Beyond inherited repeat length: somatic expansions in Huntington disease

Huntington disease (HD) is a rare, genetic, autosomal dominant neurodegenerative disease, caused by an unstable CAG repeat expansion in the HTT gene. Over the past decade, somatic instability has become a major focus of investigation. Large genome-wide association studies together with work on post-mortem tissue, animal and cellular models, have brought this mechanism to the forefront, linking it to age at onset, disease severity and progression, reshaping our understanding of HD as a dynamic DNA-driven process over the lifetime, and highlighting it as a potentially actionable target. However, the extent of its causal contribution and precisely how it contributes to disease pathogenesis remain incompletely understood. This review focuses on the current understanding of the mechanisms driving somatic expansion, its consequences, the tissue-specific patterns of instability and their clinical impact, while critically considering the evidence for, and limitations of, its role in disease pathogenesis and emerging therapeutic strategies targeting repeat instability.