Incidental copy-number variants identified by routine genome testing in a clinical population

Genet Med. 2013 Jan;15(1):45-54. doi: 10.1038/gim.2012.95. Epub 2012 Aug 9.


Purpose: 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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age of Onset
  • Base Sequence
  • Chromosome Mapping
  • Comparative Genomic Hybridization*
  • DNA Copy Number Variations*
  • Female
  • Gene Order
  • Genetic Predisposition to Disease*
  • Humans
  • Inheritance Patterns
  • Male
  • Reproducibility of Results