Whole-exome sequencing uncovers the genetic complexity of bicuspid aortic valve in families with early-onset complications.

Pubmed ID: 39226896

Pubmed Central ID: PMC11480851

Journal: American journal of human genetics

Publication Date: Oct. 3, 2024

MeSH Terms: Humans, Male, Adult, Female, Genetic Predisposition to Disease, Age of Onset, Heart Valve Diseases, Phenotype, Exome, Pedigree, Bicuspid Aortic Valve Disease, Exome Sequencing, Aortic Valve, Myosin Heavy Chains, Fibrillin-2, Cardiac Myosins

Authors: Bamshad MJ, Mansoorshahi S, Yetman AT, Bissell MM, Kim YY, Hui DS, Caffarelli A, Andreassi MG, Foffa I, Guo D, Citro R, De Marco M, Tretter JT, Morris SA, Body SC, Chong JX, Milewicz DM, Prakash SK, Michelena HI, De Backer J, Mosquera LM

Cite As: Mansoorshahi S, Yetman AT, Bissell MM, Kim YY, Michelena HI, De Backer J, Mosquera LM, Hui DS, Caffarelli A, Andreassi MG, Foffa I, Guo D, Citro R, De Marco M, Tretter JT, Morris SA, Body SC, Chong JX, Bamshad MJ, University of Washington Center for Rare Disease Research, BAVCon Investigators, EBAV Investigators, Milewicz DM, Prakash SK. Whole-exome sequencing uncovers the genetic complexity of bicuspid aortic valve in families with early-onset complications. Am J Hum Genet 2024 Oct 3;111(10):2219-2231. Epub 2024 Sep 2.

Studies:

Abstract

Bicuspid aortic valve (BAV) is the most common congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that specific gene variants predispose to early-onset complications of BAV (EBAV). We analyzed whole-exome sequences (WESs) to identify rare coding variants that contribute to BAV disease in 215 EBAV-affected families. Predicted damaging variants in candidate genes with moderate or strong supportive evidence to cause developmental cardiac phenotypes were present in 107 EBAV-affected families (50% of total), including genes that cause BAV (9%) or heritable thoracic aortic disease (HTAD, 19%). After appropriate filtration, we also identified 129 variants in 54 candidate genes that are associated with autosomal-dominant congenital heart phenotypes, including recurrent deleterious variation of FBN2, MYH6, channelopathy genes, and type 1 and 5 collagen genes. These findings confirm our hypothesis that unique rare genetic variants drive early-onset presentations of BAV disease.