Journal article
De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects
PLoS genetics, Vol.12(4), pp.e1005963-e1005963
04/2016
DOI: 10.1371/journal.pgen.1005963
PMCID: PMC4825975
PMID: 27058611
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.
Details
- Title: Subtitle
- De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects
- Creators
- James R Priest - Cardiovascular Institute, Stanford University School of Medicine, Stanford University, Stanford, California, United States of AmericaKazutoyo Osoegawa - Department of Pathology, Stanford University School of Medicine, Stanford University, Stanford, California, United States of AmericaNebil Mohammed - University of California San Francisco Benioff Children's Hospital Oakland, University of California San Francisco, San Francisco, California, United States of AmericaVivek Nanda - Department of Vascular Surgery, Stanford University School of Medicine, Stanford University, Stanford, California, United States of AmericaRamendra Kundu - Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, California, United States of AmericaKathleen Schultz - University of California San Francisco Benioff Children's Hospital Oakland, University of California San Francisco, San Francisco, California, United States of AmericaEdward J Lammer - University of California San Francisco Benioff Children's Hospital Oakland, University of California San Francisco, San Francisco, California, United States of AmericaSanthosh Girirajan - Departments of Biochemistry, Molecular Biology, and Anthropology, Pennsylvania State University, University Park, Pennsylvania, United States of AmericaTodd Scheetz - College of Engineering, University of Iowa, Iowa City, Iowa, United States of AmericaDaryl Waggott - Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, California, United States of AmericaFrancois Haddad - Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, California, United States of AmericaSushma Reddy - Cardiovascular Institute, Stanford University School of Medicine, Stanford University, Stanford, California, United States of AmericaDaniel Bernstein - Cardiovascular Institute, Stanford University School of Medicine, Stanford University, Stanford, California, United States of AmericaTrudy Burns - College of Public Health, University of Iowa, Iowa City, Iowa, United States of AmericaJeffrey D Steimle - Department of Pathology, University of Chicago, Chicago, Illinois, United States of AmericaXinan H Yang - Department of Pathology, University of Chicago, Chicago, Illinois, United States of AmericaIvan P Moskowitz - Department of Pathology, University of Chicago, Chicago, Illinois, United States of AmericaMatthew Hurles - Wellcome Trust Sanger Institute, Hinxton, Cambridge, United KingdomRichard P Lifton - Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of AmericaDebbie Nickerson - Department of Genome Sciences, University of Washington, Seattle, Washington, United States of AmericaMichael Bamshad - Department of Pediatrics, University of Washington, Seattle, Washington, United States of AmericaEvan E Eichler - Department of Genome Sciences, University of Washington, Seattle, Washington, United States of AmericaSeema Mital - Department of Pediatrics, University of Toronto, Toronto, Ontario, CanadaVal Sheffield - Division of Medical Genetics, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of AmericaThomas Quertermous - Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, California, United States of AmericaBruce D Gelb - Mindich Child Health and Development Institute, Icahn School of Medicine at Mt. Sinai, New York, New York, United States of AmericaMichael Portman - Department of Pediatrics, University of Washington, Seattle, Washington, United States of AmericaEuan A Ashley - Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, California, United States of America
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.12(4), pp.e1005963-e1005963
- DOI
- 10.1371/journal.pgen.1005963
- PMID
- 27058611
- PMCID
- PMC4825975
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7390
- eISSN
- 1553-7404
- Publisher
- United States
- Grant note
- UM1 HG006493 / NHGRI NIH HHS\nUM1 HG006504 / NHGRI NIH HHS\nT32 HL007381 / NHLBI NIH HHS\nUM1 HL098123 / NHLBI NIH HHS\nR01 HL109512 / NHLBI NIH HHS\nR01 EY017168 / NEI NIH HHS\nK12-HD000850 / NICHD NIH HHS\nR01 HL092153 / NHLBI NIH HHS\nK99 HL130523 / NHLBI NIH HHS\nK12 HD000850 / NICHD NIH HHS
- Language
- English
- Date published
- 04/2016
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Stead Family Department of Pediatrics; Epidemiology; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
- Record Identifier
- 9983979978702771
Metrics
22 Record Views