Title | Genomic analyses implicate noncoding de novo variants in congenital heart disease. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Richter, F, Morton, SU, Kim, SWon, Kitaygorodsky, A, Wasson, LK, Chen, KM, Zhou, J, Qi, H, Patel, N, DePalma, SR, Parfenov, M, Homsy, J, Gorham, JM, Manheimer, KB, Velinder, M, Farrell, A, Marth, G, Schadt, EE, Kaltman, JR, Newburger, JW, Giardini, A, Goldmuntz, E, Brueckner, M, Kim, R, Porter, GA, Bernstein, D, Chung, WK, Srivastava, D, Tristani-Firouzi, M, Troyanskaya, OG, Dickel, DE, Shen, Y, Seidman, JG, Seidman, CE, Gelb, BD |
Journal | Nat Genet |
Volume | 52 |
Issue | 8 |
Pagination | 769-777 |
Date Published | 2020 08 |
ISSN | 1546-1718 |
Keywords | Adolescent, Adult, Animals, Female, Genetic Predisposition to Disease, Genetic Variation, Genomics, Heart, Heart Defects, Congenital, Humans, Male, Mice, Middle Aged, Open Reading Frames, RNA, Untranslated, RNA-Binding Proteins, Transcription, Genetic, Young Adult |
Abstract | <p>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.</p> |
DOI | 10.1038/s41588-020-0652-z |
Alternate Journal | Nat Genet |
PubMed ID | 32601476 |
PubMed Central ID | PMC7415662 |
Grant List | UM1 HL098162 / HL / NHLBI NIH HHS / United States T32 HD075735 / HD / NICHD NIH HHS / United States R01 GM120609 / GM / NIGMS NIH HHS / United States / HHMI / Howard Hughes Medical Institute / United States U01 HL131003 / HL / NHLBI NIH HHS / United States U01 HL098153 / HL / NHLBI NIH HHS / United States UM1 HL098166 / HL / NHLBI NIH HHS / United States R01 GM071966 / GM / NIGMS NIH HHS / United States UM1 HL128761 / HL / NHLBI NIH HHS / United States UM1 HL098147 / HL / NHLBI NIH HHS / United States R24 HL123879 / HL / NHLBI NIH HHS / United States R03 HL147197 / HL / NHLBI NIH HHS / United States UM1 HL098123 / HL / NHLBI NIH HHS / United States UL1 TR002538 / TR / NCATS NIH HHS / United States R03 HL138352 / HL / NHLBI NIH HHS / United States U01 HL098163 / HL / NHLBI NIH HHS / United States T32 GM007280 / GM / NIGMS NIH HHS / United States U24 HD090743 / HD / NICHD NIH HHS / United States UM1 HL128711 / HL / NHLBI NIH HHS / United States |