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

TitleDe Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects.
Publication TypeJournal Article
Year of Publication2016
AuthorsPriest, JR, Osoegawa, K, Mohammed, N, Nanda, V, Kundu, R, Schultz, K, Lammer, EJ, Girirajan, S, Scheetz, T, Waggott, D, Haddad, F, Reddy, S, Bernstein, D, Burns, T, Steimle, JD, Yang, XH, Moskowitz, IP, Hurles, M, Lifton, RP, Nickerson, D, Bamshad, M, Eichler, EE, Mital, S, Sheffield, V, Quertermous, T, Gelb, BD, Portman, M, Ashley, EA
JournalPLoS Genet
Volume12
Issue4
Paginatione1005963
Date Published2016 Apr
ISSN1553-7404
KeywordsAnimals, Female, Heart Septal Defects, Heterozygote, Homozygote, Humans, Male, Mice, Mice, Knockout, Mutation, Pedigree
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.

DOI10.1371/journal.pgen.1005963
Alternate JournalPLoS Genet.
PubMed ID27058611
PubMed Central IDPMC4825975
Grant ListK12-HD000850 / HD / NICHD NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States
UM1 HL098123 / HL / NHLBI NIH HHS / United States
R01 HL092153 / HL / NHLBI NIH HHS / United States
K12 HD000850 / HD / NICHD NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
K99 HL130523 / HL / NHLBI NIH HHS / United States