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Identification of a novel pathogenic MLH1 mutation and recommended genetic screening strategy: An investigation of three Chinese Lynch syndrome pedigrees.

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.

SUBMITTER: Li F

PROVIDER: S-EPMC7434735 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Identification of a novel pathogenic MLH1 mutation and recommended genetic screening strategy: An investigation of three Chinese Lynch syndrome pedigrees.

Li Fan F Xia Yunwei Y Wang Guoguang G Tang Chaoyang C Zhan Tian T Shen Jian J Zhang Jianping J

Molecular genetics & genomic medicine 20200603 8

<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>Multigene panel screening revealed three mutL homolog 1 (MLH1) pathogenic mutations (c.199G ...[more]

PMID: 32490589

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Project description:BACKGROUND:Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome, characterized by autosomal dominant inheritance and germline mutations in DNA mismatch repair genes. Despite several genetic variations that have been identified in various populations, the penetrance is highly variable and the reasons for this have not been fully elucidated. This study investigates whether, besides pathogenic mutations, environment and low penetrance genetic risk factors may result in phenotype modification in a Tunisian LS family. PATIENTS AND METHODS:A Tunisian family with strong colorectal cancer (CRC) history that fulfill the Amsterdam I criteria for the diagnosis of Lynch syndrome was proposed for oncogenetic counseling. The index case was a man, diagnosed at the age of 33 years with CRC. He has a monozygotic twin diagnosed at the age of 35 years with crohn disease. Forty-seven years-old was the onset age of his paternal uncle withCRC. An immunohistochemical (IHC) labeling for the four proteins (MLH1, MSH2, MSH6 and PMS2) of the MisMatchRepair (MMR) system was performed for the index case. A targeted sequencing of MSH2, MLH1 and a panel of 85 DNA repair genes was performed for the index case and for his unaffected father. RESULTS:The IHC results showed a loss of MSH2 but not MLH1, MSH6 and PMS2 proteins expression. Genomic DNA screening, by targeted DNA repair genes sequencing, revealed an MSH2 pathogenic mutation (c.1552C>T; p.Q518X), confirmed by Sanger sequencing. This mutation was suspected to be a causal mutation associated to the loss of MSH2 expression and it was found in first and second degree relatives. The index case has smoking and alcohol consumption habits. Moreover, he harbors extensive genetic variations in other DNA-repair genes not shared with his unaffected father. CONCLUSION:In our investigated Tunisian family, we confirmed the LS by IHC, molecular and in silico investigations. We identified a novel pathogenic mutation described for the first time in Tunisia. These results come enriching the previously reported pathogenic mutations in LS families. Our study brings new arguments to the interpretation of MMR expression pattern and highlights new risk modifiers genes eventually implicated in CRC. Twins discordance reported in this work underscore that disease penetrance could be influenced by both genetic background and environmental factors.

Dataset Information

Identification of a novel pathogenic MLH1 mutation and recommended genetic screening strategy: An investigation of three Chinese Lynch syndrome pedigrees.

Publications

Identification of a novel pathogenic MLH1 mutation and recommended genetic screening strategy: An investigation of three Chinese Lynch syndrome pedigrees.

Similar Datasets

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