Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease highlight shared and tissue-specific effects

Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium, Wills, Christopher, Massey, Thomas ORCID: https://orcid.org/0000-0002-9804-2131 and Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412 2025. Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease highlight shared and tissue-specific effects. Nature Genetics 10.1038/s41588-025-02191-5 Item availability restricted.

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Abstract

An inherited, expanded CAG repeat in HTT undergoes further somatic expansion to cause Huntington’s disease (HD). To gain insights into this molecular mechanism, we compared genome-wide association studies of somatic expansion in blood and somatic expansion-driven HD clinical phenotypes. Here, we show that somatic expansion is driven by a mismatch repair-related process whose genetic modification and consequences show unexpected complexity, including cell-type specificity. The HD clinical trajectory is further modified by non-DNA repair genes that differentially influence measures of cognitive and motor dysfunction. In addition to shared (DNA repair genes MSH3, PMS2 and FAN1) and distinct trans-modifiers, a synonymous CAG-adjacent variant in HTT dramatically hastens motor onset without increasing somatic expansion, while a cis-acting 5′-untranslated region variant promotes blood repeat expansion without influencing clinical HD. Our findings are directly relevant to the therapeutic suppression of expansion in DNA repeat disorders and provide additional clues to HD pathogenic mechanisms beyond somatic expansion.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Publisher:	Nature Publishing Group
ISSN:	1061-4036
Date of First Compliant Deposit:	10 June 2025
Date of Acceptance:	11 April 2025
Last Modified:	11 Jun 2025 12:15
URI:	https://orca.cardiff.ac.uk/id/eprint/178833

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