Rare but Relevant: Assessing Variants in Dystonia-linked Genes in Parkinson’s Disease

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

· 2025-07-11

Research overview

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Background Dystonia and Parkinson’s disease (PD) show clinical and genetic overlap, but the relevance of dystonia gene variants in PD remains unclear. Objective To assess the frequency of dystonia-linked pathogenic variants in PD. Methods We screened sequencing data from 15,738 individuals (7,851 PD, 4,287 atypical parkinsonism, and 3,600 unaffected) from GP2 and AMP-PD for variants in genes linked to isolated dystonia, dystonia-parkinsonism, and myoclonus-dystonia. Results Pathogenic variants were only identified in PD patients. Forty-five PD individuals (0.57%) 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, while variants identified in other genes are rare and of sometimes uncertain relation to the PD phenotype.

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