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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. <jats:bold>Results:<\/jats:bold> A total of 257 cases of European descent and 962 ethnically matched, disease\u2010free 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 (<jats:italic>p<\/jats:italic>\u2009=\u20097.30 \u00d7 10<jats:sup>\u22123<\/jats:sup>, case\/control ratio\u2009=\u20091.26) and when restricted either to deletions (<jats:italic>p<\/jats:italic>\u2009=\u20097.58 \u00d7 10<jats:sup>\u22123<\/jats:sup>, case\/control ratio\u2009=\u20091.20) or duplications (3.02 \u00d7 10<jats:sup>\u22123<\/jats:sup>, case\/control ratio\u2009=\u20091.43). Neither gene\u2010based, functional nor knowledge\u2010based 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. <jats:bold>Conclusion:<\/jats:bold> This 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. 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