Journal
NATURE GENETICS
Volume 49, Issue 11, Pages 1593-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/ng.3970
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Funding
- National Center for Research Resources [U01 HL098153, UL1TR000003]
- National Center for Advancing Translational Sciences, National Institutes of Health [UM1-HL098147, UM1-HL128761, UM1-HL098123, UM1-HL128711, UM1-HL098162, UO1-HL131003, UO1-HL098188, UO1-HL098153, UO1-HL098163]
- NIH Centers for Mendelian Genomics [5U54HG006504]
- Howard Hughes Medical Institute
- Simons Foundation
- Yale University School of Medicine
- Harvard Medical School
- Brigham and Women's Hospital
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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 similar to 5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for similar to 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 similar to 3% of isolated CHD patients and similar to 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 similar to 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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