@article {69,
	title = {De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects.},
	journal = {PLoS Genet},
	volume = {12},
	year = {2016},
	month = {2016 Apr},
	pages = {e1005963},
	abstract = {<p>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. </p>},
	keywords = {Animals, Female, Heart Septal Defects, Heterozygote, Homozygote, Humans, Male, Mice, Mice, Knockout, Mutation, Pedigree},
	issn = {1553-7404},
	doi = {10.1371/journal.pgen.1005963},
	author = {Priest, James R and Osoegawa, Kazutoyo and Mohammed, Nebil and Nanda, Vivek and Kundu, Ramendra and Schultz, Kathleen and Lammer, Edward J and Girirajan, Santhosh and Scheetz, Todd and Waggott, Daryl and Haddad, Francois and Reddy, Sushma and Bernstein, Daniel and Burns, Trudy and Steimle, Jeffrey D and Yang, Xinan H and Moskowitz, Ivan P and Hurles, Matthew and Lifton, Richard P and Nickerson, Debbie and Bamshad, Michael and Eichler, Evan E and Mital, Seema and Sheffield, Val and Quertermous, Thomas and Gelb, Bruce D and Portman, Michael and Ashley, Euan A}
}
