Abstract
Purpose:The goal of this study was to identify the contribution of large copy-number variants to Down syndrome-associated atrioventricular septal defects, the risk for which in the trisomic population is 2,000-fold more as compared with that of the general disomic population.Methods:Genome-wide copy-number variant analysis was performed on 452 individuals with Down syndrome (210 cases with complete atrioventricular septal defects; 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 copy-number variants with substantial effect sizes (OR > 2.0) do not account for the increased risk observed in Down syndrome-associated atrioventricular septal defects. By contrast, cases had a greater burden of large, rare deletions (P < 0.01) and intersected more genes (P < 0.007) as compared with controls. We also observed a suggestive enrichment of deletions intersecting ciliome genes in cases as compared with controls.Conclusion:Our data provide strong evidence that large, rare deletions increase the risk of Down syndrome-associated atrioventricular septal defects, whereas large, common copy-number variants do not appear to increase the risk of Down syndrome-associated atrioventricular septal defects. The genetic architecture of atrioventricular septal defects is complex and multifactorial in nature.Genet Med 17 7, 554-560.
Original language | English (US) |
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Pages (from-to) | 554-560 |
Number of pages | 7 |
Journal | Genetics in Medicine |
Volume | 17 |
Issue number | 7 |
DOIs | |
State | Published - Jul 2 2015 |
Externally published | Yes |
Keywords
- Down syndrome
- atrioventricular septal defects
- ciliome
- congenital heart defect
- copy-number variation
ASJC Scopus subject areas
- Genetics(clinical)