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

Abstract

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.