Whole-Exome Sequencing Uncovers the Genetic Complexity of Bicuspid Aortic Valve in Families With Early-Onset Complications

Authors

Sara Mansoorshahi
Anji T Yetman
Malenka M Bissell
Yuli Y Kim
Hector I Michelena
Julie De Backer
Laura Muiño Mosquera
Dawn S Hui
Anthony Caffarelli
Maria G Andreassi
Ilenia Foffa
Dongchuan Guo
Rodolfo Citro
Margot De Marco
Justin T Tretter
Shaine A Morris
Simon C Body
Jessica X Chong
Michael J Bamshad
Dianna M Milewicz
Siddharth K Prakash

Language

English

Publication Date

10-3-2024

Journal

American Journal of Human Genetics

DOI

10.1016/j.ajhg.2024.08.001

PMID

39226896

PMCID

PMC11480851

PubMedCentral® Posted Date

9-2-2024

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Bicuspid Aortic Valve Disease, Exome Sequencing, Aortic Valve, Heart Valve Diseases, Male, Female, Pedigree, Genetic Predisposition to Disease, Age of Onset, Phenotype, Exome, Adult, Myosin Heavy Chains, Fibrillin-2, Cardiac Myosins, bicuspid aortic valve, whole-exome sequencing, thoracic aortic aneurysm, congenital heart disease, cardiovascular genetics

Published Open-Access

yes

Recommended Citation

Mansoorshahi, Sara; Yetman, Anji T; Bissell, Malenka M; et al., "Whole-Exome Sequencing Uncovers the Genetic Complexity of Bicuspid Aortic Valve in Families With Early-Onset Complications" (2024). Faculty, Staff and Student Publications. 6274.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6274