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

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

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

Purpose of the Study:

• To investigate if FGF14 repeat expansions contribute to Parkinson's disease (PD).
• To explore the role of FGF14 in neurodegenerative diseases beyond ataxia.

Main Methods:

• Long-read whole-genome sequencing was employed.
• Analysis included 411 individuals with PD and 1,626 controls from diverse cohorts.
• Clinical evaluation, DaTSCAN imaging, and α-synuclein seeding assays were utilized.

Main Results:

• Pathogenic FGF14 GAA repeat expansions were found in five individuals with PD and one control.
• All affected individuals met clinical criteria for PD and showed neurodegeneration on DaTSCAN.
• Positive α-synuclein seeding assays confirmed aggregation in four affected individuals.

Conclusions:

• FGF14 repeat expansions represent a rare, previously unrecognized genetic contributor to Parkinson's disease.
• This finding broadens the phenotypic spectrum of FGF14-associated disorders.
• Long-read sequencing is valuable for detecting complex genetic variations in neurodegenerative diseases.