Dataset Information

Integrative modeling of transmitted and de novo variants identifies novel risk genes for congenital heart disease.

ABSTRACT:

Background

Whole-exome sequencing (WES) studies have identified multiple genes enriched for de novo mutations (DNMs) in congenital heart disease (CHD) probands. However, risk gene identification based on DNMs alone remains statistically challenging due to heterogenous etiology of CHD and low mutation rate in each gene.

Methods

In this manuscript, we introduce a hierarchical Bayesian framework for gene-level association test which jointly analyzes de novo and rare transmitted variants. Through integrative modeling of multiple types of genetic variants, gene-level annotations, and reference data from large population cohorts, our method accurately characterizes the expected frequencies of both de novo and transmitted variants and shows improved statistical power compared to analyses based on DNMs only.

Results

Applied to WES data of 2,645 CHD proband-parent trios, our method identified 15 significant genes, half of which are novel, leading to new insights into the genetic bases of CHD.

Conclusion

These results showcase the power of integrative analysis of transmitted and de novo variants for disease gene discovery.

SUBMITTER: Li M

PROVIDER: S-EPMC9000521 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

Integrative modeling of transmitted and <i>de novo</i> variants identifies novel risk genes for congenital heart disease.

Li Mo M Zeng Xue X Jin Chentian C Jin Sheng Chih SC Dong Weilai W Brueckner Martina M Lifton Richard R Lu Qiongshi Q Zhao Hongyu H

Quantitative biology (Beijing, China) 20210601 2

<h4>Background</h4>Whole-exome sequencing (WES) studies have identified multiple genes enriched for <i>de novo</i> mutations (DNMs) in congenital heart disease (CHD) probands. However, risk gene identification based on DNMs alone remains statistically challenging due to heterogenous etiology of CHD and low mutation rate in each gene.<h4>Methods</h4>In this manuscript, we introduce a hierarchical Bayesian framework for gene-level association test which jointly analyzes <i>de novo</i> and rare tra ...[more]

PMID: 35414959

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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.

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