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

• Type of Material: Article
• Authors: Dhanya Ramachandran, Emory University; Jennifer G. Mulle, Emory University; Adam E. Locke, Emory University; Lora Bean, Emory University; Tracie Rosser, Emory University; Promise Bose, Emory University; Kenneth Dooley, Emory University; Clifford L. Cua, Nationwide Children’s Hospital; George T. Capone, Kennedy Krieger Institute; Roger H. Reeves, Johns Hopkins University; Cheryl L. Maslen, Oregon Health & Science University; David Cutler, Emory University; Stephanie Sherman, Emory University; Michael Zwick, Emory University
• Language: English
• Date: 2014-10-23
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 American College of Medical Genetics and Genomics.
• Final Published Version (URL): http://dx.doi.org/10.1038/gim.2014.144
• Title of Journal or Parent Work: Genetics in Medicine
• ISSN: 1098-3600
• Volume: 17
• Issue: 7
• Start Page: 554
• End Page: 560
• Grant/Funding Information: 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.; 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).
• Keywords: PATHWAY GENES; CONGENITAL HEART-DISEASE; DOWN-SYNDROME; ciliome; copy-number variation; MALFORMATIONS; GENOME-WIDE ASSOCIATION; Life Sciences & Biomedicine; Down syndrome; atrioventricular septal defects; RISK; POPULATION; congenital heart defect; DE-NOVO MUTATIONS; Genetics & Heredity; RARE VARIANTS; Science & Technology; ABNORMALITIES
• Research Categories: Biology, Genetics; Biology, Molecular; Health Sciences, Epidemiology

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.