• Peter S White, Hongbo M Xie, Petra Werner, Joseph Glessner, Brande Latney, Hakon Hakonarson, and Elizabeth Goldmuntz.
• The Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
• Birth Defects Res. Part A Clin. Mol. Teratol. 2014 Dec 1; 100 (12): 951-64.

BackgroundWe sought to characterize the landscape of structural variation associated with the subset of congenital cardiac defects characterized by left-sided obstruction.MethodsCases with left-sided cardiac defects (LSCD) and pediatric controls were uniformly genotyped and assessed for copy number variant (CNV) calls. Significance testing was performed to ascertain differences in overall CNV incidence, and for CNV enrichment of specific genes and gene functions in LSCD cases relative to controls.ResultsA total of 257 cases of European descent and 962 ethnically matched, disease-free pediatric controls were included. Although there was no difference in CNV rate between cases and controls, a significant enrichment in rare LSCD CNVs was detected overall (p=7.30 × 10(-3) , case/control ratio=1.26) and when restricted either to deletions (p=7.58 × 10(-3) , case/control ratio=1.20) or duplications (3.02 × 10(-3) , case/control ratio=1.43). Neither gene-based, functional nor knowledge-based analyses identified genes, loci or pathways that were significantly enriched in cases as compared to controls when appropriate corrections for multiple tests were applied. However, several genes of interest were identified by virtue of their association with cardiac development, known human conditions, or reported disruption by CNVs in other patient cohorts.ConclusionThis study examines the largest cohort to date with LSCD for structural variation. These data suggest that CNVs play a role in disease risk and identify numerous genes disrupted by CNVs of potential disease relevance. These findings further highlight the genetic heterogeneity and complexity of these disorders.© 2014 Wiley Periodicals, Inc.

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