Long-read sequencing identifies <i>FGF14</i> repeat expansions in Parkinson’s disease
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, we analyzed 411 individuals with PD and 197 neurologically healthy controls from the PPMI cohort, together with 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.
Authors
- Androo J. Markham
- Melissa Meredith (ORCID: https://orcid.org/0000-0001-5736-3193)
- Fulya Akçimen
- Miten Jain (ORCID: https://orcid.org/0000-0002-4571-3982)
- Cedric Kouam (ORCID: https://orcid.org/0000-0003-4949-9052)
- Paige Jarreau (ORCID: https://orcid.org/0000-0002-3963-2641)
- Zih‐Hua Fang (ORCID: https://orcid.org/0000-0002-0225-8772)
- Mark Chaisson (ORCID: https://orcid.org/0000-0001-5395-1457)
- Pilar Álvarez Jerez (ORCID: https://orcid.org/0000-0002-5812-1898)
- Bradford Casey (ORCID: https://orcid.org/0000-0002-2623-5997)
- Paula Saffie Awad (ORCID: https://orcid.org/0000-0002-8056-365X)
- Sara Bandrés‐Ciga (ORCID: https://orcid.org/0000-0003-0056-1361)
- Lara Mariah Lange (ORCID: https://orcid.org/0000-0002-7162-9821)
- Abraham Moller (ORCID: https://orcid.org/0000-0002-7324-8678)
- Laksh Malik (ORCID: https://orcid.org/0000-0002-2498-146X)
- Abigail Miano‐Burkhardt (ORCID: https://orcid.org/0000-0002-0447-4698)
- Kensuke Daida (ORCID: https://orcid.org/0000-0002-9177-9587)
- Breeana Baker
- Cornelis Blauwendraat (ORCID: https://orcid.org/0000-0001-9358-8111)
- Hirotaka Iwaki (ORCID: https://orcid.org/0000-0002-8982-7885)
- Kimberly Paquette
- Andrew B. Singleton
- Jessica Anderson
- J. A. A. Mingle
- Mike A. Nalls
Institutions
- University of Southern California (US)
- Northeastern University (US)
- National Institutes of Health (US)
- University of Concepción (CL)
- German Center for Neurodegenerative Diseases (DE)
- Michael J. Fox Foundation (US)
- National Institute of Neurological Disorders and Stroke (US)
- All Russian Research Institute of Hydrometeorological information World Data Center (RU)
- National Institute on Aging (US)
- Clinica Santa Maria (CL)
- Oxford Nanopore Technologies (United Kingdom) (GB)
Publication Details
- Journal
- Brain
- Published
- 2025-11-29
- DOI
- https://doi.org/10.1093/brain/awaf456
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Health and Human Services
- National Institutes of Health
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke