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

SC Jin, J Homsy, S Zaidi, Q Lu, S Morton… - Nature …, 2017 - nature.com
SC Jin, J Homsy, S Zaidi, Q Lu, S Morton, SR DePalma, X Zeng, H Qi, W Chang, MC Sierant
Nature genetics, 2017nature.com
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 …
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.
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