Abstract
Background and aims: Congenital heart defects (CHDs) represent the most common structural birth defect in humans. While the identification of specific genes in these disorders have contributed to our understanding of cardiac development, they have not provided significant insight into the etiology of common, non-syndromic forms of CHDs. Our goal was to identify the copy number variants (CNVs) associated with CHDs. Methods: We used a systematic approach using high-resolution SNP genotyping arrays to identify CNVs priority ranked based on their potential pathogenicity using a program, Perl Copy Numbers of Potential Interest (PECONPI), developed in our lab. PECONPI identifies disruptions in highly conserved non-coding regions 1 Mb upstream or downstream to known developmental cardiac loci. We screened of 362 probands with CHDs and 3000 controls using PECONPI. Results: We identified over 150 candidate CNVs that meet the criteria: 1) highly or ultra-conservation, 2) within 1 Mb of a candidate locus, and 3) not present in control samples. We identified a cluster of overlapping deletions involving a conserved non-coding element (CNCE) on 2p 13.3 in 7 unrelated probands, 6 with identical 5 Kb deletions and one with a smaller I Kb deletion, not seen in 3000 controls. This included 4 with TGA, 1 with TOF, 1 with a vascular ring, and 1 with unbalanced atrioventricular canal. Conclusions: The presence of TGAs in 4/7 (57%) is discordant from the total population screened in which TGAs were present in 46/362 (13%) of the probands. Thus we have identified a novel CNCE for CHD.
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