Paradoxical effects of repeat interruptions on spinocerebellar ataxia type 10 expansions and repeat instability

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder caused by a noncoding ATTCT pentanucleotide expansion. An inverse correlation between SCA10 expansion size and age at onset has been reported, and genetic anticipation has been documented. Interruptions in the ATTCT expansion are known to occur within the expansion. In order to determine the effect of repeat interruptions in SCA10 expansions, we designed a PCR assay to easily identify ATCCT repeat interruptions in the 5′-end of the expansion. We screened a cohort of 31 SCA10 families of Mexican, Brazilian and Argentinean ancestry to identify those with ATCCT repeat interruptions within their SCA10 expansions. We then studied the effects of ATCCT interruptions on intergenerational repeat instability, anticipation and age at onset. We find that the SCA10 expansion size is larger in SCA10 patients with an interrupted allele, but there is no difference in the age at onset compared with those expansions without detectable interruptions. An inverse correlation between the expansion size and the age at onset was found only with SCA10 alleles without interruptions. Interrupted expansion alleles show anticipation but are accompanied by a paradoxical contraction in intergenerational repeat size. In conclusion, we find that SCA10 expansions with ATCCT interruptions dramatically differ from SCA10 expansions without detectable ATCCT interruptions in repeat-size-instability dynamics and pathogenicity.