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

Lara Mariah Lange; Zih‐Hua Fang; Laurel A. Screven; Ai Huey Tan; Roy N. Alcalay; Rim Amouri; Roberta Bovenzi; Matilda Fenn; Joshua L.I. Frost; Joseph J. Jankovic; Simona Jasaityte; Zane Jaunmuktane; Beomseok Jeon; Ignacio Juan Keller Sarmiento; Rejko Krüger; Gregor Kuhlenbäumer; Chin‐Hsien Lin; Lukas Pavelka; María Teresa Periñán; Samia Ben Sassi; Tommaso Schirinzi; Jung Hwan Shin; Joshua M Shulman; Yi Wen Tay; Ryan J. Uitti; Thomas T. Warner; Zbigniew K. Wszołek; Lesley Wu; Ruey‐Meei Wu; Kirsten E. Zeuner

doi:10.1002/mds.70073

Genetic & Genomic MedicineMovement DisordersOct 11, 2025

Peer-reviewed journal article

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

Lara Mariah Lange iD, Zih‐Hua Fang iD, Laurel A. Screven iD, Ai Huey Tan iD, Roy N. Alcalay iD, Rim Amouri iD, Roberta Bovenzi iD, Matilda Fenn, Joshua L.I. Frost, Joseph J. Jankovic iD, Simona Jasaityte iD, Zane Jaunmuktane iD, Beomseok Jeon iD, Ignacio Juan Keller Sarmiento iD, Rejko Krüger iD, Gregor Kuhlenbäumer iD, Chin‐Hsien Lin iD, Lukas Pavelka iD, María Teresa Periñán iD, Samia Ben Sassi iD, Tommaso Schirinzi iD, Jung Hwan Shin iD, Joshua M Shulman iD, Yi Wen Tay iD, Ryan J. Uitti iD, , the Global Parkinson's Genetics Program (GP2)

Abstract

BackgroundDystonia and Parkinsons disease (PD) show clinical and genetic overlap, but the relevance of dystonia gene variants in PD remains unclear. ObjectiveTo assess the frequency of dystonia-linked pathogenic variants in PD. MethodsWe 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. ResultsPathogenic 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. 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, while variants identified in other genes are rare and of sometimes uncertain relation to the PD phenotype.

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