title: Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect.
abstract: OBJECTIVE
  The genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of nonsyndromic individuals with AVSD.
  
  
  METHODS
  Whole-exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD.
  
  
  RESULTS
  A significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls (odds ratio (OR): 1.52; 95% confidence interval (CI): 1.35-1.71; P = 4.8 × 10(-11)). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR: 2.25; 95% CI: 1.84-2.76; P = 2.2 × 10(-16)). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2, and MDM4) were enriched for rare variants in AVSD compared with controls, including three syndrome-associated genes (NIPBL, CHD7, and CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands.
  
  
  CONCLUSIONS
  Mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD, even in those with isolated heart disease. The identification of a gene set associated with AVSD will facilitate targeted genetic screening in this cohort.
authors.affiliation: Division of Cardiology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lisa C A
authors.identifier: http://orcid.org/0000-0002-9734-7152
authors.initials: LC
authors.lastname: D'Alessandro
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|Department of Pathology, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: Saeed
authors.initials: S
authors.lastname: Al Turki
authors.affiliation: Division of Cardiology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ashok Kumar
authors.initials: AK
authors.lastname: Manickaraj
authors.affiliation: Division of Cardiology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Dorin
authors.initials: D
authors.lastname: Manase
authors.affiliation: Heart Center, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Barbara J M
authors.initials: BJ
authors.lastname: Mulder
authors.affiliation: Division of Cardiology, Department of Medicine, London Health Sciences Centre, London, Ontario, Canada.
authors.forename: Lynn
authors.initials: L
authors.lastname: Bergin
authors.affiliation: Department of Paediatrics, London Health Sciences Centre, London, Ontario, Canada.
authors.forename: Herschel C
authors.initials: HC
authors.lastname: Rosenberg
authors.affiliation: Department of Pediatrics, Hamilton Health Sciences Centre, Hamilton, Ontario, Canada.
authors.forename: Tapas
authors.identifier: http://orcid.org/0000-0003-2077-1710
authors.initials: T
authors.lastname: Mondal
authors.affiliation: Division of Cardiology, Department of Medicine, Hamilton Health Sciences Centre, Hamilton, Ontario, Canada.
authors.forename: Elaine
authors.initials: E
authors.lastname: Gordon
authors.affiliation: Division of Cardiology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: Jane
authors.initials: J
authors.lastname: Lougheed
authors.affiliation: Department of Pediatrics, Kingston General Hospital, Kingston, Ontario, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Smythe
authors.affiliation: Centre for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.affiliation: Radcliffe Department of Medicine & Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Shoumo
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Radcliffe Department of Medicine & Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Bentham
authors.affiliation: Division of Genetics, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bowdin
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.affiliation: Division of Cardiology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Seema
authors.identifier: http://orcid.org/0000-0002-7643-4484
authors.initials: S
authors.lastname: Mital
mesh_terms: D000293:Adolescent; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006343:Heart Septal Defects / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D017422:Sequence Analysis, DNA