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Author Notes:

Corresponding author: Michael E. Zwick, PhD, Department of Human Genetics, Emory University, Whitehead Biomedical Research Building, Suite 301, Atlanta, GA- 30322, Email: mzwick@emory.edu, Phone: 404-727-9924, Fax: 404-727-3949

We gratefully acknowledge the individuals with DS and their families for participating in this research.

Our thanks to Katy Lesowski and Jessica Hunter (Oregon Health and Science University), Kay Taylor and Valerie Deleon (John Hopkins University/Kennedy Krieger Institute), Lindsay Kehoe (Children’s National Medical Center) and Helen Smith and Elizabeth Sablon (Emory University) who engaged and collaborated with the families to gather the needed information.

CNV validation experiments were performed by Emory Integrated Genomics Core (EIGC).

Authors thank Shoshona Lee, Weiya He and Ashima Amin (Emory University) for technical assistance.

The authors declare no conflicts of interest.


Research Funding:

This work is a collaborative effort with DS Heart Project (R.H.R) and was supported by R01 HL092981-01A1 (M.E.Z.), R01 HL083300 (R.H.R) from NIH/NHLBI, R01 HD38979 (S.L.S and E. Feingold) from NIH/NICHD, Training program in Human Disease Genetics 1T32MH087977 (D.R.), and the American Heart Association Pre-doctoral Fellowship (A.E.L).

Additional support was provided by OCTRI (UL1 RR024140) from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • atrioventricular septal defects
  • ciliome
  • congenital heart defect
  • copy-number variation
  • Down syndrome
  • RISK

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

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Journal Title:

Genetics in Medicine


Volume 17, Number 7


, Pages 554-560

Type of Work:

Article | Post-print: After Peer Review


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.

Copyright information:

© 2015 American College of Medical Genetics and Genomics.

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