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We revealed systematic mis-sizing of the <jats:italic>ATXN3<\/jats:italic> repeat and high levels of inaccuracy of the traditional fragment length analysis that have important implications for attempts to identify modifiers of clinical and molecular phenotypes. Quantification of somatic expansion in blood DNA and multivariate regression revealed the expected effects of age at sampling and CAG repeat length, although the effect of repeat length was surprisingly modest with much stronger associations with age. We also observed an association of the downstream rs12895357 single nucleotide variant with the rate of somatic expansion, and a higher level of somatic expansion in buccal swab DNA compared to blood. These data suggest that the <jats:italic>ATXN3<\/jats:italic> locus in SCA3 patients in blood or buccal swab DNA might serve as a good biomarker for clinical trials testing suppressors of somatic expansion with peripheral exposure.<\/jats:p>","DOI":"10.1007\/s00439-024-02698-7","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T03:36:28Z","timestamp":1728358588000},"page":"1363-1378","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Age-dependent somatic expansion of the ATXN3 CAG repeat in the blood and buccal swab DNA of individuals with spinocerebellar ataxia type 3\/Machado-Joseph disease"],"prefix":"10.1007","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6306-1079","authenticated-orcid":false,"given":"Ahmed M.","family":"Sidky","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1759-762X","authenticated-orcid":false,"given":"Ana Rosa Vieira","family":"Melo","sequence":"additional","affiliation":[]},{"given":"Teresa T.","family":"Kay","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6899-0352","authenticated-orcid":false,"given":"Mafalda","family":"Raposo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3357-3273","authenticated-orcid":false,"given":"Manuela","family":"Lima","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8298-8264","authenticated-orcid":false,"given":"Darren G.","family":"Monckton","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2024,10,8]]},"reference":[{"key":"2698_CR1","doi-asserted-by":"publisher","first-page":"W3","DOI":"10.1093\/nar\/gkw343","volume":"44","author":"E Afgan","year":"2016","unstructured":"Afgan E, Baker D, van den Beek M et al (2016) The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2016 update. 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