Genetic Modifiers of Huntington Disease: Biological Insights and Therapeutic Opportunities

Presented on September 8th, 2023.

Darren Monckton, PhD
University of Glasgow, Scotland, United Kingdom

Huntington disease (HD) is a typically late onset neurodegenerative condition characterized by loss of motor control, cognitive decline and behavioral and psychiatric changes. HD is caused by the expansion of a polyglutamine encoding CAG repeat in the HTT gene. Inherited repeat length is inversely associated with age at onset. The repeat tract is genetically unstable in the germline and is biased toward expansion, explaining the anticipation observed in affected families. The repeat is also somatically unstable in a process that is expansion-biased, cell type-specific, allele-length and age-dependent. Notably, very large expansions up to 1,000s of repeats are observed in striatal neurons. High-throughput ultra-deep sequencing of the HTT repeat has revealed rare synonymous CAA variants in the polyglutamine encoding CAG/CAA array that are associated with decreased somatic instability and a later age at onset. Bafflingly, rare synonymous CCA/CCG variants in the downstream polyproline encoding region also have dramatic impacts on HD severity. Contrary to expectations, large scale genome-wide associations studies for modifiers of disease severity in HD have revealed multiple hits in DNA repair genes, most of which have established roles in somatic expansion. Similarly, genome-wide association studies of the modifiers of somatic expansion have confirmed a major role for largely overlapping components of the DNA mismatch repair pathway in humans. Multiple lines of evidence have converged on somatic expansion as a key driver of HD pathology and multiple academic and commercial entities are developing strategies to suppress somatic expansion, primarily via targeting of components of the DNA mismatch repair pathway.

Click here to learn more about the 2023 MDF Annual Conference.