Innella Giovanni, Coccia Emanuele, Cristalli Carlotta Pia, Zacchi Eliana, Calabrese Sara, Bacchi Isabelle, Palombo Flavia, Taormina Sara, Evangelisti Cecilia, Lanzoni Giulia, Carelli Valerio, Diquigiovanni Chiara, Ferrari Simona, Panza Emanuele, Rossi Cesare, Vaisfeld Alessandro, Bonora Elena, Turchetti Daniela
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Clin Genet. 2025 May;107(5):570-575. doi: 10.1111/cge.14684. Epub 2024 Dec 21.
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.
广谱基因检测常常会发现意义未明的变异（VUS），这是现代临床遗传学中的一个主要问题。相当一部分VUS可能会改变剪接过程，但其解读具有挑战性。本研究旨在通过将外周血mRNA的转录本分析整合到常规诊断中，为可能影响剪接的VUS提供一种分类方法。在具有相关综合征兼容表型的患者中发现的DICER1、MSH2、MLH1、DYNC1H1、RPS6KA3和SCN9A基因中的VUS改变了剪接，导致它们被重新分类为致病性/可能致病性。这对从遗传性肿瘤易感性到神经和先天性综合征性疾病等不同疾病产生了重大临床影响。转录本分析在VUS临床评估中具有重要价值，将其纳入常规诊断工作流程有助于及时、准确地做出临床决策。
