Genomic analyses implicate noncoding de novo variants in congenital heart disease.

TitleGenomic analyses implicate noncoding de novo variants in congenital heart disease.
Publication TypeJournal Article
Year of Publication2020
AuthorsRichter, 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
JournalNat Genet
Volume52
Issue8
Pagination769-777
Date Published2020 08
ISSN1546-1718
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>

DOI10.1038/s41588-020-0652-z
Alternate JournalNat Genet
PubMed ID32601476
PubMed Central IDPMC7415662
Grant ListUM1 HL098162 / HL / NHLBI NIH HHS / United States
T32 HD075735 / HD / NICHD NIH HHS / United States
UM1 HL098123 / HL / NHLBI NIH HHS / United States
U01 HL098163 / HL / NHLBI NIH HHS / United States
U01 HL131003 / 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
U01 HL098153 / 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
/ HHMI / Howard Hughes Medical Institute / United States