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CNVs affecting cancer predisposing genes (CPGs) detected as incidental findings in routine germline diagnostic chromosomal microarray (CMA) testing.

Accepted version
Peer-reviewed

Type

Article

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Authors

Innes, Josie 
Reali, Lisa 
Clayton-Smith, Jill 
Hall, Georgina 
Lim, Derek Hk 

Abstract

BACKGROUND: Identification of CNVs through chromosomal microarray (CMA) testing is the first-line investigation in individuals with learning difficulties/congenital abnormalities. Although recognised that CMA testing may identify CNVs encompassing a cancer predisposition gene (CPG), limited information is available on the frequency and nature of such results. METHODS: We investigated CNV gains and losses affecting 39 CPGs in 3366 pilot index case individuals undergoing CMA testing, and then studied an extended cohort (n=10 454) for CNV losses at 105 CPGs and CNV gains at 9 proto-oncogenes implicated in inherited cancer susceptibility. RESULTS: In the pilot cohort, 31/3366 (0.92%) individuals had a CNV involving one or more of 16/39 CPGs. 30/31 CNVs involved a tumour suppressor gene (TSG), and 1/30 a proto-oncogene (gain of MET). BMPR1A, TSC2 and TMEM127 were affected in multiple cases. In the second stage analysis, 49/10 454 (0.47%) individuals in the extended cohort had 50 CNVs involving 24/105 CPGs. 43/50 CNVs involved a TSG and 7/50 a proto-oncogene (4 gains, 3 deletions). The most frequently involved genes, FLCN (n=10) and SDHA (n=7), map to the Smith-Magenis and cri-du-chat regions, respectively. CONCLUSION: Incidental identification of a CNV involving a CPG is not rare and poses challenges for future cancer risk estimation. Prospective data collection from CPG-CNV cohorts ascertained incidentally and through syndromic presentations is required to determine the risks posed by specific CNVs. In particular, ascertainment and investigation of adults with CPG-CNVs and adults with learning disability and cancer, could provide important information to guide clinical management and surveillance.

Description

Keywords

copy-number, genetic screening/counselling, genetics, microarray, Bone Morphogenetic Protein Receptors, Type I, Child, Preschool, Chromosome Deletion, Cohort Studies, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Humans, Incidental Findings, Infant, Male, Membrane Proteins, Microarray Analysis, Neoplasms, Oncogenes, Pilot Projects, Proto-Oncogene Mas, Tuberous Sclerosis Complex 2 Protein

Journal Title

J Med Genet

Conference Name

Journal ISSN

0022-2593
1468-6244

Volume Title

55

Publisher

BMJ
Sponsorship
European Research Council (323004)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0616-10035)