As Frequent as Polyglutamine Spinocerebellar Ataxias: <scp>SCA27B</scp> in a Large German Autosomal Dominant Ataxia Cohort

German Autosomal Dominant Ataxia CohortIntronic GAA repeat expansions in the fibroblast growth factor 14 gene (FGF14) have recently been shown to be a common cause of adult-onset degenerative ataxia (spinocerebellar ataxia 27B [SCA27B], MIM: 620174), 1,2 but frequencies in strictly consecutive SCA cohorts are unknown.Here we studied the relative frequencies of SCA27B in a cohort of genetically undetermined autosomal dominant cerebellar ataxia (ADCAs) and relative to other forms of genetically confirmed SCAs. ADCA ScreeningWe screened a consecutive cohort of 79 German patients from 51 families with genetically undetermined ADCA for the intronic FGF14 GAA repeat expansion.All index patients were negative for SCA types 1, 2, 3, 6, 7, and 17 and negative on either exome or short-read genome sequencing.Detailed inclusion criteria and methods are outlined in the Supporting Information.Twenty-Six of 51 families (26/79 patients) were found to carry a FGF14 (GAA) ≥250 expansion, thus accounting for 31% of patients with ADCA (Fig. 1A).Although only expansions of at least 250 GAA repeat units were considered pathogenic 1,2 and used for the current frequency analysis, we identified one family with late-onset largely pure cerebellar ataxia, and thus compatible with SCA27B, 3 in which the index patient had a repeat count of 256 GAA units, whereas her affected mother had a repeat count of 234 repeat units (Supporting Information Fig. S2).This indicates that the pathogenic threshold might be even be lower than the previously established cutoff of 250 repeat units.This hypothesis warrants further confirmation in future larger segregation and population studies.Moreover, a (GAAGGA) n repeat expansion was found in three index patients.This hexanucleotide expansion did not segregate with disease in all three families (Supporting Information Fig. S1).This provides further evidence for previous observations suggesting that non-GAA repeat expansions are unlikely pathogenic 1 and warrants caution on recent discussions of its pathogenicity.

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