Effectiveness and Impact of Transcript Analysis in Clinical Genetics Daily Practice

Broad-spectrum genetic tests often lead to the identification of variants of uncertain significance (VUS), a major issue in modern clinical genetics. A fair proportion of VUS may alter the splicing processes, but their interpretation is challenging. This study aimed at providing a classification approach for VUS potentially-affecting splicing by integrating transcript analysis from peripheral blood mRNA into routine diagnostics. VUS in DICER1, MSH2, MLH1, DYNC1H1, RPS6KA3, and SCN9A, found in patients with phenotypes compatible with the related syndromes, altered splicing, leading to their re-classification as Pathogenic/Likely Pathogenic. This had a significant clinical impact for different diseases, from hereditary tumor predisposition to neurological and congenital syndromic disorders. Transcript analysis is valuable in VUS clinical evaluation, and its incorporation into routine diagnostic workflows facilitates timely and accurate clinical decision-making.