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 Maslen, David J. Cutler, Stephanie L. Sherman, Michael E. Zwick

    Research output: Contribution to journalArticle

    15 Citations (Scopus)

    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

    Fingerprint

    Down Syndrome
    Viverridae
    Population
    Genes
    Single Nucleotide Polymorphism
    Atrioventricular Septal Defect
    Genome

    Keywords

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

    ASJC Scopus subject areas

    • Genetics(clinical)

    Cite this

    Ramachandran, D., Mulle, J. G., Locke, A. E., Bean, L. J. H., Rosser, T. C., Bose, P., ... 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

    Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects. / Ramachandran, Dhanya; Mulle, Jennifer G.; Locke, Adam E.; Bean, Lora J H; Rosser, Tracie C.; Bose, Promita; Dooley, Kenneth J.; Cua, Clifford L.; Capone, George T.; Reeves, Roger H.; Maslen, Cheryl; Cutler, David J.; Sherman, Stephanie L.; Zwick, Michael E.

    In: Genetics in Medicine, Vol. 17, No. 7, 02.07.2015, p. 554-560.

    Research output: Contribution to journalArticle

    Ramachandran, D, Mulle, JG, Locke, AE, Bean, LJH, Rosser, TC, Bose, P, Dooley, KJ, Cua, CL, Capone, GT, Reeves, RH, Maslen, C, Cutler, DJ, Sherman, SL & Zwick, ME 2015, 'Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects', Genetics in Medicine, vol. 17, no. 7, pp. 554-560. https://doi.org/10.1038/gim.2014.144
    Ramachandran, Dhanya ; Mulle, Jennifer G. ; Locke, Adam E. ; Bean, Lora J H ; Rosser, Tracie C. ; Bose, Promita ; Dooley, Kenneth J. ; Cua, Clifford L. ; Capone, George T. ; Reeves, Roger H. ; Maslen, Cheryl ; Cutler, David J. ; Sherman, Stephanie L. ; Zwick, Michael E. / Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects. In: Genetics in Medicine. 2015 ; Vol. 17, No. 7. pp. 554-560.
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    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.",
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    AU - Mulle, Jennifer G.

    AU - Locke, Adam E.

    AU - Bean, Lora J H

    AU - Rosser, Tracie C.

    AU - Bose, Promita

    AU - Dooley, Kenneth J.

    AU - Cua, Clifford L.

    AU - Capone, George T.

    AU - Reeves, Roger H.

    AU - Maslen, Cheryl

    AU - Cutler, David J.

    AU - Sherman, Stephanie L.

    AU - Zwick, Michael E.

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    N2 - 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.

    AB - 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.

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