TY - JOUR
T1 - Genomic analyses implicate noncoding de novo variants in congenital heart disease
AU - Richter, Felix
AU - Morton, Sarah U.
AU - Kim, Seong Won
AU - Kitaygorodsky, Alexander
AU - Wasson, Lauren K.
AU - Chen, Kathleen M.
AU - Zhou, Jian
AU - Qi, Hongjian
AU - Patel, Nihir
AU - DePalma, Steven R.
AU - Parfenov, Michael
AU - Homsy, Jason
AU - Gorham, Joshua M.
AU - Manheimer, Kathryn B.
AU - Velinder, Matthew
AU - Farrell, Andrew
AU - Marth, Gabor
AU - Schadt, Eric E.
AU - Kaltman, Jonathan R.
AU - Newburger, Jane W.
AU - Giardini, Alessandro
AU - Goldmuntz, Elizabeth
AU - Brueckner, Martina
AU - Kim, Richard
AU - Porter, George A.
AU - Bernstein, Daniel
AU - Chung, Wendy K.
AU - Srivastava, Deepak
AU - Tristani-Firouzi, Martin
AU - Troyanskaya, Olga G.
AU - Dickel, Diane E.
AU - Shen, Yufeng
AU - Seidman, Jonathan G.
AU - Seidman, Christine E.
AU - Gelb, Bruce D.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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 × 10−4). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10−5). 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 × 10−3). 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 × 10−5). 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.
AB - 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 × 10−4). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10−5). 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 × 10−3). 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 × 10−5). 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.
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U2 - 10.1038/s41588-020-0652-z
DO - 10.1038/s41588-020-0652-z
M3 - Article
C2 - 32601476
AN - SCOPUS:85087032848
SN - 1061-4036
VL - 52
SP - 769
EP - 777
JO - Nature genetics
JF - Nature genetics
IS - 8
ER -