Assessment of the 2022 Constitutional Mismatch Repair Deficiency Syndrome Diagnostic Criteria Using the International Replication Repair Deficiency Consortium

Inherited biallelic loss of a mismatch repair (MMR) gene

Constitutional mismatch repair deficiency (CMMRD) syndrome, caused by inherited biallelic loss of an MMR gene, combines early-onset cancers with neurofibromatosis type 1 features; seven diagnostic criteria (CMMRD1 to CMMRD7) were established in 2022. The study applies them to individuals referred with suspected CMMRD to the International Replication Repair Deficiency Consortium in Toronto: of 580 identified, 421 could be assessed. Of these, 358 (85%) were classified: 270 CMMRD or suspected CMMRD, 78 Lynch syndrome or likely Lynch syndrome and 10 other hereditary conditions; 63 remained unclassifiable owing to missing or discordant results. Of the 270 CMMRD patients, 241 met the published criteria, 57% of them (n = 137) the CMMRD1 criterion, and 29 were suspected despite a discordant functional result or a suspicious genotype/phenotype. Early-onset gliomas and gastrointestinal cancers also occurred in Lynch syndrome and in carriers of POLE, TP53 and NF1 alterations, alongside digenic Lynch syndrome and concurrent hereditary cancer syndromes.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The 2022 criteria work as a diagnostic framework, but 63 of 421 patients remain unclassifiable because of missing or discordant functional results, a reminder that genotype alone is not enough. Phenotypic overlap with Lynch syndrome, POLE, TP53 and NF1 rules out a CMMRD diagnosis based on clinical presentation alone. Referral bias towards a specialised consortium limits extrapolation to routine practice.

Analysis by Dr Thibaut Benquey