Molecular and presymptomatic analysis of a Moroccan Lynch syndrome family revealed a novel frameshift MLH1 germline mutation

Özet

Lynch syndrome (LS) is an autosomal dominant disorder characterized by an increased risk of extracolonic cancers and early age ofonset. It is associated with germline mutations in the DNA mismatch repair (MMR) genes. We report a case of a patient with colorectalcancer referred to our medical genetics department for molecular analysis and genetic counseling. The proband is a 64-year-old womandiagnosed with a tumor of the cecum. Histopathological examination showed a moderately differentiated mucinous adenocarcinomacategorized by pT3 N0. Analysis of her pedigree revealed three siblings who had colon cancer, as well as one relative with brain cancer.Based on these findings, molecular genetic investigation was found to be necessary in order to identify the disease-causing mutation.Immunohistochemistry staining of MMR proteins was performed on the tumor sample of the index proband. Mutational analysis of theMLH1/MSH2 genes was carried out. Analysis was extended to the family members and the general population. This led to the identification of a heterozygous frameshift duplication in the MLH1 gene at position 910 (c.910dupG). Three siblings had inherited the mutationfrom their mother, two of whom were asymptomatic at the time of diagnosis. To the best of our knowledge, this is a novel pathogenicduplication that has not been reported in the databases and literature. The outcome of the present case suggests that this mutationwas the primary cause of LS in the family