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

Abstract

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.

FIGURE 1

Molecular characterization of the Care4Rare Canada unsolved adult‐onset ataxia cohort. (A) Self‐reported ethnicity of the families included in our Care4Rare unsolved dominant adult‐onset ataxia cohort. (B) Approximate allele size obtained by flanking PCR (clinical testing) in 22 participants. Red dots represent allele ‘a’ (pathogenically expanded, > 300 repeats) and black dots represent allele ‘b’. The gray zone represents the incomplete penetrance range of 250–299 repeats. (C) Overall results of molecular testing for the pathogenic expansion in FGF14, where red represents the positive diagnosis and dark gray the negative ones. The proportion of FC families, in blue, is depicted for both positive and negative results. (D) Approximate allele sizes obtained from the tandem repeat genotyping tool TRGT in seven participants tested by HiFi LR‐GS. (E) Correlation of repeat number, between LR‐GS and RP‐PCR. (F) Representative screenshot of the FGF14 gene in the genome view in Bionano Access. The region in blue represents the insertion called by the de novo pipeline. (G) Size of the insertion in FGF14, corresponding to the repeat expansion and if the insertion was either called by the de novo pipeline or assessed manually, for each participant tested by OGM.

FIGURE 2

Clinical characterization of the SCA27B cohort. (A) Distribution of the presence of episodic features (EF), the age at onset of EF, the definitive age at onset of ataxia and presence of cerebellar atrophy by MRI in the 24 deeply‐phenotyped participants. Red represents yes (feature present), dark gray represents no (feature absent) and black represents unknown (either unrecognized by participant or MRI not performed). Decades of life are represented by orange (second decade), yellow (third decade), green (fourth decade), blue (fifth decade), purple (sixth decade), and white (seventh decade). (B) Distribution of SARA score in our deeply‐phenotyped participants. Each dot represents a value (corresponding to 1 participant), the line represents the mean, and the error bars represent the standard error of the mean (SEM). (C) Detailed phenotype and (D) known ataxia triggers assessed in our deeply‐phenotyped cohort. Red represents yes (feature present), dark gray represents no (feature absent) and black represents unknown (either not recognized by participant or, for the triggers, does not exercise, does not drink caffeinated beverages or alcohol).