Journal Article

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

Tristani-Firouzi, Martin, Zhang, Peng, Sevim Bayrak, Cigdem, Itan, Yuval, Gelb, Bruce D.

2020

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Bioinformatics / Biomedical and Life Sciences / Biomedicine / Birth defects / Cancer Research / Cardiovascular disease / Cardiovascular diseases / Clinical interpretation of genome variation / Congenital defects / Congenital diseases / Congenital heart defects / Congenital heart disease / Coronary artery disease / De novo variants / Diseases / Enrichment analysis / Exome / Gene Regulatory Networks / Genes / Genetic disorders / Genetic Predisposition to Disease / Genomics / Heart Defects, Congenital - genetics / Heart diseases / HSP90 Heat-Shock Proteins - genetics / HSP90 Heat-Shock Proteins - metabolism / Human Genetics / Humans / IQGAP1 protein / Medicine/Public Health / Metabolomics / Mi-2 Nucleosome Remodeling and Deacetylase Complex - genetics / Mi-2 Nucleosome Remodeling and Deacetylase Complex - metabolism / Mutation / Novels / Pathway / 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 / Risk factors / Systems Biology / Trios