Genetics of Huntington’s disease and related disorders: beyond triplet repeats

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder due to a triplet repeat expansion in the HTT gene. The identification of this gene variation was a lengthy process, but it has since provided an explanation of clinical observations including the variability in age at onset observed across generations (phenomenon of anticipation). Further molecular genetic investigations have allowed the discovery of genes modifying the phenotype presenting differences in terms of age at the onset and course of the disease. Pathogenic gene variations have also been found in other diseases with a similar presentation, such as HD, allowing precise genetic diagnosis. This narrative review examines these data in the context of their historical development. Their implication in our understanding of these disorders and treatment modalities is also highlighted.