SCIENCE INC. 2019: 566

  View details for Web of Science ID 000460565900566

• Loss of function, missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts GENETIC EPIDEMIOLOGY Helle, E., Cordova-Palomera, A., Ojala, T., Saha, P., Potiny, P., Gustafsson, S., Ingelsson, E., Bamshad, M., Nickerson, D., Chong, J. X., Ashley, E., Priest, J. R., Univ Washington Ctr Mendelia 2019; 43 (2): 215–26

  View details for DOI 10.1002/gepi.22176

  View details for Web of Science ID 000462061900008

• Substantial Cardiovascular Morbidity in Adults with Lower-Complexity Congenital Heart Disease. Circulation Saha, P., Potiny, P., Rigdon, J., Morello, M., Tcheandjieu, C., Romfh, A., Fernandes, S. M., McElhinney, D. B., Bernstein, D., Lui, G. K., Shaw, G. M., Ingelsson, E., Priest, J. R. 2019

  Abstract

  BACKGROUND: Although lower-complexity cardiac malformations constitute the majority of adult congenital heart disease (ACHD), the long-term risks of adverse cardiovascular events and relationship with conventional risk factors in this population are poorly understood. We aimed to quantify the risk of adverse cardiovascular events associated with lower-complexity ACHD that is unmeasured by conventional risk factors.METHODS: A multi-tiered classification algorithm was used to select individuals with lower-complexity ACHD and individuals without ACHD for comparison amongst >500,000 British adults in the UK Biobank (UKB). ACHD diagnoses were sub-classified as "isolated aortic valve (AoV)" and "non-complex" defects. Time-to-event analyses were conducted for primary endpoints of fatal or non-fatal acute coronary syndrome (ACS), ischemic stroke, heart failure (HF), and atrial fibrillation, and a secondary combined endpoint for major adverse cardiovascular event (MACE). Maximum follow-up time for the study period was 22 years using retrospectively and prospectively collected data from the UKB.RESULTS: We identified 2,006 individuals with lower-complexity ACHD and 497,983 unexposed individuals in the UKB (median [IQR] age at enrollment 58 [51,63]). Of the ACHD-exposed group, 59% were male; 51% were current or former smokers; 30% were obese; 69%, 41%, and 7% were diagnosed or treated for hypertension, hyperlipidemia, and diabetes respectively. After adjustment for 12 measured cardiovascular risk factors, ACHD remained strongly associated with the primary endpoints, with hazard ratios (HR) ranging from 2.0 (95% confidence interval [CI] 1.5-2.8, p<0.001) for ACS to 13.0 (95% CI 9.4-18.1, p<0.001) for HF. ACHD-exposed individuals with ≤2 cardiovascular risk factors had a 29% age-adjusted incidence rate of MACE in contrast to 13% in non-ACHD individuals with ≥5 risk factors.CONCLUSIONS: Individuals with lower-complexity ACHD had higher burden of adverse cardiovascular events relative to the general population that was unaccounted for by conventional cardiovascular risk factors. These findings highlight the need for closer surveillance of patients with mild to moderate ACHD and further investigation into management and mechanisms of cardiovascular risk unique to this growing population of high-risk adults.

  View details for PubMedID 30813762

• 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

  View details for DOI 10.1093/nar/gky1105

  View details for Web of Science ID 000462587400141

• Single-Cell RNA-Seq of the Developing Cardiac Outflow Tract Reveals Convergent Development of the Vascular Smooth Muscle Cells. Cell reports Liu, X. n., Chen, W. n., Li, W. n., Li, Y. n., Priest, J. R., Zhou, B. n., Wang, J. n., Zhou, Z. n. 2019; 28 (5): 1346–61.e4

  Abstract

  Cardiac outflow tract (OFT) is a major hotspot for congenital heart diseases. A thorough understanding of the cellular diversity, transitions, and regulatory networks of normal OFT development is essential to decipher the etiology of OFT malformations. We performed single-cell transcriptomic sequencing of 55,611 mouse OFT cells from three developmental stages that generally correspond to the early, middle, and late stages of OFT remodeling and septation. Known cellular transitions, such as endothelial-to-mesenchymal transition, have been recapitulated. In particular, we identified convergent development of the vascular smooth muscle cell (VSMC) lineage where intermediate cell subpopulations were found to be involved in either myocardial-to-VSMC trans-differentiation or mesenchymal-to-VSMC transition. Finally, we uncovered transcriptional regulators potentially governing cellular transitions. Our study provides a single-cell reference map of cell states for normal OFT development and paves the way for further studies of the etiology of OFT malformations at the single-cell level.

  View details for DOI 10.1016/j.celrep.2019.06.092

  View details for PubMedID 31365875

• IMPACT OF CARDIAC ALGORITHM ON CYTOGENETIC TESTING Floyd, B. J., Hintz, S. R., Suarez, C. J., Cherry, A., Yu, L., Benitz, W., Priest, J. R., Wright, G. E., Bhombal, S., Davis, A., Chock, V. Y., Weigel, N., Kobayashi, D., Fluharty, B., Stevenson, D. BMJ PUBLISHING GROUP. 2019: 207

  View details for DOI 10.1136/jim-2018-000939.327

  View details for Web of Science ID 000457712500337

• Weakly supervised classification of rare aortic valve malformations using unlabeled cardiac MRI sequences Nature Communications Fries, J. A., Varma, P., Chen, V. S., Xiao, K., Tejeda, H., Saha, P., Dunnmon, J., Chubb, H., Maskatia, S., Fiterau, M., Delp, S., Ashley, E., Ré, C., Priest, J. R. 2019; 10

  View details for DOI 10.1038/s41467-019-11012-3

• Loss of function, missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts. Genetic epidemiology Helle, E., Cordova-Palomera, A., Ojala, T., Saha, P., Potiny, P., Gustafsson, S., Ingelsson, E., Bamshad, M., Nickerson, D., Chong, J. X., University of Washington Center for Mendelian Genomics, Ashley, E., Priest, J. R. 2018

  Abstract

  Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes.

  View details for PubMedID 30511478

• 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

• CONGENITAL HEART DISEASE CONFERS SUBSTANTIAL RISK OF ACQUIRED CARDIOVASCULAR DISEASE AMONGST BRITISH ADULTS Saha, P., Potiny, P., Tcheandjieu, C., Fernandes, S. M., Romfh, A., Bernstein, D., Lui, G. K., Ingelsson, E., Priest, J. ELSEVIER SCIENCE INC. 2018: 553

  View details for DOI 10.1016/S0735-1097(18)31094-5

  View details for Web of Science ID 000429659701403

• Ring Finger Protein 207 Degrades T613M Kv11.1 Channel Ledford, H. A., Park, S., Sirish, P., Xu, W., Emigh, A. M., Timofeyev, V., Priest, J. R., Perez, M. V., Ashley, E. A., Yarov-Yarovoy, V., Zhang, X., Chiamvimonvat, N. CELL PRESS. 2018: 625A

  View details for Web of Science ID 000430563300120

• First Trimester Plasma Glucose Values in Women without Diabetes are Associated with Risk for Congenital Heart Disease in Offspring. The Journal of pediatrics Helle, E. I., Biegley, P. n., Knowles, J. W., Leader, J. B., Pendergrass, S. n., Yang, W. n., Reaven, G. R., Shaw, G. M., Ritchie, M. n., Priest, J. R. 2018; 195: 275–78

  Abstract

  In a retrospective study of 19 171 mother-child dyads, elevated random plasma glucose values during early pregnancy were directly correlated with increased risk for congenital heart disease in offspring. Plasma glucose levels proximal to the period of cardiac development may represent a modifiable risk factor for congenital heart disease in expectant mothers without diabetes.

  View details for PubMedID 29254757

  View details for PubMedCentralID PMC5869072

• Birthweight, Type 2 Diabetes Mellitus, and Cardiovascular Disease: Addressing the Barker Hypothesis With Mendelian Randomization. Circulation. Genomic and precision medicine Zanetti, D. n., Tikkanen, E. n., Gustafsson, S. n., Priest, J. R., Burgess, S. n., Ingelsson, E. n. 2018; 11 (6): e002054

  Abstract

  Low birthweight has been associated with a higher risk of hypertension, type 2 diabetes mellitus (T2D), and cardiovascular disease. The Barker hypothesis posits that intrauterine growth restriction resulting in lower birthweight is causal for these diseases, but causality is difficult to infer from observational studies.We performed regression analyses to assess associations of birthweight with cardiovascular disease and T2D in 237 631 individuals from the UK Biobank. Further, we assessed the causal relationship of such associations using Mendelian randomization.In the observational analyses, birthweight showed inverse associations with systolic and diastolic blood pressure (β, -0.83 and -0.26; per raw unit in outcomes and SD change in birthweight; 95% confidence interval [CI], -0.90 to -0.75 and -0.31 to -0.22, respectively), T2D (odds ratio, 0.83; 95% CI, 0.79-0.87), lipid-lowering treatment (odds ratio, 0.84; 95% CI, 0.81-0.86), and coronary artery disease (hazard ratio, 0.85; 95% CI, 0.78-0.94), whereas the associations with adult body mass index and body fat (β, 0.04 and 0.02; per SD change in outcomes and birthweight; 95% CI, 0.03-0.04 and 0.01-0.02, respectively) were positive. The Mendelian randomization analyses indicated inverse causal associations of birthweight with low-density lipoprotein cholesterol, 2-hour glucose, coronary artery disease, and T2D and positive causal association with body mass index but no associations with blood pressure.Our study indicates that lower birthweight, used as a proxy for intrauterine growth retardation, is causally related with increased susceptibility to coronary artery disease and T2D. This causal relationship is not mediated by adult obesity or hypertension.

  View details for PubMedID 29875125

• Beyond Gene Panels: Whole Exome Sequencing for Diagnosis of Congenital Heart Disease. Circulation. Genomic and precision medicine Paige, S. L., Saha, P. n., Priest, J. R. 2018; 11 (3): e002097

  View details for PubMedID 29555674

• A primer to clinical genome sequencing. Current opinion in pediatrics Priest, J. R. 2017; 29 (5): 513-519

  Abstract

  Genome sequencing is now available as a clinical diagnostic test. There is a significant knowledge and translation gap for nongenetic specialists of the processes necessary to generate and interpret clinical genome sequencing. The purpose of this review is to provide a primer on contemporary clinical genome sequencing for nongenetic specialists describing the human genome project, current techniques and applications in genome sequencing, limitations of current technology, and techniques on the horizon.As currently implemented, genome sequencing compares short pieces of an individual's genome with a reference sequence developed by the human genome project. Genome sequencing may be used for obtaining timely diagnostic information, cancer pharmacogenomics, or in clinical cases when previous genetic testing has not revealed a clear diagnosis. At present, the implementation of clinical genome sequencing is limited by the availability of clinicians qualified for interpretation, and current techniques in used clinical testing do not detect all types of genetic variation present in a single genome.Clinicians considering a genetic diagnosis have wide array of testing choices which now includes genome sequencing. Although not a comprehensive test in its current form, genome sequencing offers more information than gene-panel or exome sequencing and has the potential to replace targeted single-gene or gene-panel testing in many clinical scenarios.

  View details for DOI 10.1097/MOP.0000000000000532

  View details for PubMedID 28786837

  View details for PubMedCentralID PMC5590671

• Transcriptomic Profiling Maps Anatomically Patterned Subpopulations among Single Embryonic Cardiac Cells DEVELOPMENTAL CELL Li, G., Xu, A., Sim, S., Priest, J. R., Tian, X., Khan, T., Quertermous, T., Zhou, B., Tsao, P. S., Quake, S. R., Wu, S. M. 2016; 39 (4): 491-507

  Abstract

  Embryonic gene expression intricately reflects anatomical context, developmental stage, and cell type. To address whether the precise spatial origins of cardiac cells can be deduced solely from their transcriptional profiles, we established a genome-wide expression database from 118, 949, and 1,166 single murine heart cells at embryonic day 8.5 (e8.5), e9.5, and e10.5, respectively. We segregated these cells by type using unsupervised bioinformatics analysis and identified chamber-specific genes. Using a random forest algorithm, we reconstructed the spatial origin of single e9.5 and e10.5 cardiomyocytes with 92.0% ± 3.2% and 91.2% ± 2.8% accuracy, respectively (99.4% ± 1.0% and 99.1% ± 1.1% if a ±1 zone margin is permitted) and predicted the second heart field distribution of Isl-1-lineage descendants. When applied to Nkx2-5(-/-) cardiomyocytes from murine e9.5 hearts, we showed their transcriptional alteration and lack of ventricular phenotype. Our database and zone classification algorithm will enable the discovery of novel mechanisms in early cardiac development and disease.

  View details for DOI 10.1016/j.devcel.2016.10.014

  View details for Web of Science ID 000389162800013

  View details for PubMedID 27840109

• Early somatic mosaicism is a rare cause of long-QT syndrome PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Priest, J. R., Gawad, C., Kahlig, K. M., Yu, J. K., O'Hara, T., Boyle, P. M., Rajamani, S., Clark, M. J., Garcia, S. T., Ceresnak, S., Harris, J., Boyle, S., Dewey, F. E., Malloy-Walton, L., Dunn, K., Grove, M., Perez, M. V., Neff, N. F., Chen, R., Maeda, K., Dubin, A., Belardinelli, L., West, J., Antolik, C., Macaya, D., Quertermous, T., Trayanova, N. A., Quake, S. R., Ashley, E. A. 2016; 113 (41): 11555-11560

  Abstract

  Somatic mosaicism, the occurrence and propagation of genetic variation in cell lineages after fertilization, is increasingly recognized to play a causal role in a variety of human diseases. We investigated the case of life-threatening arrhythmia in a 10-day-old infant with long QT syndrome (LQTS). Rapid genome sequencing suggested a variant in the sodium channel NaV1.5 encoded by SCN5A, NM_000335:c.5284G > T predicting p.(V1762L), but read depth was insufficient to be diagnostic. Exome sequencing of the trio confirmed read ratios inconsistent with Mendelian inheritance only in the proband. Genotyping of single circulating leukocytes demonstrated the mutation in the genomes of 8% of patient cells, and RNA sequencing of cardiac tissue from the infant confirmed the expression of the mutant allele at mosaic ratios. Heterologous expression of the mutant channel revealed significantly delayed sodium current with a dominant negative effect. To investigate the mechanism by which mosaicism might cause arrhythmia, we built a finite element simulation model incorporating Purkinje fiber activation. This model confirmed the pathogenic consequences of cardiac cellular mosaicism and, under the presenting conditions of this case, recapitulated 2:1 AV block and arrhythmia. To investigate the extent to which mosaicism might explain undiagnosed arrhythmia, we studied 7,500 affected probands undergoing commercial gene-panel testing. Four individuals with pathogenic variants arising from early somatic mutation events were found. Here we establish cardiac mosaicism as a causal mechanism for LQTS and present methods by which the general phenomenon, likely to be relevant for all genetic diseases, can be detected through single-cell analysis and next-generation sequencing.

  View details for DOI 10.1073/pnas.1607187113

  View details for PubMedID 27681629

• Standards of Evidence and Mechanistic Inference in Autosomal Recessive Hypercholesterolemia ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Priest, J. R., Knowles, J. W. 2016; 36 (8): 1465-1466

  View details for DOI 10.1161/ATVBAHA.116.307714

  View details for Web of Science ID 000381474000002

  View details for PubMedID 27466618

• Prepregnancy Diabetes and Offspring Risk of Congenital Heart Disease A Nationwide Cohort Study CIRCULATION Oyen, N., Diaz, L. J., Leirgul, E., Boyd, H. A., Priest, J., Mathiesen, E. R., Quertermous, T., Wohlfahrt, J., Melbye, M. 2016; 133 (23): 2243-2253

  Abstract

  Maternal diabetes mellitus is associated with an increased risk of offspring congenital heart defects (CHD); however, the causal mechanism is poorly understood. We further investigated this association in a Danish nationwide cohort.In a national cohort study, we identified 2 025 727 persons born from 1978 to 2011; among them were 7296 (0.36%) persons exposed to maternal pregestational diabetes mellitus. Pregestational diabetes mellitus was identified by using the National Patient Register and individual-level information on all prescriptions filled in Danish pharmacies. Persons with CHD (n=16 325) were assigned to embryologically related cardiac phenotypes. The CHD prevalence in the offspring of mothers with pregestational diabetes mellitus was 318 per 10 000 live births (n=232) in comparison with a baseline risk of 80 per 10 000; the adjusted relative risk for CHD was 4.00 (95% confidence interval, 3.51-4.53). The association was not modified by year of birth, maternal age at diabetes onset, or diabetes duration, and CHD risks associated with type 1 (insulin-dependent) and type 2 (insulin-independent) diabetes mellitus did not differ significantly. Persons born to women with previous acute diabetes complications had a higher CHD risk than those exposed to maternal diabetes mellitus without complications (relative risk, 7.62; 95% confidence interval, 5.23-10.6, and relative risk, 3.49; 95% confidence interval, 2.91-4.13, respectively; P=0.0004). All specific CHD phenotypes were associated with maternal pregestational diabetes mellitus (relative risk range, 2.74-13.8).The profoundly increased CHD risk conferred by maternal pregestational diabetes mellitus neither changed over time nor differed by diabetes subtype. The association with acute pregestational diabetes complications was particularly strong, suggesting a role for glucose in the causal pathway.

  View details for DOI 10.1161/CIRCULATIONAHA.115.017465

  View details for Web of Science ID 000377439900007

  View details for PubMedID 27166384

  View details for PubMedCentralID PMC4890838

• De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects. PLoS genetics Priest, J. R., Osoegawa, K., Mohammed, N., Nanda, V., Kundu, R., Schultz, K., Lammer, E. J., Girirajan, S., Scheetz, T., Waggott, D., Haddad, F., Reddy, S., Bernstein, D., Burns, T., Steimle, J. D., Yang, X. H., Moskowitz, I. P., Hurles, M., Lifton, R. P., Nickerson, D., Bamshad, M., Eichler, E. E., Mital, S., Sheffield, V., Quertermous, T., Gelb, B. D., Portman, M., Ashley, E. A. 2016; 12 (4)

  Abstract

  Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk.

  View details for DOI 10.1371/journal.pgen.1005963

  View details for PubMedID 27058611

• 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

• Maternal Midpregnancy Glucose Levels and Risk of Congenital Heart Disease in Offspring JAMA PEDIATRICS Priest, J. R., Yang, W., Reaven, G., Knowles, J. W., Shaw, G. M. 2015; 169 (12): 1112-1116

  Abstract

  There is a well-described association between maternal diabetes mellitus and risk of congenital heart disease (CHD) in offspring. Although the clinical diagnoses of type 2 diabetes or gestational diabetes are strong risk factors for CHD, subclinical abnormalities of glucose and insulin metabolism are common within the general population and could also confer risk for CHD. We hypothesize that continuous measures of blood analytes related to maternal diabetes are related to odds of cardiac malformations.To explore the potential association of 2 different CHD phenotypes in offspring with maternal midpregnancy measures of glucose and insulin.Case-control study from a population-based cohort of 277 pregnant women in southern and central California carrying infants with tetralogy of Fallot (TOF) (n = 55), dextrotransposition of the great arteries (dTGA) (n = 42), or healthy infants without CHD (n = 180). Serum samples were collected from 2003 through 2007. The analysis was conducted from March through June 2015.Blood analytes related to maternal glucose metabolism were measured from random nonfasting second-trimester blood samples. We measured serum insulin levels by a validated radioimmunoassay, and we measured glucose levels. Multivariable logistic regression models estimated the association between these levels and case status.Serum glucose values were elevated in the maternal samples for offspring with TOF (median, 97.0 mg/dL [to convert to millimoles per liter, multiply by 0.0555]) relative to controls (median, 91.5 mg/dL) (P = .01, Wilcoxon rank sum test), a phenomenon not observed in the maternal samples for offspring with dTGA (median, 90.0 mg/dL) relative to controls (P = .18, Wilcoxon rank sum test). Serum insulin levels were significantly different between controls (median, 18.8 μIU/mL [to convert to picomoles per liter, multiply by 6.945]) and maternal samples for offspring with dTGA (median, 13.1 μIU/mL; P = .048, Wilcoxon rank sum test) but not with TOF (median, 14.3 μIU/mL; P = .35, Wilcoxon rank sum test). Relative to maternal blood glucose levels of infants without cardiac malformations, we observed that maternal blood glucose levels in models including insulin were strongly associated with odds of TOF (adjusted odds ratio = 7.54; 95% CI, 2.30-24.69) but not with dTGA (adjusted odds ratio = 1.16; 95% CI, 0.28-4.79).These results represent a direct correlation of glucose as a continuous variable to odds of specific cardiac malformations. The association between serum glucose and odds of TOF indicates the need for additional epidemiological and mechanistic investigations into the risk conferred by insulin signaling and glucose metabolism during early pregnancy.

  View details for DOI 10.1001/jamapediatrics.2015.2831

  View details for Web of Science ID 000366334600014

  View details for PubMedID 26457543

  View details for PubMedCentralID PMC4996656

• Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome HUMAN MUTATION Cordeddu, V., Yin, J. C., Gunnarsson, C., Virtanen, C., Drunat, S., Lepri, F., De Luca, A., Rossi, C., Ciolfi, A., Pugh, T. J., Bruselles, A., Priest, J. R., Pennacchio, L. A., Lu, Z., Danesh, A., Quevedo, R., Hamid, A., Martinelli, S., Pantaleoni, F., Gnazzo, M., Daniele, P., Lissewski, C., Bocchinfuso, G., Stella, L., Odent, S., Philip, N., Faivre, L., Vlckova, M., Seemanova, E., Digilio, C., Zenker, M., Zampino, G., Verloes, A., Dallapiccola, B., Roberts, A. E., Cave, H., Gelb, B. D., Neel, B. G., Tartaglia, M. 2015; 36 (11): 1080-1087

  Abstract

  The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.

  View details for DOI 10.1002/humu.22834

  View details for Web of Science ID 000362991400011

  View details for PubMedID 26173643

  View details for PubMedCentralID PMC4604019

• 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

• 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 PubMedID 26448358

• Molecular diagnosis of long QT syndrome at 10 days of life by rapid whole genome sequencing HEART RHYTHM Priest, J. R., Ceresnak, S. R., Dewey, F. E., Malloy-Walton, L. E., Dunn, K., Grove, M. E., Perez, M. V., Maeda, K., Dubin, A. M., Ashley, E. A. 2014; 11 (10): 1707-1713

  Abstract

  The advent of clinical next generation sequencing is rapidly changing the landscape of rare disease medicine. Molecular diagnosis of long QT syndrome (LQTS) can impact clinical management, including risk stratification and selection of pharmacotherapy based on the type of ion channel affected, but results from current gene panel testing requires 4 to 16 weeks before return to clinicians.A term female infant presented with 2:1 atrioventricular block and ventricular arrhythmias consistent with perinatal LQTS, requiring aggressive treatment including epicardial pacemaker, and cardioverter-defibrillator implantation and sympathectomy on day of life two. We sought to provide a rapid molecular diagnosis for optimization of treatment strategies.We performed CLIA-certified rapid whole genome sequencing (WGS) with a speed-optimized bioinformatics platform to achieve molecular diagnosis at 10 days of life.We detected a known pathogenic variant in KCNH2 that was demonstrated to be paternally inherited by followup genotyping. The unbiased assessment of the entire catalog of human genes provided by whole genome sequencing revealed a maternally inherited variant of unknown significance in a novel gene.Rapid clinical WGS provides faster and more comprehensive diagnostic information by 10 days of life than standard gene-panel testing. In selected clinical scenarios such as perinatal LQTS, rapid WGS may be able to provide more timely and clinically actionable information than a standard commercial test.

  View details for DOI 10.1016/j.hrthm.20l4.06.030

  View details for Web of Science ID 000343112200012

• Molecular diagnosis of long QT syndrome at 10 days of life by rapid whole genome sequencing. Heart rhythm Priest, J. R., Ceresnak, S. R., Dewey, F. E., Malloy-Walton, L. E., Dunn, K., Grove, M. E., Perez, M. V., Maeda, K., Dubin, A. M., Ashley, E. A. 2014; 11 (10): 1707-1713

  Abstract

  The advent of clinical next generation sequencing is rapidly changing the landscape of rare disease medicine. Molecular diagnosis of long QT syndrome (LQTS) can impact clinical management, including risk stratification and selection of pharmacotherapy based on the type of ion channel affected, but results from current gene panel testing requires 4 to 16 weeks before return to clinicians.A term female infant presented with 2:1 atrioventricular block and ventricular arrhythmias consistent with perinatal LQTS, requiring aggressive treatment including epicardial pacemaker, and cardioverter-defibrillator implantation and sympathectomy on day of life two. We sought to provide a rapid molecular diagnosis for optimization of treatment strategies.We performed CLIA-certified rapid whole genome sequencing (WGS) with a speed-optimized bioinformatics platform to achieve molecular diagnosis at 10 days of life.We detected a known pathogenic variant in KCNH2 that was demonstrated to be paternally inherited by followup genotyping. The unbiased assessment of the entire catalog of human genes provided by whole genome sequencing revealed a maternally inherited variant of unknown significance in a novel gene.Rapid clinical WGS provides faster and more comprehensive diagnostic information by 10 days of life than standard gene-panel testing. In selected clinical scenarios such as perinatal LQTS, rapid WGS may be able to provide more timely and clinically actionable information than a standard commercial test.

  View details for DOI 10.1016/j.hrthm.2014.06.030

  View details for PubMedID 24973560

• Self-reported history of childhood smoking is associated with an increased risk for peripheral arterial disease independent of lifetime smoking burden. PloS one Priest, J. R., Nead, K. T., Wehner, M. R., Cooke, J. P., Leeper, N. J. 2014; 9 (2)

  Abstract

  Atherosclerotic disorders are well known to be associated with obesity, lipid profile, smoking, hypertension and other medical comorbidities, and large cohort studies have explored the childhood correlates to these adult risk factors. However, there has been little investigation into the childhood risk factors for peripheral arterial disease (PAD). We endeavored to better understand the role of smoking in childhood in the risk for PAD in a well described cohort of 1,537 adults at high risk for cardiovascular disease. In a multivariate regression model, we observed an increased risk of PAD among those who reported a history of smoking during childhood (OR = 2.86; 95% CI, 1.99-4.11; P<0.001), which remained statistically significant after controlling for lifetime smoking burden (OR = 1.55; 95% CI, 1.00-2.41; P = 0.049). Our novel observation of disproportionate risk of PAD conferred by a history of childhood smoking may reflect an unrecognized biological mechanism such as a unique susceptibility to vascular injury or an unaccounted for covariate such as secondhand smoke exposure in childhood. This observation suggests further investigation is required into the pathophysiology of smoking in the developing vasculature and the need for detailed clinical data about patterns of childhood smoking and smoke exposure.

  View details for DOI 10.1371/journal.pone.0088972

  View details for PubMedID 24558458

• Self-reported history of childhood smoking is associated with an increased risk for peripheral arterial disease independent of lifetime smoking burden. PloS one Priest, J. R., Nead, K. T., Wehner, M. R., Cooke, J. P., Leeper, N. J. 2014; 9 (2)

  View details for DOI 10.1371/journal.pone.0088972

  View details for PubMedID 24558458

• Ebstein anomaly and Trisomy 21: A rare association. Annals of pediatric cardiology Siehr, S. L., Punn, R., Priest, J. R., Lowenthal, A. 2014; 7 (1): 67-69

  Abstract

  This is a case report of a patient with Trisomy 21 with Ebstein anomaly, a ventricular septal defect, and acquired pulmonary vein stenosis; a rare combination, diagnosed during a routine neonatal examination.

  View details for DOI 10.4103/0974-2069.126569

  View details for PubMedID 24701093

  View details for PubMedCentralID PMC3959069

• Triiodothyronine supplementation and cytokines during cardiopulmonary bypass in infants and children JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Priest, J. R., Slee, A., Olson, A. K., Ledee, D., Morrish, F., Portman, M. A. 2012; 144 (4): 938-?

  Abstract

  The Triiodothyronine Supplementation in Infants and Children Undergoing Cardiopulmonary Bypass (TRICC) study demonstrated a shortened time to extubation in children younger than 5 months old undergoing cardiopulmonary bypass for congenital heart surgery with triiodothyronine supplementation. Cardiopulmonary bypass precipitates a systemic inflammatory response that affects recovery, and triiodothyronine is related to cytokine mediators of inflammation. We sought to investigate the preoperative cytokine levels by age and relationship to the triiodothyronine levels and to examine the effect of the cytokine levels on the time to extubation.We measured 6 cytokines at preoperative time 0 and 6 and 24 hours after crossclamp removal in 76 subjects.The preoperative cytokine levels were related to both the triiodothyronine levels and the patient age. The postoperative cytokine levels were predictive of the triiodothyronine levels at 6, 12, 24, and 72 hours. Preoperative CCL4 was associated with an increased chance of early extubation. Inclusion of the cytokines did not change the relationship of triiodothyronine to the time to extubation, and the postoperative course of interleukin-6 was independently associated with a decreased chance of early extubation.The preoperative and postoperative cytokine levels, in particular, interleukin-1β, showed complex time-dependent relationships with triiodothyronine. The data suggest that cytokine-mediated suppression of triiodothyronine plays an important role in determining the clinical outcome after cardiopulmonary bypass.

  View details for DOI 10.1016/j.jtcvs.2012.05.063

  View details for Web of Science ID 000309111600030

  View details for PubMedID 22743177

• Rare copy number variants in isolated sporadic and syndromic atrioventricular septal defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Priest, J. R., Girirajan, S., Vu, T. H., Olson, A., Eichler, E. E., Portman, M. A. 2012; 158A (6): 1279-1284

  Abstract

  Atrioventricular septal defects (AVSDs) are a frequent but not universal component of Down syndrome (DS), while AVSDs in otherwise normal individuals have no well-defined genetic basis. The contribution of copy number variation (CNV) to specific congenital heart disease (CHD) phenotypes including AVSD is unknown. We hypothesized that de novo CNVs on chromosome 21 might cause isolated sporadic AVSDs, and separately that CNVs throughout the genome might constitute an additional genetic risk factor for AVSD in patients with DS. We utilized a custom oligonucleotide arrays targeted to CNV hotspots that are flanked by large duplicated segments of high sequence identity. We assayed 29 euploid and 50 DS individuals with AVSD, and compared to general population controls. In patients with isolated-sporadic AVSD we identified two large unique deletions outside of chromosome 21 not seen in the expanded set of 8,635 controls, each overlapping with larger deletions associated with similar CHD reported in the DECIPHER database. There was a small duplication in one patient with DS and AVSD. We conclude that isolated sporadic AVSDs may be occasionally associated with large de novo genomic structural variation outside of chromosome 21. The absence of CNVs on chromosome 21 in patients with isolated sporadic AVSD suggests that sub-chromosomal duplications or deletions of greater than 150 kbp on chromosome 21 do not cause sporadic AVSDs. Large CNVs do not appear to be an additive risk factor for AVSD in the DS population.

  View details for DOI 10.1002/ajmg.a.35315

  View details for Web of Science ID 000304133700007

  View details for PubMedID 22529060

• Relationships of the Location and Content of Rounds to Specialty, Institution, Patient-Census, and Team Size PLOS ONE Priest, J. R., Bereknyei, S., Hooper, K., Braddock, C. H. 2010; 5 (6)

  Abstract

  Existing observational data describing rounds in teaching hospitals are 15 years old, predate duty-hour regulations, are limited to one institution, and do not include pediatrics. We sought to evaluate the effect of medical specialty, institution, patient-census, and team participants upon time at the bedside and education occurring on rounds.Between December of 2007 and October of 2008 we performed 51 observations at Lucile Packard Children's Hospital, Seattle Children's Hospital, Stanford University Hospital, and the University of Washington Medical Center of 35 attending physicians. We recorded minutes spent on rounds in three location and seven activity categories, members of the care team, and patient-census.Results presented are means. Pediatric rounds had more participants (8.2 vs. 4.1 physicians, p<.001; 11.9 vs. 2.4 non-physicians, p<.001) who spent more minutes in hallways (96.9 min vs. 35.2 min, p<.001), fewer minutes at the bedside (14.6 vs. 38.2 min, p = .01) than internal medicine rounds. Multivariate regression modeling revealed that minutes at the bedside per patient was negatively associated with pediatrics (-2.77 adjusted bedside minutes; 95% CI -4.61 to -0.93; p<.001) but positively associated with the number of non-physician participants (0.12 adjusted bedside minutes per non physician participant; 95% CI 0.07 to 0.17; p = <.001). Education minutes on rounds was positively associated with the presence of an attending physician (2.70 adjusted education minutes; 95% CI 1.27 to 4.12; p<.001) and with one institution (1.39 adjusted education minutes; 95% CI 0.26 to 2.53; p = .02).Pediatricians spent less time at the bedside on rounds than internal medicine physicians due to reasons other than patient-census or the number of participants in rounds. Compared to historical data, internal medicine rounds were spent more at the bedside engaged in patient care and communication, and less upon educational activities.

  View details for DOI 10.1371/journal.pone.0011246

  View details for Web of Science ID 000279058300029

  View details for PubMedID 20574534

  View details for PubMedCentralID PMC2888591

• A near null variant of 12/15-LOX encoded by a novel SNP in ALOX15 and the risk of coronary artery disease ATHEROSCLEROSIS Assimes, T. L., Knowles, J. W., Priest, J. R., Basu, A., Borchert, A., Volcik, K. A., Grove, M. L., Tabor, H. K., Southwick, A., Tabibiazar, R., Sidney, S., Boerwinkle, E., Go, A. S., Iribarren, C., Hlatky, M. A., Fortmann, S. P., Myers, R. M., Kuhn, H., Riseh, N., Quertermous, T. 2008; 198 (1): 136-144

  Abstract

  Murine genetic models suggest that function of the 12/15-LOX enzyme promotes atherosclerosis. We tested the hypothesis that exonic and/or promoter single nucleotide polymorphisms (SNPs) in the human 12/15-LOX gene (ALOX15) alter the risk of symptomatic coronary artery disease (CAD).We resequenced ALOX15 and then genotyped a common promoter and a less common novel coding SNP (T560M) in 1809 subjects with CAD and 1734 controls from Kaiser Permanente including a subset of participants of the Coronary Artery Risk Development in Young Adults study. We found no association between the promoter SNP and the risk of CAD. However, heterozygote carriers of the 560M allele had an increased risk of CAD (adjusted OR, 1.62; P=0.02) compared to non-carriers. In vitro studies demonstrated a 20-fold reduction in the catalytic activity of 560M when compared to 560T. We then genotyped T560M in 12,974 participants of the Atherosclerosis Risk in Communities study and similarly found that heterozygote carriers had an increased risk of CAD compared to non-carriers (adjusted HR, 1.31; P=0.06). In both population studies, homozygote carriers were rare and associated with a non-significant decreased risk of CAD compared to non-carriers (adjusted OR, 0.55; P=0.63 and HR, 0.93; P=0.9).A coding SNP in ALOX15 (T560M) results in a near null variant of human 12/15-LOX. Assuming a co-dominant mode of inheritance, this variant does not protect against CAD. Assuming a recessive mode of inheritance, the effect of this mutation remains unclear, but is unlikely to provide a protective effect to the degree suggested by mouse knockout studies.

  View details for DOI 10.1016/j.atheroscierosis.2007.09.003

  View details for Web of Science ID 000255491800016

  View details for PubMedID 17959182

  View details for PubMedCentralID PMC2440699

• Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease HUMAN GENETICS Assimes, T. L., Knowles, J. W., Priest, J. R., Basu, A., Volcik, K. A., Southwick, A., Tabor, H. K., Hartiala, J., Allayee, H., Grove, M. L., Tabibiazar, R., Sidney, S., Fortmann, S. P., Go, A., Hlatky, M., Iribarren, C., Boerwinkle, E., Myers, R., Risch, N., Quertermous, T. 2008; 123 (4): 399-408

  Abstract

  Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5 and 6 SNPs in ALOX5AP in 1,552 cases with clinically significant coronary artery disease (CAD) and 1,583 controls from Kaiser Permanente including a subset of participants of the coronary artery risk development in young adults study. A nominally significant association was detected between a promoter SNP in ALOX5 (rs12762303) and CAD in our subset of white/European subjects (adjusted odds ratio per minor allele, log-additive model, 1.32; P = 0.002). In this race/ethnic group, rs12762303 has a minor allele frequency of 15% and is tightly linked to variation at the SP1 variable tandem repeat promoter polymorphism. However, the association between CAD and rs12762303 could not be reproduced in the atherosclerosis risk in communities study (hazard rate ratio per minor allele; 1.08, P = 0.1). Assuming a recessive mode of inheritance, the association was not significant in either population study but our power to detect modest effects was limited. No significant associations were observed between all other SNPs and the risk of CAD. Overall, our findings do not support a link between common allelic variation in or near ALOX5 or ALOX5AP and the risk of CAD. However, additional studies are needed to exclude modest effects of promoter variation in ALOX5 on the risk of CAD assuming a recessive mode of inheritance.

  View details for DOI 10.1007/s00439-008-0489-5

  View details for Web of Science ID 000254959600008

  View details for PubMedID 18369664

• Brucellosis and sacroiliitis: A common presentation of an uncommon pathogen JOURNAL OF THE AMERICAN BOARD OF FAMILY MEDICINE Priest, J. R., Low, D., Wang, C., Bush, T. 2008; 21 (2): 158-161

  Abstract

  Musculoskeletal problems are the most common chief complaint in ambulatory medicine across all specialties, and back pain is one of the top 10 problems encountered by the general practitioner. The differential diagnosis of lower back pain is exhaustive, but a history significant for constitutional symptoms or unusual exposures should prompt a work-up for an infectious cause. We describe the case of a 25-year-old man with a Brucella abortus sacroiliitis and possible orchiitis after consumption of unpasteurized cheese imported from El Salvador. The patient was successfully treated with gentamycin, rifampin, and doxycycline. Though the presentations of brucellosis are myriad, osteoarticular involvement of the axial skeleton is the most common presentation of this zoonotic infection. In the United States brucellosis is rarely encountered and is typically limited to people who are exposed during travel to endemic areas. Here we review briefly the epidemiology and presentation of a Brucella infection and current recommendations for treatment.

  View details for DOI 10.3122/jabfm.2008.02.070170

  View details for Web of Science ID 000253993300012

  View details for PubMedID 18343865

• Polymorphisms in hypoxia inducible factor 1 and the initial clinical presentation of coronary disease AMERICAN HEART JOURNAL Hlatky, M. A., Quertermous, T., Boothroyd, D. B., Priest, J. R., Glassford, A. J., Myers, R. M., Fortmann, S. P., Iribarren, C., Tabor, H. K., Assimes, T. L., Tibshirani, R. J., Go, A. S. 2007; 154 (6): 1035-1042

  Abstract

  Only some patients with coronary artery disease (CAD) develop acute myocardial infarction (MI), and emerging evidence suggests vulnerability to MI varies systematically among patients and may have a genetic component. The goal of this study was to assess whether polymorphisms in genes encoding elements of pathways mediating the response to ischemia affect vulnerability to MI among patients with underlying CAD.We prospectively identified patients at the time of their initial clinical presentation of CAD who had either an acute MI or stable exertional angina. We collected clinical data and genotyped 34 polymorphisms in 6 genes (ANGPT1, HIF1A, THBS1, VEGFA, VEGFC, VEGFR2).The 909 patients with acute MI were significantly more likely than the 466 patients with stable angina to be male, current smokers, and hypertensive, and less likely to be taking beta-blockers or statins. Three polymorphisms in HIF1A (Pro582Ser, rs11549465; rs1087314; and Thr418Ile, rs41508050) were significantly more common in patients who presented with stable exertional angina rather than acute MI, even after statistical adjustment for cardiac risk factors and medications. The HIF-mediated transcriptional activity was significantly lower when HIF1A null fibroblasts were transfected with variant HIF1A alleles than with wild-type HIF1A alleles.Polymorphisms in HIF1A were associated with development of stable exertional angina rather than acute MI as the initial clinical presentation of CAD.

  View details for DOI 10.1016/j.ahj.2007.07.042

  View details for Web of Science ID 000251396200006

  View details for PubMedID 18035072

• Comparative genomics: a tool to functionally annotate human DNA. Methods in molecular biology (Clifton, N.J.) Cheng, J., Priest, J. R., Pennacchio, L. A. 2007; 366: 229-251

  Abstract

  The availability of an increasing number of vertebrate genomes has enabled comparative methods to infer functional sequences based on evolutionary constraint. Although this has proved powerful for gene identification, significant progress has also been made in uncovering gene regulatory sequences such as distant acting transcriptional enhancers. These pursuits have led to the development of a variety of valuable databases and resources that should serve as a routine toolbox for biological discovery.

  View details for PubMedID 17568128

• Genomic sequencing of Pleistocene cave bears SCIENCE Noonan, J. P., Hofreiter, M., Smith, D., Priest, J. R., Rohland, N., Rabeder, G., KRAUSE, J., Detter, J. C., Paabo, S., Rubin, E. M. 2005; 309 (5734): 597-600

  Abstract

  Despite the greater information content of genomic DNA, ancient DNA studies have largely been limited to the amplification of mitochondrial sequences. Here we describe metagenomic libraries constructed with unamplified DNA extracted from skeletal remains of two 40,000-year-old extinct cave bears. Analysis of approximately 1 megabase of sequence from each library showed that despite significant microbial contamination, 5.8 and 1.1% of clones contained cave bear inserts, yielding 26,861 base pairs of cave bear genome sequence. Comparison of cave bear and modern bear sequences revealed the evolutionary relationship of these lineages. The metagenomic approach used here establishes the feasibility of ancient DNA genome sequencing programs.

  View details for DOI 10.1126/science.1113485

  View details for Web of Science ID 000230735200044

  View details for PubMedID 15933159

• Human-zebrafish non-coding conserved elements act in vivo to regulate transcription NUCLEIC ACIDS RESEARCH Shin, J. T., Priest, J. R., Ovcharenko, I., Ronco, A., Moore, R. K., Burns, C. G., MacRae, C. A. 2005; 33 (17): 5437-5445

  Abstract

  Whole genome comparisons of distantly related species effectively predict biologically important sequences--core genes and cis-acting regulatory elements (REs)--but require experimentation to verify biological activity. To examine the efficacy of comparative genomics in identification of active REs from anonymous, non-coding (NC) sequences, we generated a novel alignment of the human and draft zebrafish genomes, and contrasted this set to existing human and fugu datasets. We tested the transcriptional regulatory potential of candidate sequences using two in vivo assays. Strict selection of non-genic elements which are deeply conserved in vertebrate evolution identifies 1744 core vertebrate REs in human and two fish genomes. We tested 16 elements in vivo for cis-acting gene regulatory properties using zebrafish transient transgenesis and found that 10 (63%) strongly modulate tissue-specific expression of a green fluorescent protein reporter vector. We also report a novel quantitative enhancer assay with potential for increased throughput based on normalized luciferase activity in vivo. This complementary system identified 11 (69%; including 9 of 10 GFP-confirmed elements) with cis-acting function. Together, these data support the utility of comparative genomics of distantly related vertebrate species to identify REs and provide a scaleable, in vivo quantitative assay to define functional activity of candidate REs.

  View details for DOI 10.1093/nar/gki853

  View details for Web of Science ID 000232593700016

  View details for PubMedID 16179648

• The DNA sequence and comparative analysis of human chromosome 5 NATURE Schmutz, J., Martin, J., Terry, A., Couronne, O., Grimwood, J., Lowry, S., Gordon, L. A., Scott, D., Xie, G., Huang, W., Hellsten, U., Tran-Gyamfi, M., She, X. W., Prabhakar, S., Aerts, A., Altherr, M., Bajorek, E., Black, S., Branscomb, E., Caoile, C., Challacombe, J. F., Chan, Y. M., Denys, M., Detter, J. C., Escobar, J., Flowers, D., Fotopulos, D., Glavina, T., Gomez, M., Gonzales, E., Goodstein, D., Grigoriev, I., Groza, M., Hammon, N., Hawkins, T., Haydu, L., Israni, S., Jett, J., Kadner, K., Kimball, H., Kobayashi, A., LOPEZ, F., Lou, Y. N., Martinez, D., Medina, C., Morgan, J., Nandkeshwar, R., Noonan, J. P., Pitluck, S., Pollard, M., Predki, P., Priest, J., Ramirez, L., Retterer, J., Rodriguez, A., Rogers, S., Salamov, A., Salazar, A., Thayer, N., Tice, H., Tsai, M., Ustaszewska, A., Vo, N., Wheeler, J., Wu, K., Yang, J., Dickson, M., Cheng, J. F., Eichler, E. E., Olsen, A., Pennacchio, L. A., Rokhsar, D. S., Richardson, P., Lucas, S. M., Myers, R. M., Rubin, E. M. 2004; 431 (7006): 268-274

  Abstract

  Chromosome 5 is one of the largest human chromosomes and contains numerous intrachromosomal duplications, yet it has one of the lowest gene densities. This is partially explained by numerous gene-poor regions that display a remarkable degree of noncoding conservation with non-mammalian vertebrates, suggesting that they are functionally constrained. In total, we compiled 177.7 million base pairs of highly accurate finished sequence containing 923 manually curated protein-coding genes including the protocadherin and interleukin gene families. We also completely sequenced versions of the large chromosome-5-specific internal duplications. These duplications are very recent evolutionary events and probably have a mechanistic role in human physiological variation, as deletions in these regions are the cause of debilitating disorders including spinal muscular atrophy.

  View details for DOI 10.1038/nature02919

  View details for PubMedID 15372022