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

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 cohorts with late onset sporadic disease (n = 5040). We identified 34 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 8% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV. Author SummaryBicuspid aortic valve (BAV) is the most common form of congenital heart disease and can lead to long-term complications such as aortic stenosis, aortic regurgitation, or thoracic aortic aneurysms. Most BAV-related complications arise in late adulthood, but 10-15% of individuals with BAV develop early onset complications before age 30. Copy number variants (CNVs) are genomic structural variations that have been previously implicated in some types of congenital heart disease, including BAV. Here we demonstrate that individuals with early onset complications of BAV are enriched for specific rare CNVs compared to individuals with late-onset BAV disease. We also describe novel CNVs involving DSCAM, a gene on chromosome 21 that has not previously been associated with the development of BAV. These results may lead to improved risk stratification and targeted therapies for BAV patients.