Lynch综合症（LS）是结直肠癌（CRC）最常见的遗传性癌症易感性疾病，与4个错配修复（MMR）基因中的致病性变体相关。在这篇文章中，我们报道了一个多代华人家族，临床上被诊断为LS。为了确定潜在的致病基因变异，我们从该四代家族中获取了30个全血样本、4个结直肠癌组织样本及其临床数据。通过微卫星不稳定性高（MSI）检测、免疫组织化学（IHC）和全外显子测序（WES），我们进行了MMR/MSI以及底层基因变异的鉴定。我们使用小基因剪接试验和体外剪接试验来探究该变异的功能。通过MSI检测和IHC发现3名患者具有MSI-H和dMMR，全外显子组测序在结直肠癌患者中成功识别出MSH2第4内含子中的一个剪接变异（c.793-1G>A）。Sanger测序验证了WES结果，并通过PCR在家族中发现了携带该变异的所有“健康”个体。生物信息学分析和体外小基因试验显示，致病性变异影响了MSH2基因的剪接过程，生成了两种缺陷转录产物，从而降低了MSH2蛋白的表达水平。因为这些基因突变携带者有较高的LS风险，所以后续他们被建议每1-2年进行结肠镜检查以及其他重要的癌症诊断检查。我们发现了MSH2基因的一个致病性剪接变异（rs863225397，c.793-1G>A），并通过体外研究进一步确认了该突变在本系谱中LS患者中的重要作用。我们的研究表明，MSH2基因的一个剪接突变（c.793-1G>A）引起了LS，并且突出了LS基因测试的重要性。版权所有©2023 Li, Yu, Cui, Yin and Wu.

Lynch syndrome (LS) is the most common inherited cancer predisposition disorder of colorectal cancer (CRC) which is associated with pathogenic variants in 4 mismatch repair (MMR) genes. Here, we reported a multi-generation Chinese family clinically diagnosed with LS.To identify the underlying pathogenic gene variants, 30 whole blood samples and 4 colorectal cancer tissue samples and their clinical data were obtained from this four-generation family. Microsatellite instability-high (MSI) testing, immunohistochemistry (IHC), and Whole-Exome Sequencing (WES) were performed to identify the MMR/MSI and the underlying gene variants. The minigene splicing assay and in vitro splicing assay were used to explore the function of this variant.MSI-H and dMMR was revealed by the MSI testing and IHC, Whole-Exome Sequencing (WES) in 3 patients successfully identified a splicing variant (c.793-1G>A) in intron 4 of MSH2. Sanger sequencing validated the WES results, and all the "healthy" individuals carrying the variant have been identified in the family by PCR. Bioinformatics analysis and in vitro minigene assay showed that the pathogenic variant affected the splicing process of MSH2 gene to generate 2 kinds defective transcription products, and consequently reduced the expression of MSH2 protein. The mutation carriers were later recommended for colonoscopy and other important cancer diagnostic inspections every 1-2 years because they both have a higher risk of LS.We found a pathogenic splicing variant (rs863225397, c.793-1G>A) of MSH2 gene, and furtherly confirmed that this mutation plays an important role in LS patients of this pedigree based on the vitro study. Our study indicates that one splicing mutation in the MSH2 gene (c.793-1G>A) causes LS and highlights the importance of LS gene testing.Copyright © 2023 Li, Yu, Cui, Yin and Wu.