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A deleterious REEP4 variant, c.109C>T (p.Arg37Trp), was identified in a large African-American pedigree where the variant co-segregated with blepharospasm, a clinical feature present in dystonic disorder (PMID:39262575). This genetic evidence, while suggestive, is limited by its occurrence in only one extended family and the subsequent screening study of 307 subjects which failed to consistently identify highly deleterious REEP4 variants in patients with dystonia phenotypes (PMID:39262575).
Functional assessments, including in silico predictions reported in independent studies, provide preliminary support of a pathogenic role for REEP4; however, these findings have not been robustly replicated in larger cohorts (PMID:30956059). Taken together, both the genetic and functional evidence for the association between REEP4 and dystonic disorder remain limited, underscoring the need for additional studies to validate the clinical utility of REEP4 variants in diagnostic decision‑making.
Key take‑home sentence: While initial data hint at a potential link between REEP4 and dystonic disorder, the current evidence is limited and further validation is required before clinical implementation.
Gene–Disease AssociationLimitedLimited evidence from a single large pedigree co-segregating the c.109C>T (p.Arg37Trp) variant with blepharospasm (PMID:39262575); additional screening studies in 307 subjects did not consistently replicate these findings. Genetic EvidenceLimitedSparse genetic data with the identification of the c.109C>T (p.Arg37Trp) variant in one pedigree, and infrequent detection in broader dystonia screening efforts (PMID:39262575). Functional EvidenceLimitedPreliminary in silico predictions and limited functional assays provide modest support for a pathogenic role of REEP4 variants, but lack extensive replication (PMID:30956059). |