Optimizing Genetic Analyses for Movement Disorders: A Unified Panel Approach and Targeted Reanalysis of 4,046 Clinical Exomes

BACKGROUND: Molecular testing for genetic movement disorders (MDs) increasingly relies on exome- or genome-based virtual gene panels. In the absence of consensus guidelines, MD panel design remains heterogeneous across laboratories, with international variation in panel configuration and gene content. OBJECTIVE: The aim of this work was to develop a reproducible framework for a unified MD panel design, generate a comprehensive, curated gene-phenotype dataset, and evaluate clinical utility via targeted exome reanalysis. METHODS: Candidate genes were extracted from multiple resources and assessed using predefined criteria for panel inclusion and gene-disease validity. Genes were tiered as Green, Amber, or Red based on evidence strength. Phenotypic spectrum and age at onset were assessed for Green genes based on published literature. Newly added Green and Amber genes were investigated in 4,046 exomes from previously undiagnosed MD cases. RESULTS: Among 2,090 extracted genes, 640 were selected. The final panel included 537 Green, 36 Amber, and 67 Red genes, expanding the prior panel by 283 genes and removing 42. Across Green genes, only 17% were linked to a single MD feature, whereas the remainder associated up to eight. Age-at-onset data indicated both pediatric and adult presentations in 43% of genes. Targeted exome reanalysis using a 220-gene list identified 37 clinically relevant variants across 28 genes, resolving 16 cases and increasing diagnostic yield by 0.4%. CONCLUSIONS: This study offers a systematic framework for designing a unified MD panel by integrating evidence from multiple sources and accounting for phenotypic and age heterogeneity. Targeted reanalysis yielded actionable diagnoses, confirming its benefit in routine clinical practice.