Contribution of Copy Number Variation to Down Syndrome-associated Atrioventricular Septal Defects

PURPOSE: The goal of this study was to identify the contribution of large copy number variants (CNV) to Down syndrome (DS) associated atrioventricular septal defects (AVSD), whose risk in the trisomic population is 2000-fold more compared to general disomic population. METHODS: Genome-wide CNV analysis was performed on 452 individuals with DS (210 cases with complete AVSD; 242 controls with structurally normal hearts) using Affymetrix SNP 6.0 arrays, making this the largest heart study conducted to date on a trisomic background. RESULTS: Large common CNVs with substantial effect sizes (OR>2.0) do not account for the increased risk observed in DS-associated AVSD. In contrast, cases had a greater burden of large rare deletions (p<0.01) and intersected more genes (p<0.007) when compared to controls. We also observed a suggestive enrichment of deletions intersecting ciliome genes in cases compared to controls. CONCLUSION: Our data provide strong evidence that large rare deletions increase the risk of DS-associated AVSD, while large common CNVs do not appear to increase the risk of DS-associated AVSD. The genetic architecture of AVSD is complex and multifactorial in nature.