Curation SCA27B FGF14

Thirteen Australian individuals with adult-onset cerebellar ataxia carried pure intronic FGF14 (GAA)>250 expansions by LR-PCR/RP-PCR; eight had genome-sequence support and five were further characterized by long-read sequencing.

In 102 genetically confirmed SCA27B patients, the expanded allele had median size 337 repeats (maximum 521), and larger repeat size was associated with younger age at disease onset.

Gene-level evidence only: linkage in an autosomal dominant ataxia family mapped to chromosome 13q34 with maximum LOD score 4.28 at D13S280 and identified FGF14 F145S; not specific to the intronic GAA SCA27B repeat locus. Score was downgraded to 0.5 as the evidence is not specific to the repeat expansion.

The FGF14 (GAA)≥250 repeat expansion was significantly associated with late-onset cerebellar ataxia in two independent case–control cohorts: 66 patients and 209 controls in the French Canadian group, and 228 patients and 199 controls in the German group. Odds ratios were 105.60 (CI: 31.09–334.20) and 8.76 (CI: 3.45–20.84), respectively, with P-values <0.001 in both cohorts.

Gene-level model only: Fgf14-deficient mice were viable but developed ataxia and paroxysmal hyperkinetic dyskinesia with reduced dopamine-agonist responses. This gene-level evidence supports the role of FGF14 in ataxia but is not specific to the intronic GAA SCA27B repeat locus.

Gene-level variant evidence only: FGF14 F145S reduced Nav channel localization at the axon initial segment, attenuated sodium currents, and disrupted wild-type FGF14 interaction with Nav alpha subunits. This gene-level evidence supports the role of FGF14 in ataxia but is not specific to the intronic GAA SCA27B repeat locus.