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

TitleIncidental copy-number variants identified by routine genome testing in a clinical population.
Publication TypeJournal Article
Year of Publication2013
AuthorsBoone, PM, Soens, ZT, Campbell, IM, Stankiewicz, P, Cheung, SWai, Patel, A, Beaudet, AL, Plon, SE, Shaw, CA, McGuire, AL, Lupski, JR
JournalGenet Med
Volume15
Issue1
Pagination45-54
Date Published2013 Jan
ISSN1530-0366
KeywordsAge 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
Abstract

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.

DOI10.1038/gim.2012.95
Alternate JournalGenet. Med.
PubMed ID22878507
PubMed Central IDPMC3705759
Grant ListR01 CA138836 / CA / NCI NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
R01CA138836 / CA / NCI NIH HHS / United States
R01NS058529 / NS / NINDS NIH HHS / United States
T32 EY007102 / EY / NEI NIH HHS / United States
T32 GM007330 / GM / NIGMS NIH HHS / United States
T32EY007102 / EY / NEI NIH HHS / United States
T32GM007330 / GM / NIGMS NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States