Rare Genomic Copy Number Variants Implicate New Candidate Genes for Bicuspid Aortic Valve

Authors

Steven G Carlisle
Hasan Albasha
Hector I Michelena
Anna Sabate-Rotes
Lisa Bianco
Julie De Backer
Laura Muiño Mosquera
Anji T Yetman
Malenka M Bissell
Maria Grazia Andreassi
Ilenia Foffa
Dawn S Hui
Anthony Caffarelli
Yuli Y Kim
Dongchuan Guo
Rodolfo Citro
Margot De Marco
Justin T Tretter
Kim L McBride
Dianna M Milewicz
Simon C Body
Siddharth K Prakash
EBAV Investigators
BAVCon Investigators

Publication Date

1-1-2024

Journal

PLoS One

Abstract

Bicuspid aortic valve (BAV), the most common congenital heart defect, is a major cause of aortic valve disease requiring valve interventions and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications (EBAV) to sporadic late onset disease. Rare genomic copy number variants (CNVs) have previously been implicated in the development of BAV and thoracic aortic aneurysms. We determined the frequency and gene content of rare CNVs in EBAV probands (n = 272) using genome-wide SNP microarray analysis and three complementary CNV detection algorithms (cnvPartition, PennCNV, and QuantiSNP). Unselected control genotypes from the Database of Genotypes and Phenotypes were analyzed using identical methods. We filtered the data to select large genic CNVs that were detected by multiple algorithms. Findings were replicated in a BAV cohort with late onset sporadic disease (n = 5040). We identified 3 large and rare (< 1,1000 in controls) CNVs in EBAV probands. The burden of CNVs intersecting with genes known to cause BAV when mutated was increased in case-control analysis. CNVs intersecting with GATA4 and DSCAM were enriched in cases, recurrent in other datasets, and segregated with disease in families. In total, we identified potentially pathogenic CNVs in 9% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV.

Keywords

Humans, DNA Copy Number Variations, Aortic Valve, Bicuspid Aortic Valve Disease, Heart Valve Diseases, Polymorphism, Single Nucleotide, Male, Female, Middle Aged, Genetic Predisposition to Disease, Adult, Case-Control Studies, Aged, Aortic Valve Disease, GATA4 Transcription Factor, Genome-Wide Association Study

Comments

Supplementary Materials

Data Availability Statement

PMID: 39240962