Background & Aims: A significant proportion of Lynch syndrome cases are believed to be due to large genomic alterations in the mismatch repair genes hMLH1 and hMSH2. However, previous studies have not adequately identified the frequency and scope of such mutations, and routine clinical Lynch syndrome testing often does not include analysis for these mutations. Our aim was to characterize hMLH1 and hMSH2 genomic rearrangements in a large population of suspected Lynch syndrome patients. Methods: A total of 365 samples from probands referred for genetic testing for Lynch syndrome were analyzed for the presence of large genomic alterations in hMLH1 or hMSH2 by using a combination of techniques. Samples with a deletion in exons 1-6 in hMSH2 were further characterized by polymerase chain reaction to establish the presence of the hMSH2 American founder deletion. Results: An hMLH1 or hMSH2 mutation was identified in 153 cases, and, of these, 12 of 67 (17.9%) and 39 of 86 (45.3%) had a large genomic alteration in hMLH1 and hMSH2, respectively. Overall, 6 different hMLH1 and 12 different hMSH2 deletions/duplications, including 10 novel mutations, were identified. Analysis of the hMSH2 exon 1-6 deletion samples showed that 13 of 18 (72.2%) had the American founder deletion. Conclusions: These data show a high frequency and diverse spectrum of large genomic alterations in hMLH1 and hMSH2 in suspected Lynch syndrome patients. Thus, a comprehensive mutation identification strategy that includes the ability to detect large genomic rearrangements is imperative for the clinical genetic identification of Lynch syndrome patients and families.
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