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

Pubmed ID: 38370698

Pubmed Central ID: PMC10871469

Journal: medRxiv : the preprint server for health sciences

Publication Date: Feb. 8, 2024

Grants: R01 HL114823, R01 HL137028, R21 HL150373, R21 HL150383

Authors: Bamshad MJ, Mansoorshahi S, Yetman AT, Bissell MM, Kim YY, Michelena H, 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

Cite As: Mansoorshahi S, Yetman AT, Bissell MM, Kim YY, Michelena H, 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. medRxiv 2024 Feb 8.

Studies:

Abstract

Bicuspid Aortic Valve (BAV) is the most common adult congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that early onset complications of BAV (EBAV) are driven by specific impactful genetic variants. We analyzed whole exome sequences (WES) to identify rare coding variants that contribute to BAV disease in 215 EBAV families. Predicted pathogenic variants of causal genes were present in 111 EBAV families (51% of total), including genes that cause BAV (8%) or heritable thoracic aortic disease (HTAD, 17%). After appropriate filtration, we also identified 93 variants in 26 novel genes that are associated with autosomal dominant congenital heart phenotypes, including recurrent deleterious variation of <i>FBN2</i>, <i>MYH6</i>, channelopathy genes, and type 1 and 5 collagen genes. These findings confirm our hypothesis that unique rare genetic variants contribute to early onset complications of BAV disease.