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

Lange LM, Fang ZH, Screven L, Tan AH, Alcalay RN, Amouri R, Bovenzi R, Fenn M, Frost JLI, Jankovic J, Jasaityte S, Jaunmuktane Z, Jeon B, Sarmiento IJK, Krüger R, Kuhlenbäumer G, Lin CH, Pavelka L, Periñan MT, Sassi SB, Schirinzi T, Shin JH, Shulman JM, Tay YW, Uitti R, Warner T, Wszolek ZK, Wu L, Wu RM, Zeuner KE, Blauwendraat C, Singleton A, Mencacci NE, Morris HR, Lim SY, Lohmann K, Klein C, Global Parkinson's Genetics Program (GP2).

Mov Disord · 2025-10-11

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BackgroundDystonia and Parkinson's disease (PD) exhibit clinical and genetic overlap, but the relevance of dystonia gene variants in PD remains unclear.ObjectiveThe aim was to assess the frequency of dystonia-linked pathogenic variants in PD.MethodsWe 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.ResultsPathogenic 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.ConclusionThough 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.

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