Characterization of novel, large duplications in the MSH2 gene of three unrelated Lynch syndrome patients

Lynch syndrome (LS) is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainly MLH1, MSH2, MSH6, and PMS2. Most of genetic variants in the MMR genes predisposing to LS are point mutations, small deletions and insertions but large genomic rearrangements in the MMR genes also predisposing to Lynch syndrome. In this study, we report a novel, large rearrangement of the MSH2 gene, manifested by a duplication spanning a 14,846-bps region from intron 7 through intron 9. The breakpoints of this rearrangement were characterized by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Finally, this large duplication was identified in three unrelated patients. Breakpoint analysis revealed the same junction fragments of introns 7 and 8 in the three index cases, suggesting a recurrent duplication or, alternatively, identity of the respective alleles by descent.