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The association between REEP4 (HGNC:26176) and blepharospasm-oromandibular dystonia syndrome (MONDO_0019772) is supported by limited but suggestive genetic evidence. Multi‐patient screening studies have identified rare, potentially deleterious REEP4 variants in patients with this cranial dystonia phenotype. In one study, a deleterious variant, c.109C>T (p.Arg37Trp), was found to co‑segregate with blepharospasm in a large African‑American pedigree (PMID:39262575), and additional studies in cohorts of 78 (PMID:35044558) and 132 patients (PMID:30956059) have reported REEP4 alterations predicted to be damaging. However, the total number of unrelated probands remains modest and the segregation evidence is limited.
In parallel, functional and in silico assessment studies provide only limited supportive evidence. While preliminary data hint at a potential pathogenic mechanism—possibly through haploinsufficiency—the experimental assays have not yielded reproducible functional readouts that fully recapitulate the human phenotype. Key take‑home sentence: Although REEP4 is a promising candidate gene for blepharospasm‑oromandibular dystonia syndrome, further research is required before it can be reliably implemented in diagnostic decision‑making.
Gene–Disease AssociationLimitedEvidence includes a co‑segregating REEP4 variant in one large pedigree (PMID:39262575) and additional damaging variants reported in screening studies (PMID:35044558, PMID:30956059); however, the number of unrelated probands is low and both segregation and experimental support remain insufficient for a higher classification. Genetic EvidenceLimitedThe identification of the REEP4 variant c.109C>T (p.Arg37Trp) in a segregating pedigree offers initial genetic support, yet the overall genetic evidence is limited by the small number of independent cases. Functional EvidenceLimitedAlthough in silico predictions and preliminary functional assessments suggest a role for REEP4 variants, inconsistent functional data and lack of robust experimental validation limit the strength of the evidence. |