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Author Notes:

Corresponding author: Department of Human Genetics, Emory University School of Medicine, Whitehead Biomedical Research Bldg., 615 Michael St., Suite 301, Atlanta, GA 30322. E-mail: mzwick@emory.edu

Communicating editor: A. McCallion



  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • Down syndrome
  • congenital heart defects
  • copy number variation
  • RISK
  • SNP

Analysis of Copy Number Variants on Chromosome 21 in Down Syndrome-Associated Congenital Heart Defects

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Journal Title:



Volume 8, Number 1


, Pages 105-111

Type of Work:

Article | Final Publisher PDF


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.

Copyright information:

© 2018 Rambo-Martin et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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