Analysis of copy number variants on chromosome 21 in down syndrome-associated congenital heart defects

Benjamin L. Rambo-Martin, Jennifer G. Mulle, David J. Cutler, Lora J.H. Bean, Tracie C. Rosser, Kenneth J. Dooley, Clifford Cua, George Capone, Cheryl L. Maslen, Roger H. Reeves, Stephanie L. Sherman, Michael E. Zwick

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    Abstract

    One in five people with Down syndrome (DS) are born with an atrioventricular septal defect (AVSD), an incidence 2000 times higher than in the euploid population. The genetic loci that contribute to this risk are poorly understood. In this study, we tested two hypotheses: (1) individuals with DS carrying chromosome 21 copy number variants (CNVs) that interrupt exons may be protected from AVSD, because these CNVs return AVSD susceptibility loci back to disomy, and (2) individuals with DS carrying chromosome 21 genes spanned by microduplications are at greater risk for AVSD because these microduplications boost the dosage of AVSD susceptibility loci beyond a tolerable threshold.We tested 198 case individuals with DS+AVSD, and 211 control individuals with DS and a normal heart, using a custom microarray with dense probes tiled on chromosome 21 for array CGH (aCGH). We found that neither an individual chromosome 21 CNV nor any individual gene intersected by a CNV was associated with AVSD in DS. Burden analyses revealed that African American controls had more bases covered by rare deletions than did African American cases. Inversely, we found that Caucasian cases had more genes intersected by rare duplications than did Caucasian controls. We also showed that previously DS+AVSD (DS and a complete AVSD)-associated common CNVs on chromosome 21 failed to replicate. This research adds to the swell of evidence indicating that DS-associated AVSD is similarly heterogeneous, as is AVSD in the euploid population.

    LanguageEnglish (US)
    Pages105-111
    Number of pages7
    JournalG3: Genes, Genomes, Genetics
    Volume8
    Issue number1
    DOIs
    StatePublished - Jan 1 2018

    Fingerprint

    Chromosomes, Human, Pair 21
    Congenital Heart Defects
    Down Syndrome
    African Americans
    Atrioventricular Septal Defect
    Genes
    Genetic Loci
    Population
    Exons

    Keywords

    • Congenital heart defects
    • Copy number variation
    • Down syndrome

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Genetics(clinical)

    Cite this

    Rambo-Martin, B. L., Mulle, J. G., Cutler, D. J., Bean, L. J. H., Rosser, T. C., Dooley, K. J., ... Zwick, M. E. (2018). Analysis of copy number variants on chromosome 21 in down syndrome-associated congenital heart defects. G3: Genes, Genomes, Genetics, 8(1), 105-111. DOI: 10.1534/g3.117.300366

    Analysis of copy number variants on chromosome 21 in down syndrome-associated congenital heart defects. / Rambo-Martin, Benjamin L.; Mulle, Jennifer G.; Cutler, David J.; Bean, Lora J.H.; Rosser, Tracie C.; Dooley, Kenneth J.; Cua, Clifford; Capone, George; Maslen, Cheryl L.; Reeves, Roger H.; Sherman, Stephanie L.; Zwick, Michael E.

    In: G3: Genes, Genomes, Genetics, Vol. 8, No. 1, 01.01.2018, p. 105-111.

    Research output: Contribution to journalArticle

    Rambo-Martin, BL, Mulle, JG, Cutler, DJ, Bean, LJH, Rosser, TC, Dooley, KJ, Cua, C, Capone, G, Maslen, CL, Reeves, RH, Sherman, SL & Zwick, ME 2018, 'Analysis of copy number variants on chromosome 21 in down syndrome-associated congenital heart defects' G3: Genes, Genomes, Genetics, vol. 8, no. 1, pp. 105-111. DOI: 10.1534/g3.117.300366
    Rambo-Martin BL, Mulle JG, Cutler DJ, Bean LJH, Rosser TC, Dooley KJ et al. Analysis of copy number variants on chromosome 21 in down syndrome-associated congenital heart defects. G3: Genes, Genomes, Genetics. 2018 Jan 1;8(1):105-111. Available from, DOI: 10.1534/g3.117.300366
    Rambo-Martin, Benjamin L. ; Mulle, Jennifer G. ; Cutler, David J. ; Bean, Lora J.H. ; Rosser, Tracie C. ; Dooley, Kenneth J. ; Cua, Clifford ; Capone, George ; Maslen, Cheryl L. ; Reeves, Roger H. ; Sherman, Stephanie L. ; Zwick, Michael E./ Analysis of copy number variants on chromosome 21 in down syndrome-associated congenital heart defects. In: G3: Genes, Genomes, Genetics. 2018 ; Vol. 8, No. 1. pp. 105-111
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