Clinical validity assessment of genes for inclusion in multi‐gene panel testing: A systematic approach

摘要

Background Advances in sequencing technology have led to expanded use of multi‐gene panel tests (MGPTs) for clinical diagnostics. Well‐designed MGPTs must balance increased detection of clinically significant findings while mitigating the increase in variants of uncertain?significance (VUS). To maximize clinical utililty, design of such panels should include comprehensive gene vetting using a standardized clinical validity (CV) scoring system. Methods To assess the impact of CV‐based gene vetting on MGPT results, data from MGPTs for cardiovascular indications were retrospectively analyzed. Using our CV scoring system, genes were categorized as having definitive, strong, moderate, or limited evidence. The rates of reported pathogenic or likely pathogenic variants and VUS were then determined for each CV category. Results Of 106 total genes, 42% had definitive, 17% had strong, 29% had moderate, and 12% had limited CV. The detection rate of variants classified as pathogenic or likely pathogenic was higher for genes with greater CV, while the VUS rate showed an inverse relationship with CV score. No pathogenic or likely pathogenic findings were observed in genes with a limited CV. Conclusion These results demonstrate the importance of a standardized, evidence‐based vetting process to establish CV for genes on MGPTs. Using our proposed system may help to increase the detection rate while mitigating higher VUS rates.