Identification of a novel risk variant in the FUS gene in essential tremor

Objective: A nonsense mutation in the amyotrophic lateral sclerosis gene FUS has been found to segregate in a large family with essential tremor (ET). Coding variants in this gene have not been comprehensively evaluated in ET. We conducted a genetic analysis of FUS for pathogenic and novel coding variants in 2 case-control cohorts among ethnic Chinese.

Methods: In a study that involved 7,548 subjects, we first sequenced all the exon and exon-intronic boundaries ofFUS in 84 ET samples. Potential causative variants that were identified were then genotyped in 2 separate case-control cohorts involving 263 additional ET samples and 5,919 controls (set 1) and 250 ET cases and 250 controls (set 2), and 782 diseased controls of Chinese ethnicity from 2 different Asian countries.

Results: We identified a novel variant, Met392Ile, in exon 12 of the FUS gene. This variant was associated with ET in set 1 (odds ratio = 4.72 [95% confidence interval = 1.90–11.71], p = 0.0037). The association was subsequently validated in set 2 (joint analysis odds ratio = 3.92 [95% confidence interval = 1.57–9.82], p = 8.6 × 10⁻⁴). No association was observed in another neurologic cohort of patients with Parkinson disease, and no other potential pathogenic mutations were identified.

Conclusion: We identified a novel risk variant, Met392Ile, in the FUS gene that increases susceptibility of ET among ethnic Chinese. Further studies in other ethnic populations are needed to determine whether this is an ethnic-specific risk factor.

Neurology 2013