Integrative Whole-Exome Sequencing and Network Analysis Reveal Molecular Pathways Associated with Focal Isolated Dystonia

Background: Dystonia is a clinically heterogeneous movement disorder characterized by sustained or intermittent muscle contractions arising from dysfunction of distributed motor networks. Although multiple causative genes have been implicated, the extent to which these genetic alterations converge on common molecular pathways remains poorly understood. Methods: A total of 28 patients with focal isolated dystonia were recruited, of whom 23 samples passed quality control and were included in the final analysis. Genomic DNA was extracted from peripheral blood samples, followed by high-throughput sequencing using an Illumina platform. Identified variants were filtered, annotated, and prioritized based on pathogenicity and clinical relevance. Functional enrichment analysis was performed using DAVID, and protein–protein interaction networks were constructed using STRING. Downstream data integration and visualization were conducted using R software. Results: Pathogenic and likely pathogenic variants were identified in several dystonia-associated genes, including TOR1A, THAP1, SGCE, SPR, SDHA, SCN2A, and ANK2. The detected variants exhibited heterogeneous distribution and mutation types, with a predominance of loss-of-function alterations. Gene Ontology enrichment analysis revealed significant involvement in mitochondrial metabolism, coenzyme A biosynthesis, ion channel activity, transcriptional regulation, and neurotransmitter-related processes (p < 0.05). PPI network analysis demonstrated significant enrichment (p < 0.01), identifying key hub genes and strong functional connectivity among pathways regulating neuronal excitability and metabolic homeostasis. Gene–phenotype correlation further indicated overlapping yet distinct clinical associations, reflecting substantial molecular heterogeneity. Conclusion: Genetically diverse variants associated with dystonia converge on interconnected biological pathways governing mitochondrial function, neurotransmitter synthesis, ion channel activity, and transcriptional regulation. These findings highlight a network-level disease mechanism and support the development of pathway-oriented therapeutic strategies targeting shared molecular processes rather than individual gene defects.