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

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

Published Web Location

https://doi.org/10.1038/ng.3970
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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