1. Identification of a novel pathogenic MLH1 mutation and recommended genetic screening strategy: An investigation of three Chinese Lynch syndrome pedigrees
- Author
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Jianping Zhang, Chaoyang Tang, Tian Zhan, Yunwei Xia, Guoguang Wang, Fan Li, and Jian Shen
- Subjects
0301 basic medicine ,China ,lcsh:QH426-470 ,RNA Stability ,next‐generation sequencing ,030105 genetics & heredity ,Biology ,MLH1 ,DNA sequencing ,03 medical and health sciences ,symbols.namesake ,Germline mutation ,Protein Domains ,Loss of Function Mutation ,Genetics ,medicine ,Humans ,Genetic Testing ,Molecular Biology ,Gene ,Cells, Cultured ,Genetics (clinical) ,Sanger sequencing ,Original Articles ,medicine.disease ,Colorectal Neoplasms, Hereditary Nonpolyposis ,Lynch syndrome ,Pedigree ,lcsh:Genetics ,030104 developmental biology ,symbols ,Original Article ,DNA mismatch repair ,MutL Protein Homolog 1 - Abstract
Background Lynch syndrome (LS) is an autosomal‐dominant disorder that increases the risk of many cancers. The genetic basis of LS is germline mutations in DNA mismatch repair genes. Methods We performed next‐generation sequencing on blood cells obtained from the members of three unrelated LS pedigrees. Immunohistochemistry staining was performed to analyze protein expression. Results Multigene panel screening revealed three mutL homolog 1 (MLH1) pathogenic mutations (c.199G>A, c.790 + 1G>A, and c.1557_1558 + 8delGGGTACGTAA, unreported) confirmed by Sanger sequencing. Immunohistochemistry showed a loss of MLH1 protein expression. We also confirmed that the unreported mutant allele was inherited for at least three generations. Conclusion These results provide new insights into the molecular mechanisms underlying the pathogenicity of MLH1 mutations and reaffirm the importance of genetic screening for the early diagnosis of LS., Three pathogenic MLH1 mutations were found in unrelated Lynch syndrome pedigrees. Immunohistochemistry revealed loss of MLH1 protein expression. The mutant allele (c.1557_1558 + 8delGGGTACGTAA) was inherited for at least three generations. We get insights into the molecular mechanisms underlying MLH1 mutation pathogenicity.
- Published
- 2020