A novel intronic GAA repeat expansion inFGF14causes autosomal dominant adult-onset ataxia (SCA50, ATX-FGF14)

ABSTRACT Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified a novel intronic GAA repeat expansion in the gene encoding Fibroblast Growth Factor 14 ( FGF14 ). Genetic analysis identified 4/95 previously unresolved Australian affected individuals (4.2%) with (GAA) >335 and a further nine individuals with (GAA) >250 . Notably, PCR and long-read sequence analysis revealed these were pure GAA repeats. In comparison, no controls had (GAA) >300 and only 2/311 control individuals (0.6%) encoded a pure (GAA) >250 . In a German validation cohort 9/104 (8.7%) of affected individuals had (GAA) >335 and a further six had (GAA) >250 . In comparison no controls had (GAA) >335 and 10/190 (5.3%) encoded (GAA) >250 . The combined data suggests (GAA) >335 are disease-causing and fully penetrant [P-value 6.0×10 −8 , OR 72 (95% CI=4.3-1227)], while (GAA) >250 is likely pathogenic, albeit with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with a clinical phenotype that may include vestibular impairment, hyper-reflexia and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2=0.44 p=0.00045, slope = -0.12). This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansion loci via model free, genome-wide analysis and identifies SCA50/ATX-FGF14 is a frequent cause of adult-onset ataxia.