Genomic analyses implicate noncoding de novo variants in congenital heart disease. Author Felix Richter, Sarah Morton, Seong Kim, Alexander Kitaygorodsky, Lauren Wasson, Kathleen Chen, Jian Zhou, Hongjian Qi, Nihir Patel, Steven DePalma, Michael Parfenov, Jason Homsy, Joshua Gorham, Kathryn Manheimer, Matthew Velinder, Andrew Farrell, Gabor Marth, Eric Schadt, Jonathan Kaltman, Jane Newburger, Alessandro Giardini, Elizabeth Goldmuntz, Martina Brueckner, Richard Kim, George Porter, Daniel Bernstein, Wendy Chung, Deepak Srivastava, Martin Tristani-Firouzi, Olga Troyanskaya, Diane Dickel, Yufeng Shen, Jonathan Seidman, Christine Seidman, Bruce Gelb Publication Year 2020 Type Journal Article Abstract A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a burden of DNVs in individuals with CHD (n = 2,238 DNVs) compared to controls (n = 4,177; P = 8.7 × 10). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10). We observed significant overlap between these transcription-based approaches (odds ratio (OR) = 2.5, 95% confidence interval (CI) 1.1-5.0, P = 5.4 × 10). CHD DNVs altered transcription levels in 5 of 31 enhancers assayed. Finally, we observed a DNV burden in RNA-binding-protein regulatory sites (OR = 1.13, 95% CI 1.1-1.2, P = 8.8 × 10). Our findings demonstrate an enrichment of potentially disruptive regulatory noncoding DNVs in a fraction of CHD at least as high as that observed for damaging coding DNVs. Keywords Animals, RNA-Binding Proteins, Mice, RNA, Untranslated, Transcription, Genetic, Humans, Genomics, Open Reading Frames, Female, Male, Genetic Variation, Adult, Genetic Predisposition to Disease, Middle Aged, Heart, Young Adult, Adolescent, Heart Defects, Congenital Journal Nat Genet Volume 52 Issue 8 Pages 769-777 Date Published 2020 Aug ISSN Number 1546-1718 DOI 10.1038/s41588-020-0652-z Alternate Journal Nat Genet PMCID PMC7415662 PMID 32601476 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML