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TMEM151A has emerged as a critical gene implicated in episodic kinesigenic dyskinesia, a movement disorder characterized by brief, paroxysmal involuntary movements triggered by sudden actions (PMID:35727387). Multiple independent reports have identified heterozygous variants in TMEM151A in affected individuals, and familial co‐segregation analyses have reinforced its role in this disorder (PMID:35727387). These findings have provided substantial genetic evidence linking TMEM151A to the PKD phenotype.
In a landmark case report, a three‐generation family with five affected individuals demonstrated the typical features of PKD, and a novel heterozygous variant, c.1085A>G (p.Glu362Gly), was identified (PMID:35727387). Additional reports further supported the association by showing similar segregation patterns in affected families, thereby strengthening genetic causality. The diversity of the clinical presentations, including overlaps with benign infantile seizures in some individuals, has expanded our understanding of the phenotypic spectrum.
Large-scale genetic studies have yielded further validation. Multiple independent cohorts of PKD probands have reported heterozygous TMEM151A variants—including both missense and truncating mutations—with frequencies approximating 4.8% in PRRT2‐negative patients (PMID:34820915). The recurrent identification of these variants across different populations and the observation of de novo events support the pathogenic role of TMEM151A. Genetic evidence from these studies has been quantified based on the number of probands and the robust co‐segregation analyses performed.
Complementary functional studies have provided insights into the mechanism of disease. Experimental assays have demonstrated that loss‐of‐function, manifested by mRNA decay and haploinsufficiency, underlies the pathogenicity of TMEM151A variants (PMID:36856871, PMID:35187229). Knock‐out models and quantitative expression studies further substantiate that diminished TMEM151A function leads to a disruption in neuronal regulatory mechanisms that mirror the human PKD phenotype.
The integration of comprehensive genetic and functional data argues strongly for a significant gene-disease association. Multiple unrelated probands carrying diverse TMEM151A variants have been observed across independent reports, with segregation analysis and functional corroboration consistently supporting a loss‐of‐function mechanism (PMID:36781563). This evidence collectively positions the TMEM151A-episodic kinesigenic dyskinesia association within the strong ClinGen category, thus representing a valuable target for diagnostic decision‑making and therapeutic research.
Key take‑home: The robust genetic linkage combined with functional validation establishes TMEM151A testing as a clinically useful tool in diagnosing and managing episodic kinesigenic dyskinesia, offering clear benefits for patient care and future research directions.
Gene–Disease AssociationStrongMultiple unrelated probands (>20 [PMID:34820915]) across several families with robust co‑segregation and extensive functional data support the association. Genetic EvidenceStrongOver 24 heterozygous variants have been identified in more than 25 probands, including both missense and truncating mutations, with clear co‑segregation and de novo events documented ([PMID:35727387], [PMID:34820915]). Functional EvidenceModerateFunctional studies demonstrate loss‑of‑function through mRNA decay and knock‑out models supporting a haploinsufficiency mechanism ([PMID:36856871], [PMID:35187229]). |