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.
- genetic screening/counselling
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Contributors JI undertook the data extraction and analysis and contributed to the writing of the manuscript. LR undertook the data extraction and analysis and contributed to the writing of the manuscript. JC-S contributed to the study design. GH contributed to the data extraction. DL undertook data extraction and analysis and contributed to the writing of the manuscript. GB undertook data analysis. KF undertook data extraction. UK undertook data extraction. DW undertook data extraction. FL contributed to the study design. DGRE contributed to the writing of the manuscript. DMcM contributed to the overall study design. ERM contributed to the overall study design and writing of the manuscript. ERW was responsible for the overall design and content of the study and is overall guarantor for the study. ERW also wrote the manuscript.
Competing interests None declared.
Ethics approval Clinical audit approved by both Birmingham Women’s NHS Foundation Trust and Central Manchester University Hospitals NHS Foundation Trust.
Provenance and peer review Not commissioned; externally peer reviewed.