title: Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, USA.
authors.forename: Dhanya
authors.identifier: 0000000291767623
authors.initials: D
authors.lastname: Ramachandran
authors.affiliation: 1] Department of Human Genetics, Emory University, Atlanta, Georgia, USA [2] Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Mulle
authors.affiliation: 1] Genetics and Molecular Biology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, Georgia, USA [2] Current address: Center for Statistical Genetics and Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
authors.forename: Adam E
authors.identifier: 000000016227198X
authors.initials: AE
authors.lastname: Locke
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, USA.
authors.forename: Lora J H
authors.initials: LJ
authors.lastname: Bean
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, USA.
authors.forename: Tracie C
authors.initials: TC
authors.lastname: Rosser
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, USA.
authors.forename: Promita
authors.initials: P
authors.lastname: Bose
authors.affiliation: Sibley Heart Center Cardiology, Department of Pediatrics, Children's Hospital of Atlanta, Emory University, Atlanta, Georgia, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Dooley
authors.affiliation: Heart Center, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Clifford L
authors.initials: CL
authors.lastname: Cua
authors.affiliation: Down Syndrome Clinic and Research Center, Kennedy Krieger Institute, Baltimore, Maryland, USA.
authors.forename: George T
authors.identifier: 000000017018101X
authors.initials: GT
authors.lastname: Capone
authors.affiliation: Department of Physiology and McKusick Nathans Institute for Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Roger H
authors.identifier: 0000000286309679
authors.initials: RH
authors.lastname: Reeves
authors.affiliation: Knight Cardiovascular Institute, and Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Cheryl L
authors.identifier: 0000000291723874
authors.initials: CL
authors.lastname: Maslen
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cutler
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Sherman
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Zwick
mesh_terms: D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D056726:Genetic Association Studies; D006343:Heart Septal Defects / Q000235:genetics*; D006801:Humans; D044465:White People