title: Incidental copy-number variants identified by routine genome testing in a clinical population.
abstract: OBJECTIVE
  Mutational load of susceptibility variants has not been studied on a genomic scale in a clinical population, nor has the potential to identify these mutations as incidental findings during clinical testing been systematically ascertained.
  
  
  METHODS
  Array comparative genomic hybridization, a method for genome-wide detection of DNA copy-number variants, was performed clinically on DNA from 9,005 individuals. Copy-number variants encompassing or disrupting single genes were identified and analyzed for their potential to confer predisposition to dominant, adult-onset disease. Multigene copy-number variants affecting dominant, adult-onset cancer syndrome genes were also assessed.
  
  
  RESULTS
  In our cohort, 83 single-gene copy-number variants affected 40 unique genes associated with dominant, adult-onset disorders and unrelated to the patients' referring diagnoses (i.e., incidental) were found. Fourteen of these copy-number variants are likely disease-predisposing, 25 are likely benign, and 44 are of unknown clinical consequence. When incidental copy-number variants spanning up to 20 genes were considered, 27 copy-number variants affected 17 unique genes associated with dominant, adult-onset cancer predisposition.
  
  
  CONCLUSIONS
  Copy-number variants potentially conferring susceptibility to adult-onset disease can be identified as incidental findings during routine genome-wide testing. Some of these mutations may be medically actionable, enabling disease surveillance or prevention; however, most incidentally observed single-gene copy-number variants are currently of unclear significance to the patient.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Boone
authors.forename: Zachry T
authors.initials: ZT
authors.lastname: Soens
authors.forename: Ian M
authors.initials: IM
authors.lastname: Campbell
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.forename: Amy L
authors.initials: AL
authors.lastname: McGuire
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D017668:Age of Onset; D001483:Base Sequence; D002874:Chromosome Mapping; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D023061:Gene Order; D020022:Genetic Predisposition to Disease; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D015203:Reproducibility of Results