Abstract
Atrioventricular septal defects (AVSDs) are a frequent but not universal component of Down syndrome (DS), while AVSDs in otherwise normal individuals have no well-defined genetic basis. The contribution of copy number variation (CNV) to specific congenital heart disease (CHD) phenotypes including AVSD is unknown. We hypothesized that de novo CNVs on chromosome 21 might cause isolated sporadic AVSDs, and separately that CNVs throughout the genome might constitute an additional genetic risk factor for AVSD in patients with DS. We utilized a custom oligonucleotide arrays targeted to CNV hotspots that are flanked by large duplicated segments of high sequence identity. We assayed 29 euploid and 50 DS individuals with AVSD, and compared to general population controls. In patients with isolated-sporadic AVSD we identified two large unique deletions outside of chromosome 21 not seen in the expanded set of 8,635 controls, each overlapping with larger deletions associated with similar CHD reported in the DECIPHER database. There was a small duplication in one patient with DS and AVSD. We conclude that isolated sporadic AVSDs may be occasionally associated with large de novo genomic structural variation outside of chromosome 21. The absence of CNVs on chromosome 21 in patients with isolated sporadic AVSD suggests that sub-chromosomal duplications or deletions of greater than 150 kbp on chromosome 21 do not cause sporadic AVSDs. Large CNVs do not appear to be an additive risk factor for AVSD in the DS population. © 2012 Wiley Periodicals, Inc.
Highlights
75% of congenital heart disease (CHD) is sporadic, occurring separately from conditions such as Down syndrome (DS) or 22q11.2 deletion syndrome suggesting that genetic basis for the majority of CHD remains clinically unrecognized [Goldmuntz and Lin, 2008]
We initially identified patients with an Atrioventricular septal defects (AVSDs) from the electronic medical record, and excluded those with congenital malformations, developmental delay, or other major CHD
After filtering for common copy number polymorphisms and variants identified at an allele frequency of >0.1% (>9/8,329 controls) in the control population, we identified a total of three rare copy number variation (CNV)
Summary
75% of congenital heart disease (CHD) is sporadic, occurring separately from conditions such as Down syndrome (DS) or 22q11.2 deletion syndrome suggesting that genetic basis for the majority of CHD remains clinically unrecognized [Goldmuntz and Lin, 2008]. Other studies of AVSD associated 3p- syndrome and recurrent 8p23.1 deletions, demonstrate that there are likely multiple AVSD risk loci with incomplete penetrance scattered throughout the genome, and that genomic structural variants such as copy number variations (CNVs) are potentially etiologic in the pathogenesis of CHD [Shuib et al, 2009; Wat et al, 2009].
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