Whole genome sequencing completes the molecular genetic testing workflow of patients with Lynch syndrome.

IF 4.7 2区医学 Q1 GENETICS & HEREDITY NPJ Genomic Medicine Pub Date : 2025-01-18 DOI:10.1038/s41525-025-00461-z

Klaudia Horti-Oravecz, Anikó Bozsik, Tímea Pócza, Ildikó Vereczkey, Tamás Strausz, Erika Tóth, Tatiana Sedlackova, Diana Rusnakova, Tomas Szemes, István Likó, Edit Oláh, Henriett Butz, Attila Patócs, János Papp, Vince Kornél Grolmusz

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Abstract

Multigene panel tests (MGPTs) revolutionized the diagnosis of Lynch syndrome (LS), however noncoding pathogenic variants (PVs) can only be detected by complementary methods including whole genome sequencing (WGS). Here we present a DNA-, RNA- and tumor tissue-based WGS prioritization workflow for patients with a suspicion of LS where MGPT detected no LS-related PV. Among the 100 enrolled patients, MGPT detected 28 simple PVs and an additional 3 complex PVs. Among the 69 MGPT-negative patients, the lack of somatic MLH1 promoter methylation in a patient with a distinguished MLH1 allelic imbalance selected this sample for WGS. This returned a germline deep intronic MLH1 variant, with further functional studies confirming its' pathogenicity. Interestingly, all three complex PVs and the MLH1 deep intronic PV were found to be recurrent at our center. Our straightforward and cost-effective prioritization workflow can optimally include WGS in the genetic diagnosis of LS.

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全基因组测序完成了Lynch综合征患者的分子基因检测工作流程。

多基因面板检测（MGPTs）彻底改变了Lynch综合征（LS）的诊断，然而非编码致病变异（pv）只能通过包括全基因组测序（WGS）在内的补充方法检测。在这里，我们提出了一个基于DNA、RNA和肿瘤组织的WGS优先工作流程，用于怀疑LS的患者，其中MGPT未检测到LS相关的PV。在100例入组患者中，MGPT检测到28例单纯性pv和另外3例复合性pv。在69名mgpt阴性患者中，一名MLH1等位基因明显失衡的患者缺乏体细胞MLH1启动子甲基化，这使该样本成为WGS的选择。这返回了一个种系深内含子MLH1变异，进一步的功能研究证实了它的致病性。有趣的是，这三种复合PV和MLH1深内含子PV在我们的中心被发现是复发性的。我们的简单和具有成本效益的优先排序工作流程可以在LS的遗传诊断中最佳地包括WGS。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.40

自引率

1.90%

发文量

审稿时长

17 weeks

期刊介绍： npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.