Intronic FGF14 GAA repeat expansions impact progression and survival in multiple system atrophy

Area of Science:

• Neurogenetics
• Neurodegenerative Diseases
• Molecular Biology

Background:

• Phenotypic overlap exists between multiple system atrophy (MSA) and spinocerebellar ataxia 27B.
• Spinocerebellar ataxia 27B is caused by GAA•TTC repeat expansions in the FGF14 gene.
• Investigating FGF14 repeat expansions in MSA is essential for diagnostic clarity.

Purpose of the Study:

• To determine the frequency of FGF14 GAA•TTC repeat expansion in multiple system atrophy (MSA) cases.
• To correlate FGF14 repeat expansion with clinical phenotypes and disease progression in MSA.
• To assess the diagnostic utility of FGF14 repeat expansion screening in MSA.

Main Methods:

• Screening of 657 MSA cases (clinically diagnosed and pathologically confirmed) and 1,003 controls for FGF14 GAA•TTC repeat expansion.
• Genotyping using long-range PCR and repeat-primed PCRs.
• Confirmation of expansions using long-read Oxford Nanopore Technologies sequencing.

Main Results:

• FGF14 GAA≥250 expansion identified in 2.89% of MSA cases, significantly higher than controls (1.40%).
• Pathogenic (GAA≥300) and intermediate (GAA250-299) expansions were detected in MSA patients.
• MSA patients with FGF14 expansion showed faster progression to falls and wheelchair use, with repeat length inversely correlating with survival.

Conclusions:

• FGF14 GAA•TTC repeat expansion is a significant genetic factor in a subset of multiple system atrophy (MSA) cases.
• Screening for FGF14 expansion is recommended for MSA patients with rapid mobility loss for accurate diagnosis.
• Identifying FGF14 expansions aids in patient stratification for clinical trials and understanding disease heterogeneity.