Screening of CNVs using NGS data improves mutation detection yield and decreases costs in genetic testing for hereditary cancer

• Published in: Journal of medical genetics Vol. 59; no. 1; pp. 75 - 78
• Main Authors: Moreno-Cabrera, José Marcos, del Valle, Jesús, Feliubadaló, Lidia, Pineda, Marta, González, Sara, Campos, Olga, Cuesta, Raquel, Brunet, Joan, Serra, Eduard, Capellà, Gabriel, Gel, Bernat, Lázaro, Conxi
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.01.2022; BMJ Publishing Group LTD
• Subjects: Breast cancer; Cancer; Colorectal cancer; Costs and Cost Analysis; Diagnostics; DNA Copy Number Variations; Early Detection of Cancer; Genes; Genetic disorders; Genetic Predisposition to Disease; Genetic screening; genetic testing; Genetic Testing - economics; Genetic Testing - methods; germ-line mutation; High-Throughput Nucleotide Sequencing - economics; High-Throughput Nucleotide Sequencing - methods; Humans; molecular diagnostic techniques; Mutation; Neoplasms - congenital; Neoplasms - diagnosis; Neoplasms - genetics; Next-generation sequencing; Ovarian cancer; Patients; Prospective Studies; Retrospective Studies; Sequence Analysis, DNA - economics; Sequence Analysis, DNA - methods; Software; Testing laboratories; molecular diagnostic techniques; germ-line mutation; genetic testing
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmedgenet-2020-107366

IntroductionGermline CNVs are important contributors to hereditary cancer. In genetic diagnostics, multiplex ligation-dependent probe amplification (MLPA) is commonly used to identify them. However, MLPA is time-consuming and expensive if applied to many genes, hence many routine laboratories test only a subset of genes of interest.Methods and resultsWe evaluated a next-generation sequencing (NGS)-based CNV detection tool (DECoN) as first-tier screening to decrease costs and turnaround time and expand CNV analysis to all genes of clinical interest in our diagnostics routine. We used DECoN in a retrospective cohort of 1860 patients where a limited number of genes were previously analysed by MLPA, and in a prospective cohort of 2041 patients, without MLPA analysis. In the retrospective cohort, 6 new CNVs were identified and confirmed by MLPA. In the prospective cohort, 19 CNVs were identified and confirmed by MLPA, 8 of these would have been lost in our previous MLPA-restricted detection strategy. Also, the number of genes tested by MLPA across all samples decreased by 93.0% in the prospective cohort.ConclusionIncluding an in silico germline NGS CNV detection tool improved our genetic diagnostics strategy in hereditary cancer, both increasing the number of CNVs detected and reducing turnaround time and costs.