Abstract 10554: Copy Number Variation Impacts Sporadic and Syndromic Atrioventricular Septal Defects
Background Congenital heart disease (CHD) is often associated with Down syndrome (DS) and copy number variants (CNVs) such as 22q11.2 microdeletions. However, defined syndromes with chromosomal anomalies only account for a minority of global CHD burden. The CNV basis for specific CHD phenotypes including atrioventricular septal defects (AVSD) is not known. In this study, we explored the role of CNVs in sporadic AVSDs in euploid individuals and in individuals with DS compared to normal controls without cardiac or neurological phenotypes.
Methods and Results We utilized a custom oligonucleotide arrays targeted to CNV hotspots that are flanked by large duplicated segments of high sequence identity. We assayed 79 individuals with AVSDs (50 DS, 29 euploid) and compared to a total 8635 normal controls. Within the euploid patients with AVSD we identified two deletions overlapping with regions previously associated with Tetralogy of Fallot (ToF) and other CHD phenotypes including 3q26. One DS patient had a unique duplication outside of chromosome 21 in a region known to be associated with syndromic CHD. No euploid patients with AVSD were found to have CNVs on chromosome 21, and none of these variants were seen in our expanded set of controls
Conclusions For the first time, we have identified novel CNVs associated with isolated AVSDs, suggesting that ascertainment for a specific clinical phenotype provides sufficient power to identify highly specific regions/genes that are potentially pathogenic. The absence of CNVs on chromosome 21 implies different genetic risk factors for AVSD in the euploid and DS populations. Our results support the pathogenic role of genomic structural variation in some fraction of sporadic AVSD.
- © 2011 by American Heart Association, Inc.