# Role of Repeat Tract Structure and the rs7158733 SNP in Spinocerebellar Ataxia 3

## TL;DR

This study explores how the structure of a repeat tract and a specific SNP influence the age of onset in Spinocerebellar Ataxia 3.

## Contribution

The study identifies a specific SNP that modifies the effect of repeat size on disease onset in SCA3.

## Key findings

- A clear gap exists between normal and expanded SCA3 alleles with no intermediate alleles.
- The rs7158733 SNP is associated with earlier disease onset in SCA3 patients.
- The canonical interruptions in the ATXN3 repeat tract are typically preserved.

## Abstract

Spinocerebellar ataxia 3 (SCA3) is a neurodegenerative condition caused by an expansion of a polyglutamine tract within the ATXN3 gene. Normal alleles range from 12 to 44 repeats, while pathogenic alleles have 52 repeats or more. The canonical ATXN3 repeat tract sequence includes three interruptions at positions 3 (CAA), 4 (AAG), and 6 (CAA). The intragenic rs7158733 single-nucleotide polymorphism (SNP) flanks the ATXN3 repeat region and substitutes a TAC1118 tyrosine codon with a TAA1118 stop codon, resulting in a shorter ataxin-3aS isoform. We examined the distribution of SCA3 allele repeat sizes in a UK-based cohort presenting with an ataxic phenotype. The 6596 alleles showed a clear gap between normal and expanded alleles, with no intermediate alleles containing 41 to 57 repeats. We used clone sequencing to characterize the structure of the ATXN3 repeat region in a sub-cohort of 44 SCA3 patients. We observed that the three canonical interruptions were typically preserved. There was no association of the interruptions with age at onset detected in this cohort, given the limited power of this sub-cohort. We genotyped the rs7158733 SNP in a sub-cohort of 79 SCA3 patients and found that 74.7% of expanded alleles carried the A1118 variant, which was associated with earlier disease onset. This study highlights the importance of rs7158733 genotyping alongside ATXN3 repeat sizing for patient evaluation, as this SNP modifies the effect of repeat size on age at onset in SCA3 for pathogenic alleles up to 69 repeats.