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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  Nr1d2   tm1-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.

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