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These repeat expansion disorders can have repeat units of different size and sequence that can be located in any part of the gene and, while the pathological consequences of the expansion can differ widely, there is evidence to suggest that the underlying mutational mechanism may be similar. In the case of HD, the expanded repeat unit is a CAG trinucleotide located in exon 1 of the huntingtin ( HTT) gene, resulting in an expanded polyglutamine tract in the huntingtin protein. Expansion results in neuronal cell death, particularly in the striatum. Emerging evidence suggests that somatic CAG expansion, specifically expansion occurring in the brain during the lifetime of an individual, contributes to an earlier disease onset and increased severity. In this review we will discuss mouse models of two non-CAG repeat expansion diseases, specifically the Fragile X-related disorders (FXDs) and Friedreich ataxia (FRDA). We will compare and contrast these models with mouse and patient-derived cell models of various other repeat expansion disorders and the relevance of these findings for somatic expansion in HD. We will also describe additional genetic factors and pathways that modify somatic expansion in the FXD mouse model for which no comparable data yet exists in HD mice or humans. These additional factors expand the potential druggable space for diseases like HD where somatic expansion is a significant contributor to disease impact.<\/jats:p>","DOI":"10.3233\/jhd-200423","type":"journal-article","created":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T21:11:12Z","timestamp":1612905072000},"page":"149-163","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":32,"title":["Modifiers of Somatic Repeat Instability in Mouse Models of Friedreich Ataxia and the Fragile X-Related Disorders: Implications for the Mechanism of Somatic Expansion in Huntington\u2019s Disease"],"prefix":"10.1177","volume":"10","author":[{"given":"Xiaonan","family":"Zhao","sequence":"first","affiliation":[{"name":"Laboratory of Cell and Molecular Biology, National Institutes of Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daman","family":"Kumari","sequence":"additional","affiliation":[{"name":"Laboratory of Cell and Molecular Biology, National Institutes of Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carson J.","family":"Miller","sequence":"additional","affiliation":[{"name":"Laboratory of Cell and Molecular Biology, National Institutes of Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geum-Yi","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Cell and Molecular Biology, National Institutes of Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Hayward","sequence":"additional","affiliation":[{"name":"Laboratory of Cell and Molecular Biology, National Institutes of Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia G.","family":"Vitalo","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo Mouro","family":"Pinto","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA, USA"},{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Usdin","sequence":"additional","affiliation":[{"name":"Laboratory of Cell and Molecular Biology, National Institutes of Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2021,2,9]]},"reference":[{"key":"ref001","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2015.5"},{"issue":"6","key":"ref002","first-page":"971","volume":"72","author":"The Huntington\u2019s Disease Collaborative Research Group","year":"1993","journal-title":"The Huntington\u2019s Disease Collaborative Research Group. 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