Dataset Information

Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.

ABSTRACT: Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ?5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ?11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ?3% of isolated CHD patients and ?28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ?440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

SUBMITTER: Jin SC

PROVIDER: S-EPMC5675000 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.

Jin Sheng Chih SC Homsy Jason J Zaidi Samir S Lu Qiongshi Q Morton Sarah S DePalma Steven R SR Zeng Xue X Qi Hongjian H Chang Weni W Sierant Michael C MC Hung Wei-Chien WC Haider Shozeb S Zhang Junhui J Knight James J Bjornson Robert D RD Castaldi Christopher C Tikhonoa Irina R IR Bilguvar Kaya K Mane Shrikant M SM Sanders Stephan J SJ Mital Seema S Russell Mark W MW Gaynor J William JW Deanfield John J Giardini Alessandro A Porter George A GA Srivastava Deepak D Lo Cecelia W CW Shen Yufeng Y Watkins W Scott WS Yandell Mark M Yost H Joseph HJ Tristani-Firouzi Martin M Newburger Jane W JW Roberts Amy E AE Kim Richard R Zhao Hongyu H Kaltman Jonathan R JR Goldmuntz Elizabeth E Chung Wendy K WK Seidman Jonathan G JG Gelb Bruce D BD Seidman Christine E CE Lifton Richard P RP Brueckner Martina M

Nature genetics 20171009 11

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) account ...[more]

PMID: 28991257

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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.

Dataset Information

Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.

Publications

Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.

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