Li Juyi, Ni Haichun, Cheng Peng, Peng Yujia, Liu Lei, Wang Xiangyang, Cheng Wei, Li Hengfei, Wang Xiufang, Zhang Hongfeng, Hu Jifa, Deng Aiping, Cai Wei
Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pathology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Med (Lausanne). 2025 Jul 29;12:1635964. doi: 10.3389/fmed.2025.1635964. eCollection 2025.
This study aimed to examine pathogenic variations in three families clinically diagnosed with suspected Lynch syndrome (LS).
Three probands clinically diagnosed suspected LS were subjected to immunohistochemical analysis of DNA mismatch repair (MMR) protein. Whole-exome sequencing and Sanger sequencing were performed to screen pathogenic variations. I-TASSER and PyMOL were used to analyze changes in the functional domains of mutant proteins.
A known missense variation (GRCh37 chr2:g.47702367G>A, MSH2:NM_000251:c.1963G>A:p.V655I), a known stop-gain variant (GRCh37 chr2:g.47709984G>T, MSH2:NM_000251:c.2701G>T:p.E901X), and a known frameshift insertion variation (GRCh37 chr2:g.48032124 dupA, MSH6:NM_000179:c.3514dupA:p.R1172Kfs*5) in Family 1, Family 2, and Family 3, respectively, were observed. The c.1963G>A variation caused the 655th amino acid of MSH2 to change from valine to isoleucine, and there were no significant changes in both the overall and local protein models in MSH2. Further, the c.2701G>T variation caused the 901st amino acid of MSH2 to change from glutamic acid to a premature stop codon in exon 16, and the deletion of amino-acids 901-934 caused changes in the Domain 5 of MSH2 protein. Furthermore, the c.3514dupA variation caused the 1172nd amino acid of MSH6 to change from arginine to lysine, followed by frameshift, which caused changes in the Domain 5 of MSH6 protein.
The missense variation (MSH2:NM_000251:c.1963G>A:p.V655I) and the stop-gain variation (MSH2:NM_000251:c.2701G>T:p.E901X) were considered uncertain significance for LS, and another pathogenic variation (MSH6:NM_000179:c.3514dupA:p.R1172Kfs*5) has been further confirmed.
本研究旨在检测临床诊断为疑似林奇综合征（LS）的三个家系中的致病变异。
对三名临床诊断为疑似LS的先证者进行DNA错配修复（MMR）蛋白的免疫组化分析。进行全外显子组测序和桑格测序以筛选致病变异。使用I-TASSER和PyMOL分析突变蛋白功能域的变化。
在1号家系、2号家系和3号家系中分别观察到一个已知的错义变异（GRCh37 chr2:g.47702367G>A，MSH2:NM_000251:c.1963G>A:p.V655I）、一个已知的截短变异（GRCh37 chr2:g.47709984G>T，MSH2:NM_000251:c.2701G>T:p.E901X）和一个已知的移码插入变异（GRCh37 chr2:g.48032124 dupA，MSH6:NM_000179:c.3514dupA:p.R1172Kfs*5）。c.1963G>A变异导致MSH2的第655位氨基酸从缬氨酸变为异亮氨酸，MSH2的整体和局部蛋白质模型均无显著变化。此外，c.2701G>T变异导致MSH2的第901位氨基酸从谷氨酸变为第16外显子中的提前终止密码子，901 - 934位氨基酸的缺失导致MSH2蛋白的结构域5发生变化。此外，c.3514dupA变异导致MSH6的第1172位氨基酸从精氨酸变为赖氨酸，随后发生移码，导致MSH6蛋白的结构域5发生变化。
错义变异（MSH2:NM_000251:c.1963G>A:p.V655I）和截短变异（MSH2:NM_000251:c.2701G>T:p.E901X）对LS的意义尚不确定，另一个致病变异（MSH6:NM_000179:c.3514dupA:p.R1172Kfs*5）已得到进一步证实。
