FGF14 GAA Intronic Expansion in Unsolved Adult-Onset Ataxia in the Care4Rare Canada Consortium.

Background and objectives: Spinocerebellar ataxias (SCA) represent a clinically and genetically heterogeneous group of progressive neurodegenerative diseases with prominent cerebellar atrophy. Recently, a novel pathogenic repeat expansion in intron 1 of FGF14 was identified, causing adult-onset SCA (SCA27B). We aimed to determine the proportion of our unsolved adult-onset ataxia cohort harboring this expansion using several technologies, and to characterize the phenotypic presentation within our population.

Methods: Individuals presenting with adult-onset ataxia (> 30 years old) and negative previous genetic testing were selected from the Care4Rare patient repository. Affected individuals were from all ethnicities, and 90% had a family history suggestive of dominant ataxia, representing 19 of the 23 families included. We used multiple tools (PCR, long-read genome sequencing and optical genome mapping (OGM)) to identify the pathogenic GAA repeat in FGF14.

Results: Of the 23 families included in this study, 65.2% harbored a pathogenic GAA expansion in FGF14. Individuals of French-Canadian descent (FC) represented most of our cohort and had a 64.7% diagnostic yield. Affected individuals presented with gaze-evoked nystagmus, gait ataxia, cerebellar dysarthria, and early episodic features. The GAA expansion in FGF14 was visible by OGM in all individuals tested.

Interpretation: Our diagnostic yield demonstrates this expansion may be the most common cause of adult-onset SCA in dominant families of FC ancestry. Our FC participants have a phenotype distinct from previously published FC patients, with gaze-evoked nystagmus being the most common eye anomaly. From a diagnostic standpoint, the pathogenic GAA repeat can be identified by OGM, but additional tests are required to complement the interpretation.