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PLoS Genet. 2016 Apr 8;12(4):e1005963. doi: 10.1371/journal.pgen.1005963. eCollection 2016.

De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects.

Author information

  • 1Division of Pediatric Cardiology, Stanford University School of Medicine, Stanford University, Stanford, California, United States of America.
  • 2Cardiovascular Institute, Stanford University School of Medicine, Stanford University, Stanford, California, United States of America.
  • 3Department of Pathology, Stanford University School of Medicine, Stanford University, Stanford, California, United States of America.
  • 4University of California San Francisco Benioff Children's Hospital Oakland, University of California San Francisco, San Francisco, California, United States of America.
  • 5Department of Vascular Surgery, Stanford University School of Medicine, Stanford University, Stanford, California, United States of America.
  • 6Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, California, United States of America.
  • 7Departments of Biochemistry, Molecular Biology, and Anthropology, Pennsylvania State University, University Park, Pennsylvania, United States of America.
  • 8College of Engineering, University of Iowa, Iowa City, Iowa, United States of America.
  • 9College of Public Health, University of Iowa, Iowa City, Iowa, United States of America.
  • 10Department of Pathology, University of Chicago, Chicago, Illinois, United States of America.
  • 11Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
  • 12Department of Genetics, Yale University, New Haven, Connecticut, United States of America.
  • 13Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
  • 14Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
  • 15Department of Pediatrics, University of Washington, Seattle, Washington, United States of America.
  • 16Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
  • 17Division of Medical Genetics, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
  • 18Mindich Child Health and Development Institute, Icahn School of Medicine at Mt. Sinai, New York, New York, United States of America.

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.

PMID:
27058611
PMCID:
PMC4825975
DOI:
10.1371/journal.pgen.1005963
[PubMed - indexed for MEDLINE]
Free PMC Article
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