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

Introduction: Germline 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 Results: We 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.

Conclusion: Including 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.