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The current evidence for an association between REEP4 and benign essential blepharospasm is limited. A deleterious variant, c.109C>T (p.Arg37Trp), was identified in a large African‑American pedigree and shown to co‑segregate with blepharospasm (PMID:39262575). In a separate exome sequencing study of 31 subjects from 21 independent pedigrees, REEP4 was one of several candidate genes; however, further screening of 307 subjects did not reveal additional highly deleterious variants in its coding or splice regions (PMID:29770609). This mixed genetic evidence underscores the need for further replication and functional validation.
Functional assessments using in silico prediction tools indicate that the c.109C>T (p.Arg37Trp) variant may be deleterious, but experimental functional data are scarce and inconclusive. Given that familial segregation was observed in only one pedigree and follow‑up screening studies have been largely negative, the overall confidence in this gene–disease association remains limited. Nonetheless, the specificity of the phenotype (blepharospasm) and the initial segregation findings support the potential clinical utility of considering REEP4 in diagnostic decision‑making in select cases.
Gene–Disease AssociationLimitedA single large pedigree demonstrated co‑segregation of the deleterious variant with blepharospasm (PMID:39262575), but additional cohort screening in 307 subjects did not identify further pathogenic variants (PMID:29770609). Genetic EvidenceLimitedThe genetic evidence is based on segregation in one family and isolated case reports, with no strong enrichment across larger cohorts. Functional EvidenceLimitedIn silico predictions suggest pathogenicity of the REEP4 variant, but experimental functional studies remain inconclusive. |