title: A high-resolution copy-number variation resource for clinical and population genetics.
abstract: OBJECTIVE
  Chromosomal microarray analysis to assess copy-number variation has become a first-tier genetic diagnostic test for individuals with unexplained neurodevelopmental disorders or multiple congenital anomalies. More than 100 cytogenetic laboratories worldwide use the new ultra-high resolution Affymetrix CytoScan-HD array to genotype hundreds of thousands of samples per year. Our aim was to develop a copy-number variation resource from a new population sample that would enable more accurate interpretation of clinical genetics data on this microarray platform and others.
  
  
  METHODS
  Genotyping of 1,000 adult volunteers who are broadly representative of the Ontario population (as obtained from the Ontario Population Genomics Platform) was performed with the CytoScan-HD microarray system, which has 2.7 million probes. Four independent algorithms were applied to detect copy-number variations. Reproducibility and validation metrics were quantified using sample replicates and quantitative-polymerase chain reaction, respectively.
  
  
  RESULTS
  DNA from 873 individuals passed quality control and we identified 71,178 copy-number variations (81 copy-number variations/individual); 9.8% (6,984) of these copy-number variations were previously unreported. After applying three layers of filtering criteria, from our highest confidence copy-number variation data set we obtained >95% reproducibility and >90% validation rates (73% of these copy-number variations overlapped at least one gene).
  
  
  CONCLUSIONS
  The genotype data and annotated copy-number variations for this largely Caucasian population will represent a valuable public resource enabling clinical genetics research and diagnostics.
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Uddin
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Bhooma
authors.initials: B
authors.lastname: Thiruvahindrapuram
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Walker
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Zhuozhi
authors.identifier: http://orcid.org/0000-0002-5169-5266
authors.initials: Z
authors.lastname: Wang
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Hu
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Lamoureux
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: John
authors.identifier: http://orcid.org/0000-0001-5447-1682
authors.initials: J
authors.lastname: Wei
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jeffrey R
authors.identifier: http://orcid.org/0000-0001-5058-2393
authors.initials: JR
authors.lastname: MacDonald
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Giovanna
authors.identifier: http://orcid.org/0000-0003-4747-3473
authors.initials: G
authors.lastname: Pellecchia
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Chao
authors.identifier: http://orcid.org/0000-0003-1189-3265
authors.initials: C
authors.lastname: Lu
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Anath C
authors.initials: AC
authors.lastname: Lionel
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Gazzellone
authors.affiliation: Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.|Public Health Ontario, Toronto, Ontario, Canada.|Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: John R
authors.identifier: http://orcid.org/0000-0001-6453-7577
authors.initials: JR
authors.lastname: McLaughlin
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Brown
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.affiliation: Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.|Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Knight
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Herbrick
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Richard F
authors.identifier: http://orcid.org/0000-0003-1987-1095
authors.initials: RF
authors.lastname: Wintle
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Molecular Genetics, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Ray
authors.affiliation: Division of Molecular Genetics, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Dimitri J
authors.initials: DJ
authors.lastname: Stavropoulos
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Molecular Genetics, Department of Pediatric Laboratory Medicine, 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, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Genetics & 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
mesh_terms: D000465:Algorithms; D002875:Chromosomes; D000013:Congenital Abnormalities / Q000235:genetics; D056915:DNA Copy Number Variations; D066289:Data Curation; D030541:Databases, Genetic; D005260:Female; D005828:Genetics, Population / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D065886:Neurodevelopmental Disorders / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D015203:Reproducibility of Results