Whole‐Exome Sequencing Reveals the Genetic Landscape and Genotype–Phenotype Spectrum of Dystonia in a Chinese Cohort

ABSTRACT Aims To systematically characterize the genetic landscape of dystonia in a Mainland Chinese cohort, where over 60% of patients currently lack a molecular diagnosis due to limited large‐scale genomic studies. Methods Whole‐exome sequencing (WES) was performed in a cohort of 147 clinically diagnosed dystonia patients, with variants prioritized by population frequency, CADD/REVEL scores, and ACMG criteria; repeat expansion screening was also conducted to evaluate potential repeat‐expansion phenocopies. Results The overall diagnostic yield was 33.3%, with significantly higher rates in generalized and childhood‐onset dystonia patients. We expanded the mutational and phenotypic spectra of established dystonia genes, including ATP1A3 , KMT2B , GCH1 , and TOR1A . Repeat expansion screening identified ATXN8OS and TBP expansions of uncertain clinical significance. Notably, two heterozygous FIG4 variants (c.1038_1039del and c.2181‐2A>G) were identified as candidate findings requiring further validation. Exploratory HEK‐293 T cell analyses showed that the frameshift variant produced a truncated protein and was associated with lysosome‐related cellular alterations and reduced cell viability. Conclusion This study delineates the genetic architecture and genotype–phenotype spectrum of dystonia in a Chinese cohort, providing population‐specific evidence for the molecular classification and genetic evaluation of dystonia.