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Heterozygous pathogenic variants in DNMT1 have been causally linked to autosomal dominant hereditary sensory neuropathy-deafness-dementia syndrome (Hereditary Sensory Neuropathy-Deafness-Dementia Syndrome), also known as HSAN1E. Initial reports identified a recurrent hotspot variant p.Tyr495Cys in the targeting sequence domain leading to premature protein degradation and reduced methyltransferase activity in patient cells (PMID:25033457).
Subsequent multi-pedigree studies described nine kinships encompassing 45 affected individuals with adult-onset sensory neuropathy, hearing loss, cognitive decline and narcolepsy, including two de novo events, all harboring missense variants in the TS domain (PMID:25678562). Segregation was observed in all families, with 45 additional affected relatives sharing pathogenic DNMT1 alleles. One representative variant is c.1489A>C (p.Thr497Pro).
Across these cohorts, eight distinct missense substitutions in the TS domain have been reported, including c.1106G>T (p.Cys369Phe), c.1489A>C (p.Thr497Pro), c.1520C>T (p.Pro507Leu), c.1532A>G (p.Tyr511Cys), c.1618T>G (p.Tyr540Asp), c.1619A>C (p.Tyr540Ser) and c.1640T>A (p.Ile547Asn). There is no evidence of loss-of-function or splice variants; all alleles cluster within the TS domain, consistent with a dominant-negative or haploinsufficiency mechanism.
Functional assays demonstrate that mutant DNMT1 proteins exhibit premature proteasomal degradation, impaired recruitment to replication foci and heterochromatin, formation of cytoplasmic aggresomes, and genome-wide hypomethylation affecting >560 000 CpG sites (PMID:25033457; PMID:25678562). These data concord with the neuronal phenotype and support a mechanism of pathogenic loss of maintenance methylation activity.
No conflicting reports have emerged, and the clinical, genetic, and functional evidence collectively meet a Strong level of clinical validity. The consistency of segregation in multiple families, de novo occurrences, and concordant molecular dysfunction secure the association.
Key Take-home: DNMT1 missense variants in the targeting sequence domain cause dominantly inherited HSAN1E via impaired maintenance methylation, supporting targeted genetic testing and consideration of epigenetic-modulating therapies.
Gene–Disease AssociationStrong45 affected subjects across 9 kinships, including de novo occurrences, plus concordant functional data Genetic EvidenceStrongSeven distinct TS domain missense variants in 45 subjects across multiple families, including 2 de novo cases, fulfilling segregation criteria Functional EvidenceModeratePatient cells and models show reduced DNMT1 stability and activity, aberrant localization, and genome-wide hypomethylation |