Objective: To assess the diagnostic yield of targeted repeat-expansion testing in patients with genetically naïve ataxia after exclusion of secondary causes.

Background: Progressive ataxia is clinically and genetically heterogeneous. Repeat-expansion disorders remain an important, potentially identifiable cause. In resource-constrained settings, targeted testing is often used as a first-line strategy, but its real-world diagnostic yield in suspected genetic ataxia is unclear.

Method: We studied 9 consecutive patients with ataxia of undetermined aetiology from a single centre in Ukraine. All underwent evaluation for secondary causes before genetic testing. Samples were screened for known repeat expansions in SCA1, SCA2, SCA3, SCA6, SCA7, SCA12 and SCA17, and for FGF14-related ataxia and RFC1-related cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) using flanking polymerase chain reaction and repeat-primed polymerase chain reaction where appropriate.

Results: The cohort included 5 males and 4 females, with mean age 47 years (range 19–77). Age at ataxia onset ranged from childhood to late adulthood. Phenotypes were heterogeneous, including cerebellar ataxia with tremor, dysarthria, dysphagia, nystagmus or vestibulo-ocular abnormalities, dystonia, pyramidal signs, neuropathy, cognitive symptoms and chronic cough. All nine cases were negative on the targeted panel testing for common SCAs [Table 1; Table 2]. Three cases demonstrated fragments >1000 bp on flanking PCR but lacked the characteristic motif on repeat-primed PCR, prompting further analysis using long-read sequencing, which is currently ongoing. The remaining six cases were referred for whole-exome sequencing (WES), which is in progress.

Conclusion: In this pilot cohort, targeted testing for common spinocerebellar ataxias and FGF14– and RFC1-related ataxia yielded no further diagnostic insights into the aetiology of ataxia. This emphasizes the marked heterogeneity of idiopathic ataxia and the limitations of restricted expansion panels, supporting earlier access to broader genomic strategies in unsolved cases.

Table 1

Table 2

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MDS Abstracts - https://www.mdsabstracts.org/abstract/targeted-repeat-expansion-screening-highlights-unmet-genomic-needs-in-genetically-naive-ataxia-a-ukrainian-single-centre-pilot-study/