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Multiple independent genetic studies have nominated USP46 as a candidate gene in essential tremor (ET). In a multi‐patient study of 37 early‑onset ET families with an autosomal‑dominant inheritance pattern, exome sequencing revealed that, in three independent families, rare variants in USP46 were predicted to affect gene function (PMID:26508575). A second study screening familial ET cases further identified USP46 among several genes with candidate variants, although these were found in singular families (PMID:34072005).
The genetic evidence is based on the identification of putative functional variants in USP46 with limited segregation data, resulting in a relatively low tally of supporting families. The inheritance pattern in the primary study is consistent with autosomal‑dominant segregation and implicates USP46 as a potential etiologic factor in ET. However, the absence of a consistent and replicated variant across multiple unrelated probands precludes a stronger classification at this time.
No disease‐specific functional evidence has yet been provided for the role of USP46 in ET, despite extensive functional investigations of USP46 in other disease contexts. As such, while in vitro studies have confirmed the importance of USP46 in deubiquitination pathways, direct experimental assays linking USP46 dysfunction with the pathophysiological mechanisms of ET are currently lacking.
Furthermore, there is no conflicting evidence reported in the literature against this association, although the candidate status is tempered by limited sample sizes and segregation information. Additional investigations—including further replication studies and functional assessments in relevant neuronal models—are needed to robustly define the clinical validity of USP46 in ET.
Overall, while USP46 remains an intriguing candidate gene for essential tremor, its current evidence base is limited. Continued research into both its genetic and mechanistic roles is warranted before USP46 can be fully integrated into diagnostic decision‑making or therapeutic strategies.
Key Take‑home: USP46 is a potential candidate for essential tremor but currently lacks sufficient genetic and functional evidence for routine clinical application.
Gene–Disease AssociationLimitedCandidate variants in USP46 have been identified in three independent families from one study (PMID:26508575) and singular family reports in a second study (PMID:34072005), with limited segregation data. Genetic EvidenceLimitedFew candidate variants in USP46 reported with predicted functional impact in familial ET; replication and segregation data remain sparse. Functional EvidenceLimitedAlthough USP46 has well‐documented deubiquitinase activity in other contexts, no ET‐specific functional assays have confirmed its pathobiological role in essential tremor. |