Whole-Exome Sequencing Identified a Novel Mutation of MLH1 in an Extended Family with Lynch Syndrome

Abstract Hereditary nonpolyposis colorectal cancer or Lynch syndromeis autosomal dominant cancer predisposition syndrome characterized by early onset of colorectal cancer and neoplasia in other organs. This condition typically caused by germline mutationsin the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. To date, a considerable number of MLH1gene mutations have been found to be associated with Lynch syndrome. We were aimed at identifying a genetic mutation in an extended Iranian family affected by Lynch syndrome-related cancers. Here, we applied whole- exome sequencingto identifying mutation in the proband. Furthermore, we applied Sanger sequencingto validate the candidate variant. We found a heterozygous novel single nucleotide deletion (c.206delG) in the exon two of the MLH1gene in the proband. Also, Sanger sequencinganalysis showed that this mutation has segregated in all affected family members. The mutation (c.206delG:p.R69fs,) may create a premature stop codonfollowed by the formation of a truncated (p.R69fs) Mlh1protein. Our findings expand the mutational spectra of MLH1gene related Lynch syndromewhich is vital for screening and genetic diagnosis of the disease.