To report on a novel autosomal dominant intronic GAA repeat expansion in the first intron of the fibroblast growth factor 14  gene (FGF14) causing late-onset cerebellar ataxia (LOCA).

LOCAs have until recently largely resisted genetic diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis.

We performed whole-genome sequencing on six cases from three large French-Canadian families with unsolved autosomal dominant LOCA and identified a candidate GAA repeat expansion in the first intron of FGF14. We determined a pathogenic threshold of (GAA)_≥250 following segregation study within the three families and tested for an association between the repeat expansion and disease in (1) 66 French-Canadian cases and 209 controls, and (2) 228 German cases and 199 controls. We also screened 20 Australian and 31 Indian cases for the repeat expansion.

We identified 128 cases carrying an FGF14 GAA repeat expansion. The repeat expansion was present in 61%, 18%, 15%, and 10% of patients in the French-Canadian, German, Australian and Indian cohorts, respectively. We found a significant association between FGF14 (GAA)_≥250 expansions and LOCA in the French-Canadian (OR=105.60, 95% CI=31.09-334.20; p<0.001) and the German (OR=8.76, 95% CI=3.45-20.84; p<0.001) series. Our data suggest that (GAA)_250-300 expansions are incompletely penetrant while larger expansions are fully penetrant. Cases developed a progressive cerebellar syndrome at an average age of 59 years. The ataxia was episodic at onset in 46% of cases. Downbeat nystagmus was observed in 42% of patients. Cerebellar atrophy was found in 74% of cases on MRI. 

This novel dominantly inherited intronic GAA repeat expansion in FGF14 is a common cause of LOCA. Our study underscores the importance of identifying non-coding repeat expansions, because they likely account for some of the missing heritability in late-onset neurodegenerative disorders.