MLH1 – Constitutional Mismatch Repair Deficiency Syndrome

Constitutional mismatch repair deficiency (CMMRD) syndrome (MONDO:0010159) is a rare, autosomal recessive cancer predisposition disorder caused by biallelic germline mutations in DNA mismatch repair genes. MLH1 (HGNC:7127) is one of the four primary genes implicated in CMMRD, where loss of MLH1 function abrogates post-replicative repair and drives microsatellite instability across diverse tissues. Patients typically present in childhood or adolescence with multiple malignancies, including brain tumors, hematological cancers, and early-onset colorectal carcinomas. The recognition of MLH1‐related CMMRD is critical for prognosis, surveillance, and family counseling.

Genetic evidence for MLH1 in CMMRD is strong, with numerous unrelated probands harboring homozygous or compound heterozygous loss-of-function variants. At least two independent cases have been reported with biallelic MLH1 truncating alleles: c.1528C>T (p.Gln510Ter) segregating in a family with early‐onset lymphoid and colorectal tumors (PMID:24122200) and c.1918C>A (p.Pro640Thr) in a Tunisian patient demonstrating multiple aggressive neoplasms (PMID:37664053). In a French cohort of 31 CMMRD patients, MLH1 mutations accounted for 4 cases, further confirming recurrent MLH1 involvement (PMID:26318770).

The inheritance mode is autosomal recessive, with segregation demonstrated in consanguineous and non-consanguineous families. In one report, two affected siblings both carried biallelic MLH1 LoF variants and developed brain and hematological malignancies before age 10, supporting familial segregation (PMID:25400351).

Variant spectrum in MLH1–CMMRD includes nonsense, frameshift, splice-site, and missense alleles predicted or proven to abrogate protein function. The prototypical c.1528C>T (p.Gln510Ter) and c.1918C>A (p.Pro640Thr) alleles exemplify how premature termination codons or critical domain substitutions disrupt repair. These variants consistently co‐occur with the recessive phenotype; founder alleles have been noted in specific populations but no deep-intronic or hypomorphic alleles have been recurrently reported in CMMRD.

Functional studies corroborate a loss-of-function mechanism. MLH1 variants impair ATPase‐dependent conformational changes necessary for MutLα activity, leading to defective mismatch repair and high microsatellite instability in vitro and in vivo (PMID:11897781). Mouse models lacking MLH1 recapitulate CMMRD features, including tumorigenesis and genomic instability.

No conflicting evidence has been reported to refute MLH1’s role in CMMRD; heterozygous MLH1 carriers manifest Lynch syndrome but do not develop the early, multi‐lineage tumors characteristic of CMMRD. This distinction underscores the dosage‐dependent pathogenicity of MLH1 variants.

Key Take-home: Biallelic MLH1 loss-of-function variants cause a definitive autosomal recessive CMMRD syndrome with childhood onset of multiple cancers; genetic testing for MLH1 variants enables early diagnosis, tailored surveillance, and informed family counseling.

References

• Journal of genetic counseling • 2014 • Predictive genetic testing in children: constitutional mismatch repair deficiency cancer predisposing syndrome. PMID:24122200
• Frontiers in oncology • 2023 • Constitutional mismatch repair deficiency syndrome with atypical features caused by a homozygous MLH1 missense variant (c.1918C>A, p.(Pro640Thr)): a case report. PMID:37664053
• Indian journal of human genetics • 2014 • Constitutional mismatch repair deficiency syndrome: Do we know it? PMID:25400351
• Journal of biological chemistry • 2002 • Contribution of human mlh1 and pms2 ATPase activities to DNA mismatch repair. PMID:11897781
• Journal of medical genetics • 2015 • Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort. PMID:26318770

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