Rare but Relevant? Assessing Variants in Dystonia-Linked Genes in Parkinson's Disease

BACKGROUND: Dystonia and Parkinson's disease (PD) exhibit clinical and genetic overlap, but the relevance of dystonia gene variants in PD remains unclear.

OBJECTIVE: The aim was to assess the frequency of dystonia-linked pathogenic variants in PD.

METHODS: We screened sequencing data from 15,684 individuals (8272 PD, 3200 atypical parkinsonism, and 4212 unaffected) from the Global Parkinson's Genetics Program (GP2) and Accelerating Medicines Partnership-Parkinson's Disease (AMP-PD) for variants in genes linked to isolated dystonia, dystonia-parkinsonism, and myoclonus-dystonia.

RESULTS: Pathogenic variants were identified only in PD patients. Forty-five PD individuals (0.54%) carried 26 distinct (likely) pathogenic variants in nine dystonia-linked genes, most frequently in GCH1, followed by VPS16.

CONCLUSION: Though rare, pathogenic variants in dystonia-linked genes are present in clinically and pathologically diagnosed PD. Our results reinforce GCH1 as a PD-relevant gene with clinical implications, whereas variants identified in other genes are rare and of uncertain relation to the PD phenotype. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.