Jin, SC;
Homsy, J;
Zaidi, S;
Lu, Q;
Morton, S;
DePalma, SR;
Zeng, X;
... Brueckner, M; + view all
(2017)
Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.
Nature Genetics
, 49
pp. 1593-1601.
10.1038/ng.3970.
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Abstract
Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Exome sequencing of a single cohort of 2,871 CHD probands including 2,645 parent- offspring trios implicated rare transmitted 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 19 genes not previously implicated in CHD had > 70% probability of being disease-related; DNMs in ~440 genes are inferred to contribute to CHD. There was striking overlap between genes with damaging DNMs in probands with CHD and autism.
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