Haplotype analysis of spinocerebellar ataxia type 36 suggests a shared permissive core haplotype across populations

Spinocerebellar ataxia type 36 (SCA36)-caused by a GGCCTG hexanucleotide repeat expansion in the NOP56 gene-has traditionally been considered to originate from a founder effect in the Ashida River basin of southern Japan. However, its genetic background remains incompletely understood. In this study, we analyzed five Japanese patients with SCA36 from four unrelated families using long-read sequencing to determine repeat length and reconstruct detailed haplotypes around the NOP56 locus. We successfully resolved extended haplotypes ranging from approximately 90 kb to 1.3 Mb. All five individuals shared a 5.3-kb haplotype adjacent to the repeat expansion, while four patients from northern Japan shared a larger haplotype block of at least 95.2 kb. Comparison with seven previously reported Korean SCA36 cases revealed a shared 4.2-kb haplotype, and available data from other populations were concordant within a ~ 2.1-kb core region. Notably, the shared 5.3-kb haplotype is relatively common in the general population, suggesting that the underlying core haplotype may represent a permissive haplotypic background rather than a unique founder haplotype. These findings indicate that SCA36 is unlikely to be explained solely by a regional founder in southern Japan. Instead, a shared permissive haplotypic background may underlie repeat expansion, with large pathogenic expansion arising independently in different populations. This pattern may be consistent with a stepwise process of repeat expansion.