Clinical and Genetic Characterization of Constitutional MLH1 Promoter Hypermethylation: Implications for Lynch Syndrome Diagnosis.

Constitutional MLH1 promoter hypermethylation (CMPH): primary epimutation or secondary to germline variants

The largest published clinical cohort (422 individuals who underwent clinical CMPH testing) describes the phenotype and genetic etiology of constitutional MLH1 promoter hypermethylation (CMPH). CMPH was identified in 15.6% of tested individuals, 63 of whom had clinical features consistent with Lynch syndrome. Promoter sequencing identified 8 unique germline variants including 3 novel ones, and long-read sequencing confirmed mutant allele-specific promoter methylation. Mendelian CMPH inheritance was observed in 5 families.

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This 422-patient cohort is the largest ever published on CMPH and considerably clarifies its clinical and genetic spectrum. Identification of 3 new promoter variants and demonstration of allele-specific methylation by LRS strengthen the argument for integrating CMPH testing into Lynch syndrome diagnostic algorithms, particularly in patients with MMR deficiency and no detected germline variant.

Clinical impact: 2/3 · Evidence quality: 2/3 · Novelty: 2/2 · Sample size: 1/1 · Journal quality: 1/1 → Total: 8/10