Dataset Information

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

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^-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.

SUBMITTER: Richter F

PROVIDER: S-EPMC7415662 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Richter Felix F Morton Sarah U SU Kim Seong Won SW Kitaygorodsky Alexander A Wasson Lauren K LK Chen Kathleen M KM Zhou Jian J Qi Hongjian H Patel Nihir N DePalma Steven R SR Parfenov Michael M Homsy Jason J Gorham Joshua M JM Manheimer Kathryn B KB Velinder Matthew M Farrell Andrew A Marth Gabor G Schadt Eric E EE Kaltman Jonathan R JR Newburger Jane W JW Giardini Alessandro A Goldmuntz Elizabeth E Brueckner Martina M Kim Richard R Porter George A GA Bernstein Daniel D Chung Wendy K WK Srivastava Deepak D Tristani-Firouzi Martin M Troyanskaya Olga G OG Dickel Diane E DE Shen Yufeng Y Seidman Jonathan G JG Seidman Christine E CE Gelb Bruce D BD

Nature genetics 20200629 8

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 × ...[more]

PMID: 32601476

Similar Datasets

Project description:BackgroundDe novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.MethodsWe studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network).ResultsTwo hundred ninety-four patients (11.7%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies (P=5.63×10-12). In 1268 patients (50.4%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; P=5.33×10-04) and longer times to final extubation (hazard ratio, 0.74; P=0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival (P=0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; P=0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; P=1.61×10-05) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation.ConclusionsIn patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets