Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects

Dhanya Ramachandran, Jennifer G. Mulle, Adam E. Locke, Lora J.H. Bean, Tracie C. Rosser, Promita Bose, Kenneth J. Dooley, Clifford L. Cua, George T. Capone, Roger H. Reeves, Cheryl L. Maslen, David J. Cutler, Stephanie L. Sherman, Michael E. Zwick

    Research output: Contribution to journalArticle

    17 Scopus citations

    Abstract

    Purpose:The goal of this study was to identify the contribution of large copy-number variants to Down syndrome-associated atrioventricular septal defects, the risk for which in the trisomic population is 2,000-fold more as compared with that of the general disomic population.Methods:Genome-wide copy-number variant analysis was performed on 452 individuals with Down syndrome (210 cases with complete atrioventricular septal defects; 242 controls with structurally normal hearts) using Affymetrix SNP 6.0 arrays, making this the largest heart study conducted to date on a trisomic background.Results:Large, common copy-number variants with substantial effect sizes (OR > 2.0) do not account for the increased risk observed in Down syndrome-associated atrioventricular septal defects. By contrast, cases had a greater burden of large, rare deletions (P < 0.01) and intersected more genes (P < 0.007) as compared with controls. We also observed a suggestive enrichment of deletions intersecting ciliome genes in cases as compared with controls.Conclusion:Our data provide strong evidence that large, rare deletions increase the risk of Down syndrome-associated atrioventricular septal defects, whereas large, common copy-number variants do not appear to increase the risk of Down syndrome-associated atrioventricular septal defects. The genetic architecture of atrioventricular septal defects is complex and multifactorial in nature.Genet Med 17 7, 554-560.

    Original languageEnglish (US)
    Pages (from-to)554-560
    Number of pages7
    JournalGenetics in Medicine
    Volume17
    Issue number7
    DOIs
    StatePublished - Jul 2 2015

    Keywords

    • Down syndrome
    • atrioventricular septal defects
    • ciliome
    • congenital heart defect
    • copy-number variation

    ASJC Scopus subject areas

    • Genetics(clinical)

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    Ramachandran, D., Mulle, J. G., Locke, A. E., Bean, L. J. H., Rosser, T. C., Bose, P., Dooley, K. J., Cua, C. L., Capone, G. T., Reeves, R. H., Maslen, C. L., Cutler, D. J., Sherman, S. L., & Zwick, M. E. (2015). Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects. Genetics in Medicine, 17(7), 554-560. https://doi.org/10.1038/gim.2014.144