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

Area of Science:

• Genetics
• Neuroscience
• Neurology

Background:

• Pathogenic GAA repeat expansions in the FGF14 gene are a known cause of late-onset cerebellar ataxia.
• Repeat expansions in ataxia genes like RFC1 have been linked to atypical Parkinson's disease (PD).

Purpose of the Study:

• To investigate the potential role of FGF14 repeat expansions as a genetic contributor to Parkinson's disease (PD).

Main Methods:

• Long-read whole-genome sequencing was performed on individuals with PD and healthy controls.
• Diverse cohorts were analyzed, including the PPMI cohort, NIH CARD initiative, 1000 Genomes Project, and All of Us program.

Main Results:

• Pathogenic FGF14 GAA repeat expansions were identified in five individuals with PD and one control.
• The affected individuals met clinical criteria for PD and showed neurodegeneration on DaTSCAN imaging.
• Alpha-synuclein aggregation was confirmed in four of the affected individuals.

Conclusions:

• FGF14 repeat expansions represent a rare, previously unrecognized genetic cause of Parkinson's disease.
• This finding broadens the phenotypic spectrum of FGF14-associated disorders.
• Long-read sequencing is valuable for identifying complex genetic variations in unresolved neurological cases.