Investigation into the genetic nature of familial congenital bicuspid aortic valve

Abstract

Bicuspid aortic valve (BAV) affects approximately 1% of the general population and its etiology remains unknown. Based on literature reports, we hypothesized that congenital BAV (cBAV) was a developmental defect inherited as an autosomal dominant trait with variable penetrance. We evaluated the NOS3 candidate gene based on the reported phenotype of a mouse mutant, and the FBLN2 and TIMP4 genes based on their role in heart development. DNA sequencing of these genes in our BAV families did not reveal the presence of any potential disease-causing mutations. We also examined the 3p25 region, which showed suggestive linkage at the D3S1259 marker locus in a previous 20 cM genome-wide screen. Linkage analysis with additional markers in the region suggested that the initial hit at D3S1259 had probably been obtained by chance in most families. We are currently recruiting additional families and plan to undertake a 10 cM genome screen to uncover new loci. This work represents the first effort to investigate the genetic nature of cBAV.