Novel ATXN10 repeat motif patterns in Peruvian families modify disease age at onset

Objectives: Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by large 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 merely repeat length alone—can significantly modify disease features such as seizure prevalence and penetrance. Methods: We employed a novel multiplex 20-gene panel with Cas9-targeted, amplification-free long-read sequencing and optical genome mapping to elucidate ATXN10 repeat motif patterns and investigate potential genotype-phenotype correlations in index cases of six clinically well-characterized multigenerational SCA10 kindreds from Peru. Results: We detected ATXN10 repeat expansions ranging from 990 to 2002 pentanucleotide repeats (4.9 to 10 kb expansions) across six families. Importantly, we identified three mixed repeat motif patterns and ratios of (ATTCT)ₙ(ATTCC)ₙ, which were associated with differences in age at disease onset and anticipation. Discussion: Specific ATXN10 repeat motif patterns and (ATTCT) _n (ATTCC) _n motif ratios may serve as modifiers of SCA10 age at onset rather than repeat length. ATXN10 repeat composition can only be fully resolved with long-read sequencing and makes it a fundamental diagnostic for clinical practice and genetic counseling. These findings underscore the need to adapt long-read sequencing clinical workflows to fully characterize large repeat expansions at the nucleotide level.