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

Sheng Chih Jin, Jason Homsy, Samir Zaidi, Qiongshi Lu, Sarah Morton, Steven R. Depalma, Xue Zeng, Hongjian Qi, Weni Chang, Michael C. Sierant, Wei Chien Hung, Shozeb Haider, Junhui Zhang, James Knight, Robert D. Bjornson, Christopher Castaldi, Irina R. Tikhonoa, Kaya Bilguvar, Shrikant M. Mane, Stephan J. SandersSeema Mital, Mark W. Russell, J. William Gaynor, John Deanfield, Alessandro Giardini, George A. Porter, Deepak Srivastava, Cecelia W. Lo, Yufeng Shen, W. Scott Watkins, Mark Yandell, H. Joseph Yost, Martin Tristani-Firouzi, Jane W. Newburger, Amy E. Roberts, Richard Kim, Hongyu Zhao, Jonathan R. Kaltman, Elizabeth Goldmuntz, Wendy K. Chung, Jonathan G. Seidman, Bruce D. Gelb, Christine E. Seidman, Richard P. Lifton, Martina Brueckner

Research output: Contribution to journalArticlepeer-review

516 Scopus citations


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.

Original languageEnglish
Pages (from-to)1593-1601
Number of pages9
JournalNature Genetics
Issue number11
StatePublished - Nov 1 2017


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