Abstract
Autosomal dominant spinocerebellar ataxia 27B (SCA27B), caused by an intronic (GAA•TTC) repeat expansion in FGF14, is a common cause of late-onset cerebellar ataxia, but its genotypic and phenotypic spectrum remains to be fully established.
We analysed the FGF14 (GAA•TTC) repeat expansion in a cohort of 134 patients with ataxia and 822 controls from Quebec. We conducted segregation study in large families to further characterize intergenerational repeat instability.
We found a significant enrichment of (GAA•TTC)
alleles in the ataxia cohort compared to controls (53.0%, 71/134, vs 3.6%, 30/822, p < 0.0001), including for (GAA•TTC)
alleles (8.2% vs 2.6%, p = 0.0026). We identified 12 ataxic patients with a phenotype compatible with SCA27B carrying a (GAA•TTC)
expansion supporting the pathogenicity of these alleles in some patients. We further delineated the phenotype of 125 symptomatic individuals from 69 families who carried an FGF14 (GAA•TTC)
repeat expansion. Patients with (GAA•TTC)
, (GAA•TTC)
, and (GAA•TTC)
had a similar phenotype. We observed that 14% of patients with episodic symptoms (13/92) had severe episodes that were initially misdiagnosed as stroke, vestibular neuritis, Wernicke's encephalopathy, or seizures.
This large cohort demonstrates that (GAA•TTC)
alleles are enriched in patients with ataxia compared to controls and can be pathogenic for SCA27B, supporting the need to define a lower pathogenic threshold in the presence of specific clinical criteria.
