title: Genome-wide rare copy number variations contribute to genetic risk for transposition of the great arteries.
abstract: BACKGROUND
  Transposition of the great arteries (TGA) is an uncommon but severe congenital heart malformation of unknown etiology. Rare copy number variations (CNVs) have been implicated in other, more common conotruncal heart defects like tetralogy of Fallot (TOF), but there are as yet no CNV studies dedicated to TGA.
  
  
  METHODS
  Using high-resolution genome-wide microarrays and rigorous methods, we investigated CNVs in a group of prospectively recruited adults with TGA (n=101) from a single center. We compared rare CNV burden to well-matched cohorts of controls and TOF cases, adjudicating rarity using 10,113 independent population-based controls and excluding all subjects with 22q11.2 deletions. We identified candidate genes for TGA based on rare CNVs that overlapped the same gene in unrelated individuals, and pre-existing evidence suggesting a role in cardiac development.
  
  
  RESULTS
  The TGA group was significantly enriched for large rare CNVs (2.3-fold increase, p=0.04) relative to controls, to a degree comparable with the TOF group. Extra-cardiac features were not reliable predictors of rare CNV burden. Smaller rare CNVs helped to narrow critical regions for conotruncal defects at chromosomes 10q26 and 13q13. Established and novel candidate susceptibility genes identified included ACKR3, IFT57, ITGB8, KL, NF1, NKX1-2, RERE, SLC8A1, SOX18, and ULK1.
  
  
  CONCLUSIONS
  These data demonstrate a genome-wide role for rare CNVs in genetic risk for TGA. The findings provide further support for a genetically-related spectrum of congenital heart disease that includes TGA and TOF.
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Medical Genetics Residency Training Program, University of Toronto, and Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Gregory
authors.initials: G
authors.lastname: Costain
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Anath C
authors.initials: AC
authors.lastname: Lionel
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Lucas
authors.initials: L
authors.lastname: Ogura
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: The Toronto Congenital Cardiac Centre for Adults & Division of Cardiology in the Department of Medicine, University Health Network, Toronto, Ontario, Canada. Electronic address: candice.silversides@uhn.ca.
authors.forename: Candice K
authors.initials: CK
authors.lastname: Silversides
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; The Toronto Congenital Cardiac Centre for Adults & Division of Cardiology in the Department of Medicine, University Health Network, Toronto, Ontario, Canada; Department of Psychiatry, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; The Dalglish Family Hearts and Minds Clinic for 22q11.2 Deletion Syndrome, University Health Network, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. Electronic address: anne.bassett@utoronto.ca.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Bassett
mesh_terms: D000328:Adult; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D014188:Transposition of Great Vessels / Q000175:diagnosis* / Q000235:genetics*
keywords: Congenital heart disease; Copy number variation; Genetics; Reproductive fitness; Transposition of the great arteries