Novel ATXN10 Repeat Motif Patterns in Peruvian Families Modify Disease Onset

Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by intronic expansions of pentanucleotide repeats in the ATXN10 gene. While various repeat motifs have been described, emerging evidence suggests that specific repeat motifs, rather than repeat length alone, can modify disease features such as seizure prevalence and penetrance.

We used a novel multiplex 20-gene panel with Cas9-targeted, amplification-free long-read sequencing (LRS) and optical genome mapping to elucidate ATXN10 repeat motif patterns and investigated genotype-phenotype correlations in index cases of 6 multigenerational SCA10 kindreds from Peru.

We detected ATXN10 repeat expansions ranging from 990 to 2,002 pentanucleotide repeats (4.9-10 kb) across 6 families. It is important to note that we identified 3 mixed repeat motif patterns and ratios of (ATTCT)_n(ATTCC)_n, which were associated with differences in age at disease onset and anticipation.

Our key novel finding is the prominence of the alternate ATTCC motif alongside the common ATTCT motif. While repeat length alone does not appear to drive disease onset in SCA10, we uncovered that the ratio of the ATTCC motif within distinct repeat patterns might correlate with disease onset. These findings underscore the need to adapt LRS clinical workflows to fully characterize large repeat expansions at the nucleotide level.