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KCNS2 – Essential Tremor

Genetic studies of essential tremor have identified KCNS2 as one of several candidate genes with autosomal dominant inheritance. In multi‑patient exome studies of 37 early‑onset ET families, KCNS2 variants were observed in singular families, and a reported variant, c.1137>A (p.Asp379Glu), was shown to co‑segregate with the disease (PMID:26508575, PMID:34072005). Although the genetic evidence is presently limited by the lack of replication in additional cohorts, these findings provide a starting point for further investigation and indicate a potential role for KCNS2 in modulating neuronal excitability.

Functional assessment using a Drosophila model demonstrated that neuronal expression of the ET‐causing variant produces increased channel inactivation and spontaneous firing, recapitulating aspects of the essential tremor phenotype (PMID:29769701). This experimental confirmation, while supportive of a pathogenic mechanism involving altered potassium channel activity, is currently the only functional evidence available. Key take‑home message: although promising, the clinical utility of KCNS2 as a biomarker for essential tremor depends on further replication and expanded genetic studies.

References

  • European Journal of Human Genetics • 2016 • Identification of candidate genes for familial early‑onset essential tremor PMID:26508575
  • Pharmaceuticals • 2021 • Genomic Markers for Essential Tremor PMID:34072005
  • Scientific Reports • 2018 • A Drosophila Model of Essential Tremor PMID:29769701

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

KCNS2 variants have been observed in singular ET families with autosomal dominant inheritance, and the supporting evidence is limited by the lack of replication beyond isolated cases (PMID:26508575, PMID:34072005).

Genetic Evidence

Limited

One candidate variant, c.1137>A (p.Asp379Glu), was reported in a family and demonstrated co‑segregation with essential tremor, though additional genetic studies are required to reach a higher confidence level (PMID:29769701).

Functional Evidence

Moderate

Functional assays in a Drosophila model showed that expression of the mutant KCNS2 leads to pronounced neuronal hyperexcitability, corroborating the predicted pathogenic mechanism (PMID:29769701).