De novo variants in exomes of congenital heart disease patients identify risk genes and pathways

Genome Med. 2020 Jan 15;12(1):9. doi: 10.1186/s13073-019-0709-8.


Background: Congenital heart disease (CHD) affects ~ 1% of live births and is the most common birth defect. Although the genetic contribution to the CHD has been long suspected, it has only been well established recently. De novo variants are estimated to contribute to approximately 8% of sporadic CHD.

Methods: CHD is genetically heterogeneous, making pathway enrichment analysis an effective approach to explore and statistically validate CHD-associated genes. In this study, we performed novel gene and pathway enrichment analyses of high-impact de novo variants in the recently published whole-exome sequencing (WES) data generated from a cohort of CHD 2645 parent-offspring trios to identify new CHD-causing candidate genes and mutations. We performed rigorous variant- and gene-level filtrations to identify potentially damaging variants, followed by enrichment analyses and gene prioritization.

Results: Our analyses revealed 23 novel genes that are likely to cause CHD, including HSP90AA1, ROCK2, IQGAP1, and CHD4, and sharing biological functions, pathways, molecular interactions, and properties with known CHD-causing genes.

Conclusions: Ultimately, these findings suggest novel genes that are likely to be contributing to CHD pathogenesis.

Keywords: Congenital heart disease; De novo variants; Enrichment analysis; Pathway; Trios.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Exome
  • Gene Regulatory Networks
  • Genetic Predisposition to Disease*
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Heart Defects, Congenital / genetics*
  • Humans
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism
  • Pedigree
  • Polymorphism, Single Nucleotide*
  • Protein Interaction Maps
  • ras GTPase-Activating Proteins / genetics
  • ras GTPase-Activating Proteins / metabolism
  • rho-Associated Kinases / genetics
  • rho-Associated Kinases / metabolism


  • CHD4 protein, human
  • HSP90 Heat-Shock Proteins
  • HSP90AA1 protein, human
  • IQ motif containing GTPase activating protein 1
  • ras GTPase-Activating Proteins
  • ROCK2 protein, human
  • rho-Associated Kinases
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex