Lynch Syndrome (LS) is caused by mutations in DNA mismatch repair genes. Diagnosis is not always trivial and may be costly. Knowledge of incidence, genotype-phenotype correlation, spectrum of mutations and genes involved in specific populations, facilitates the diagnostic process and contributes to clinical work-up. Aim:To report the unique features of LS, gene distribution, mutations detected and co-occurrence of related syndromes in Ashkenazi Jews.METHODS:Patients were identified in dedicated high risk clinics. Diagnostic process followed a multi-step scheme. It included testing for founder mutations, tumor testing, gene sequencing and MLPA. LS was defined by positive tumor analysis and/or positive mutation testing. RESULTS: We describe a cohort of 120 carriers from 75 Ashkenazi families with LS. Mutations were identified in 51/75 (68%) families:36 in MSH2,9 in MSH6, and 6 inMLH1. 37/51 (73%) families with known mutations carried one of the 3 'Ashkenazi' founder mutations in MSH2 or MSH6. Each of the other 14 families carried a private mutation. 3 (6%) were large deletions. Only 25/75 (33%) families were Amsterdam Criteria positive, 62 (83%) were positive for theBethesdaguidelines and 13 (17%) did not comply with any clinical criteria. We report C-MMRD and co-occurrence of BRCA and LS in our cohort.CONCLUSIONS: Mutation spectrum and gene distribution among Ashkenazi Jews are unique. Three founder mutations cause LS in 73% families with known mutations.MSH2andMSH6cause the majority of cases, whileMLH1comes third. These features affect the phenotype, the diagnostic process, risk estimation, and genetic counseling.
