SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance

We recently described an untranslated CTG expansion that causes a previousl y undescribed form of spinocerebellar ataxia (SCA8), The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract, with the configuration (CT A)(1-21)(CTG)(n). The CTG portion of the repeat is elongated on pathogenic alleles, which nearly always change in size when transmitted from generatio n to generation. To better understand the reduced penetrance and maternal p enetrance bias associated with SCA8 we analyzed the sequence configurations and instability patterns of the CTG repeat in affected and unaffected fami ly members. In contrast to other triplet repeat diseases, expanded alleles found in affected SCA8 individuals can have either a pure uninterrupted CTG repeat tract or an allele with one or more CCG, CTA, CTC, CCA or CTT inter ruptions. Surprisingly, we found six different sequence configurations of t he CTG repeat on expanded alleles in a seven generation family. In two inst ances duplication of CCG interruptions occurred over a single generation an d in other instances duplications that had occurred in different branches o f the family could be inferred. We also evaluated SCA8 instability in sperm samples from individuals with expansions ranging in size from 80 to 800 re peats in blood. Surprisingly the SCA8 repeat tract in sperm underwent contr actions, with nearly all of the resulting expanded alleles having repeat le ngths of <100 CTGs, a size that is not often associated with disease. These en masse repeat contractions in sperm likely underlie the reduced penetran ce associated with paternal transmission.