Objective: To evaluate the contribution of rare SLC38A6 variants to essential tremor (ET) susceptibility in an independent Chinese cohort through gene-level burden analysis and family co-segregation.

Background: ET is a heritable movement disorder recently linked to loss-of-function variants in SLC38A6 in East Asian populations. However, independent replication is lacking, and the strength of individual variant associations remains uncertain.

Method: All coding exons and flanking splice sites of SLC38A6 were sequenced in 724 unrelated Han Chinese ET patients (383 familial, 341 sporadic) and 606 neurologically healthy controls. Gene-level burden was assessed by carrier-frequency comparison (Fisher exact test) and Sequence Kernel Association Test (SKAT). Co-segregation was evaluated by Sanger sequencing of available relatives.

Results: Eleven rare SLC38A6 variants were identified (one nonsense, nine missense, one splice-region). The most recurrent variant, c.323A>T (p.Tyr108Phe), was present in 3.45% of cases versus 1.16% of controls (OR 3.06, 95% CI 1.31–7.12, P = 0.0065), but did not survive Bonferroni correction. At the gene level, rare variant carriers were significantly enriched in cases (56/724, 7.73% vs 22/606, 3.63%; OR 2.23, 95% CI 1.34–3.69, P = 0.0015), corroborated by SKAT (P = 0.0257). In six multiplex families, SLC38A6 variants co-segregated with ET across two to three generations consistent with autosomal dominant inheritance.

Conclusion: Gene-level rare variant burden analysis supports SLC38A6 as a potential risk gene for ET, although no single variant survived multiple-testing correction. These findings, together with family co-segregation data, are consistent with SLC38A6 variants acting as risk alleles rather than fully penetrant mutations. Replication in multi-ethnic cohorts and functional studies are needed to confirm this association.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-analysis-of-the-slc38a6-gene-in-chinese-patients-with-essential-tremor/