Expanded ATXN10 Alleles in Neurodegenerative Disorders: A Case Series and Review of the Literature

Abstract Background: Spinocerebellar ataxia type 10 (SCA10) is typically attributed to large intronic ATTCT repeat expansions in ATXN10 , yet interpretation is complicated by repeat interruptions, reduced penetrance, and assay limitations. Cases: We describe three patients referred for SCA10 evaluation in whom ATXN10 repeat-primed PCR (RP-PCR) reported “>32 repeats, probable pathogenic.” Targeted long-read sequencing (LRS) identified two individuals with intermediate, mixed repeat tracts (~100–150 repeats) and one individual with a very large, highly pure ATTCT expansion (~1,127 repeats). Each phenotype was explained by an alternative disorder: spastic ataxia syndrome caused by biallelic pathogenic FA2H variants, full-penetrance ATXN3 CAG expansion consistent with MJD/SCA3, and clinically established MSA-C. Literature Review: We identified three studies reporting four SCA10 cases coexisting with Huntington’s disease (one case) and SCA2 (three cases). Conclusion: Our three cases suggest that intermediate ATXN10 alleles in the 100–150 range may not be pathogenic and that even very large, pure expansions may be non-pathogenic. Comprehensive genetic testing beyond RP-PCR is necessary for accurate diagnosis.