J8 Two case studies demonstrating transmission of unstable huntington’s disease intermediate alleles and the implications for genetic counselling practice

Abstract

BackgroundHuntington’s disease (HD) is caused by an expanded CAG trinucleotide repeat within the Huntingin gene, with affected individuals inheriting >36 CAG repeats. Intermediate alleles (IAs) are classed as 27–35 CAG repeats. Although IAs do not fall within the disease causing range, they are susceptible to paternal germline instability, and so may expand into the reduced penetrance or full mutation range upon transmission to the next generation. There are several factors which are thought to influence CAG repeat instability. However, the risk of IAs expanding into the HD disease causing range has been difficult to establish. Case history and conclusionsWe present two cases, where intermediate alleles have expanded into the full mutation range. The first case describes a family where a paternally inherited intermediate allele of 29 CAG repeats has expanded into a full mutation of 45 CAG repeats. This finding has been confirmed by PCR and linkage analysis and as far as we are aware, this degree of expansion has not been described in the literature before. The second case describes a family where an intermediate allele of 32 has expanded to 44 CAG repeats. We discuss the implications of this both for the family, and the genetic counsellor involved and present some of the challenges associated with genetic counselling for IAs.