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[Preprint]. 2025 Jul 11:2025.07.10.25330831.

doi: 10.1101/2025.07.10.25330831.

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

Lara M Lange^{1

2}, Zih-Hua Fang³, Laurel Screven⁴, Ai Huey Tan⁵, Roy N Alcalay⁶, Rim Amouri⁷, Roberta Bovenzi^{8

9}, Matilda Fenn¹⁰, Joshua L I Frost¹⁰, Joseph Jankovic¹¹, Simona Jasaityte¹⁰, Zane Jaunmuktane^{10

12

13}, Beomseok Jeon¹⁴, Ignacio Juan Keller Sarmiento⁹, Rejko Krüger^{15

16}, Gregor Kuhlenbäumer¹⁷, Chin-Hsien Lin¹⁸, Lukas Pavelka¹⁶, Maria Teresa Periñan^{19

20}, Samia Ben Sassi⁷, Tommaso Schirinzi⁸, Jung Hwan Shin¹⁴, Joshua M Shulman^{11

21}, Yi Wen Tay⁵, Ryan Uitti²², Tom Warner^{10

12}, Zbigniew K Wszolek²², Lesley Wu¹⁰, Ruey-Meei Wu¹⁸, Kirsten E Zeuner¹⁷, Cornelis Blauwendraat^{4

23}, Andrew Singleton⁴, Niccolò E Mencacci⁹, Huw R Morris^{10

24}, Shen-Yang Lim⁵, Katja Lohmann², Christine Klein²

Affiliations

¹ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA.
² Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
³ German Center for Neurodegenerative Diseases (DZNE), Tubingen, Germany.
⁴ Global Parkinson's Genetics Program (GP2), Maryland, USA.
⁵ Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁶ Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Department of Neurology, Columbia Irving Medical School, New York, NY, USA.
⁷ National Institute Mongi Ben Hamida of Neurology, Tunis, Tunisia.
⁸ Neurology Unit, Department of Systems Medicine, Tor Vergata University of Rome, Rome, Italy.
⁹ Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹⁰ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
¹¹ Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
¹² Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, WC1N 1PJ, UK.
¹³ Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London, UK, WC1N 3BG.
¹⁴ Department of Neurology, Seoul National University Hospital, Seoul, South Korea.
¹⁵ Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg.
¹⁶ Luxembourg Institute of Health (LIH), Strassen, Luxembourg and Centre Hospitalier de Luxembourg (CHL), Luxembourg.
¹⁷ University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany.
¹⁸ Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
¹⁹ Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, United Kingdom.
²⁰ Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas (CSIC)/Universidad de Sevilla, Seville, Spain.
²¹ Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
²² Mayo Clinic, Jacksonville, FL, USA.
²³ Coalition for Aligning Science, Chevy Chase, Maryland, USA.
²⁴ UCL Movement Disorders Centre, University College London, London, UK.

PMID: 40672488
PMCID: PMC12265777
DOI: 10.1101/2025.07.10.25330831

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

Lara M Lange et al. medRxiv. 2025.

[Preprint]. 2025 Jul 11:2025.07.10.25330831.

doi: 10.1101/2025.07.10.25330831.

Authors

Affiliations

¹ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA.
² Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
³ German Center for Neurodegenerative Diseases (DZNE), Tubingen, Germany.
⁴ Global Parkinson's Genetics Program (GP2), Maryland, USA.
⁵ Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁶ Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Department of Neurology, Columbia Irving Medical School, New York, NY, USA.
⁷ National Institute Mongi Ben Hamida of Neurology, Tunis, Tunisia.
⁸ Neurology Unit, Department of Systems Medicine, Tor Vergata University of Rome, Rome, Italy.
⁹ Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹⁰ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
¹¹ Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
¹² Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, WC1N 1PJ, UK.
¹³ Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London, UK, WC1N 3BG.
¹⁴ Department of Neurology, Seoul National University Hospital, Seoul, South Korea.
¹⁵ Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg.
¹⁶ Luxembourg Institute of Health (LIH), Strassen, Luxembourg and Centre Hospitalier de Luxembourg (CHL), Luxembourg.
¹⁷ University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany.
¹⁸ Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
¹⁹ Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, United Kingdom.
²⁰ Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas (CSIC)/Universidad de Sevilla, Seville, Spain.
²¹ Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
²² Mayo Clinic, Jacksonville, FL, USA.
²³ Coalition for Aligning Science, Chevy Chase, Maryland, USA.
²⁴ UCL Movement Disorders Centre, University College London, London, UK.

PMID: 40672488
PMCID: PMC12265777
DOI: 10.1101/2025.07.10.25330831

Abstract

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.

Keywords: Dystonia; GCH1; Monogenic; Parkinson’s disease; VPS16.

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Conflict of interest statement

LML received support for a dystonia research fellowship from the Bachmann Strauss Dystonia Foundation and a fellowship stipend from the German Research Foundation (DFG, project number 553295018). ZHF has a contract with the Michael J Fox Foundation for work on the Global Parkinson’s Genetics Program. She received support from the Aligning Science Across Parkinson’s Initiative (Global Parkinson’s Genetics Program). IJKS reports support from the Michael J Fox Foundation (MJFF-023355). CHL received funding from the National Science and Technology Council (NSTC) and the National Health Research Institutes (NHRI). RMW received grants from the National Science and Technology Council and the National Taiwan University Hospital. AS received grants from the Michael J Fox Foundation and has a contract for the Global Parkinson’s Genetics Program. NEM received honoraria from the Parkinson’s foundation to be part of the PDGENEration steering committee. HRM received grants from Parkinson’s UK, Cure Parkinson’s Trust, the Medical Research Council, and the Michael J Fox Foundation. SYL reports consultancies from the Michael J. Fox Foundation for Parkinson’s research (MJFF), and the Aligning Science Across Parkinson’s-Global Parkinson’s Genetics Program (ASAP-GP2). CK received grant support from the German Research Foundation (DFG), the Aligning Science Across Parkinson’s-Global Parkinson’s Genetics Program (ASAP-GP2) and from the Michael J Fox Foundation (MJFF). She also serves as a medical advisor to Centogene and Biogen. All other authors report no financial disclosures and conflicts of interest related to this manuscript.

Figures

**Figure 1.. Study design and workflow.**
We screened short-read whole-genome sequencing (WGS) data from the Global Parkinson’s Genetics Program (GP2; Release 8 [R8]) and the Accelerating Medicines Partnership - Parkinson’s disease (AMP-PD, Release 4 [R4]) for known variants in genes linked to different forms of dystonia. We included genes linked to isolated as well as combined dystonia phenotypes, the latter including dystonia-parkinsonism and myoclonus-dystonia. Only rare variants predicted to be pathogenic or likely pathogenic were included in further analyses. For identified carriers, we evaluated genotype-phenotype correlations, investigated segregation, and assessed ancestry distributions, where possible. This figure was created with BioRender.

See this image and copyright information in PMC

References

1. Albanese A, Bhatia KP, Fung VSC, Hallett M, Jankovic J, Klein C, et al. Definition and classification of dystonia. Mov Disord [Internet]. 2025. May 6; Available from: 10.1002/mds.30220 - DOI - PMC - PubMed
1. Lange LM, Gonzalez-Latapi P, Rajalingam R, Tijssen MAJ, Ebrahimi-Fakhari D, Gabbert C, et al. Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force - an update. Mov Disord. 2022. May;37(5):905–35. - PubMed
1. Zech M, Jech R, Boesch S, Škorvánek M, Weber S, Wagner M, et al. Monogenic variants in dystonia: an exome-wide sequencing study. Lancet Neurol. 2020. Nov;19(11):908–18. - PMC - PubMed
1. Atasu B, Simón-Sánchez J, Hanagasi H, Bilgic B, Hauser AK, Guven G, et al. Dissecting genetic architecture of rare dystonia: genetic, molecular and clinical insights. J Med Genet. 2024. Apr 19;61(5):443–51. - PMC - PubMed
1. Hamosh A, Scott AF, Amberger JS, Bocchini CA, McKusick VA. Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res. 2005. Jan 1;33(Database issue):D514–7. - PMC - PubMed

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This is a preprint.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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This is a preprint.

Abstract

Conflict of interest statement

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