The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype

摘要: Germline mutations of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2, and deletions affecting EPCAM gene adjacent to underlie Lynch syndrome by predisposing early-onset colorectal, endometrial other cancers. An alternative but rare cause is constitutional epimutation whereby promoter methylation transcriptional silencing one allele occurs throughout normal tissues. A dominantly transmitted MLH1 has been linked an haplotype bearing two single-nucleotide variants, NM_000249.2: c.−27C>A c.85G>T, in a Caucasian family with from Western Australia. Subsequently, second seemingly unrelated Australian case same concomitant was reported. We now describe three additional, ostensibly unrelated, cancer-affected families European heritage this association epimutation, bringing number index cases reported five. Array-based genotyping four these revealed shared haplotypes between individual that extended across ≤2.6–≤6.4 megabase regions chromosome 3p, indicating common ancestry. minimal ≤2.6 founder all identified, which encompassed additional flanking segregated each family. Our findings indicate c.85G>T variants are borne on ancestral provide conclusive evidence for its pathogenicity via mechanism epigenetic within Additional descendants may exist who also at high risk developing syndrome-related