Pathogenic GAA repeat expansions in FGF14 are an established cause of late-onset cerebellar ataxia, but have not been linked to Parkinson’s disease (PD). Given emerging evidence that repeat expansions in ataxia-associated genes like RFC1, can contribute to atypical or familial forms of PD, we investigated whether FGF14 expansions might play a similar role. Using long-read whole-genome sequencing on 411 individuals with PD and 197 neurologically healthy controls from the PPMI cohort, alongside 1,429 additional controls from the NIH CARD initiative, the 1000 Genomes Project, and the All of Us program, representing globally diverse populations. We identified pathogenic FGF14 GAA repeat expansions in five individuals with PD and one control. All five individuals fit the clinical criteria of PD and showed typical patterns of neurodegeneration on DaTSCAN imaging; α-synuclein aggregation was confirmed by a positive seeding assay among four individuals with available data. These findings broaden the phenotypic spectrum of FGF14 repeat-associated disease and suggest a rare, previously unrecognized genetic contributor to PD. To our knowledge, this is the first report implicating FGF14 in PD and underscores the utility of long-read sequencing for detecting hidden forms of pathogenic variation in unresolved cases.

M.A.N. 's participation in this project was part of a competitive contract awarded to DataTecnica LLC by the National Institutes of Health to support open science research; he also currently owns stock in Character Bio and Neuron23 Inc.

This work was supported in part by the Intramural Research Programs of the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Department of Health and Human Services (project numbers Z01-AG000949 and 1ZIANS003154). Computational analyses were performed using the NIH HPC Biowulf cluster (http://hpc.nih.gov). This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH authors were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. Clinical data and biosamples used in this study were obtained from the MJFF Parkinsons Progression Markers Initiative (PPMI). PPMI a public-private partnership is funded by the Michael J. Fox Foundation for Parkinsons Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinsons, AskBio, Avid Radiopharmaceuticals, BIAL, BioArctic, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Capsida Biotherapeutics, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Jazz Pharmaceuticals, Johnson & Johnson Innovative Medicine, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Neuron23, Neuropore, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager Therapeutics, the Weston Family Foundation and Yumanity Therapeutics. The PPMI Investigators did not participate in the analysis or preparation of this manuscript. For additional study information, see www.ppmi-info.org. The All of Us Research Program is supported by the National Institutes of Health, Office of the Director, under multiple cooperative agreements (see full list below*). K.D. was supported in part by the JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH. K.J.B. was supported in part by the William H. Gates Sr. Fellowship from the Alzheimers Disease Data Initiative. *All of Us funding acknowledgments: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA #: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study used ONLY openly available human data that were originally located at www.ppmi-info.org/access-data-specimens/download-data). Extracted DNA for 1000 Genomes Project was obtained from the Coriell Institute for Medical Research and was consented for the full public release of genomic data. Please see Coriell (https://www.coriell.org) for more information on specific cell lines. 1000 Genomes Project ONT dataset was generated at the Institute of Molecular Pathology (Vienna, Austria) with funds provided by Boehringer-Ingelheim. All of Us genomic data are publicly available to registered researchers on the All of Us Researcher Workbench at https://www.researchallofus.org/data-tools/workbench/. Researchers can apply for access to the All of Us database following the instructions at https://www.researchallofus.org/register/.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Extracted DNA for 1000 Genomes Project was obtained from the Coriell Institute for Medical Research and was consented for the full public release of genomic data. Please see Coriell (https://www.coriell.org) for more information on specific cell lines. 1000 Genomes Project ONT dataset was generated at the Institute of Molecular Pathology (Vienna, Austria) with funds provided by Boehringer-Ingelheim. All of Us genomic data are publicly available to registered researchers on the All of Us Researcher Workbench at https://www.researchallofus.org/data-tools/workbench/. Researchers can apply for access to the All of Us database following the instructions at https://www.researchallofus.org/register/. PPMI data used in the preparation of this article were obtained on 2025-06-01 from the PPMI database (www.ppmi-info.org/access-data-specimens/download-data), RRID: SCR_006431. For up-to-date information on the study, visit www.ppmi-info.org. The PPMI ONT data will be available at the LONI IDA.