Long-read sequencing identifies FGF14 repeat expansions in Parkinson's disease.

Abstract

Pathogenic GAA repeat expansions in FGF14 are an established cause of late-onset cerebellar ataxia, but have not been linked to Parkinson's disease. Given emerging evidence that repeat expansions in ataxia-associated genes like RFC1 can contribute to atypical or familial forms of Parkinson's disease, we investigated whether FGF14 expansions might play a similar role. Using long-read whole-genome sequencing, we analysed 411 individuals with Parkinson's disease and 197 neurologically healthy controls from the Parkinson's Progression Markers Initiative (PPMI) cohort, together with 1429 additional controls from the National Institutes of Health (NIH) Center for Alzheimer's Disease and Related Dementias (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 Parkinson's disease and one control subject. All five individuals fit the clinical criteria of Parkinson's disease 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 Parkinson's disease. To our knowledge, this is the first report implicating FGF14 in Parkinson's disease and underscores the utility of long-read sequencing for detecting hidden forms of pathogenic variation in unresolved cases.