Abstract 17616: Recurrent Copy Number Variants are Enriched in Bicuspid Aortic Valve and Affect Cardiac Developmental Genes

Abstract

Introduction: Bicuspid Aortic Valve (BAV) is the most common adult congenital heart defect. The spectrum of BAV ranges from chromosomal disorders such as Turner syndrome to sporadic isolated disease of unknown cause. We hypothesized that genomic copy number variants (CNVs) contribute causally to BAV. Methods: We conducted genome-wide SNP array analyses of BAV cases in six European American cohorts (3533 total subjects, 31% BAV, 45% female, ages 1-94 years) with sporadic or familial thoracic aortic aneurysms (37%), congenital left ventricular outflow tract obstructive defects (47%) or Turner syndrome (10%). Genotyping was performed on Illumina Omni microarrays, using PennCNV, Nexus and CNVPartition for CNV detection. Thresholds were set at a minimum of six consecutive SNPs for CNVs that were identified by at least two algorithms and intersect with known genes. A total of 1380 BAV cases were compared to 1065 cases with tricuspid aortic valves and 7013 dbGAP controls without a history of cardiovascular disease using association tests for rare CNVs as implemented in PLINK. Pathway and functional analyses of rare CNVs were performed using the ToppGene analysis suite. Genes within rare CNVs were prioritized by their connectivity to genes in the Notch pathway or established roles in human or animal cardiac phenotypes. Results: We identified 12 rare CNV regions that were recurrent in at least three different BAV groups and were absent or extremely rare (frequency <0.1%) in controls. Four of these regions involved genes that cause aortic valve or outflow tract defects when mutated. The largest and most prevalent of the recurrent CNVs were at Xq28 (four duplications and two deletions), at 22q11.21, telomeric to the DiGeorge syndrome critical region (four deletions, three duplications), and at 7p15.2 (four deletions). The percentage of individuals harboring rare CNVs was significantly greater in BAV cases than in tricuspid or dbGAP controls. Conclusions: We identified multiple loci affected by rare CNVs in BAV subjects, demonstrating the genetic heterogeneity of BAV and implicating alterations of candidate genes at these loci in the pathogenesis of BAV.