GAA-FGF14 Ataxia Is a Frequently Overlooked Cause of Sporadic Adult-Onset Ataxia

GAA-FGF14 ataxia (spinocerebellar ataxia 27B, SCA27B), identified in 2023, is a major cause of adult-onset autosomal dominant cerebellar ataxia (ADCA). In this study, we assessed the frequency of GAA-FGF14 ataxia in a predominantly sporadic German cohort of 107 genetically unresolved index patients using long-range PCR and nanopore sequencing. Somatic mosaicism of GAA repeat length was assessed using a custom bioinformatics pipeline based on a modified cyclic Smith-Waterman algorithm. This approach provided streamlined detection and enabled precise genotyping. Among sporadic cases, 10% had a pathogenic and 6% an intermediate repeat expansion. Across the entire cohort, 13% carried a pathogenic and 5% an intermediate repeat expansion. Diagnostic yield varied substantially by clinical presentation: 50% in cases with typical GAA-FGF14-ataxia features, 13% in patients with compatible but less characteristic features and 5% in atypical presentations. In conclusion, this study further corroborates existing evidence that GAA-FGF14 ataxia is a frequent cause of both sporadic and familial cerebellar ataxia. Given its high diagnostic yield and the limited detectability by standard short-read genome sequencing, targeted testing should be more widely implemented.