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We detected a novel <jats:italic>POLG2<\/jats:italic> variant (c.1270\u00a0T\u2009&gt;\u2009C, p.Ser424Pro) in a family with adult-onset cerebellar ataxia and progressive ophthalmoplegia. We demonstrated altered mitochondrial integrity in patients\u2019 fibroblast cultures but no changes of the mitochondrial DNA were found when compared to controls. We consider this novel, segregating <jats:italic>POLG2<\/jats:italic> variant as disease-causing in this family. Moreover, we systematically screened the literature for <jats:italic>POLG2<\/jats:italic>-linked phenotypes and re-evaluated all mutations published to date for pathogenicity according to current knowledge. Thereby, we identified twelve published, likely disease-causing variants in 19 patients only. The core features included progressive ophthalmoplegia and cerebellar ataxia; parkinsonism, neuropathy, cognitive decline, and seizures were also repeatedly found in adult-onset heterozygous <jats:italic>POLG2<\/jats:italic>-related disease. A severe phenotype relates to biallelic\u00a0pathogenic variants in <jats:italic>POLG2,\u00a0<\/jats:italic>i.e.,\u00a0newborn-onset liver failure, referred to as mitochondrial depletion syndrome. Our work underlines the broad clinical spectrum of <jats:italic>POLG2<\/jats:italic>-related disease and highlights the importance of functional characterization of variants of uncertain significance to enable meaningful genetic counseling.<\/jats:p>","DOI":"10.1007\/s12311-023-01557-x","type":"journal-article","created":{"date-parts":[[2023,4,22]],"date-time":"2023-04-22T03:26:48Z","timestamp":1682134008000},"page":"479-488","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["POLG2-Linked Mitochondrial Disease: Functional Insights from New Mutation Carriers and Review of the Literature"],"prefix":"10.1007","volume":"23","author":[{"given":"Max","family":"Borsche","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marija","family":"Dulovic-Mahlow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hauke","family":"Baumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinem","family":"Tunc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"L\u00fcth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susen","family":"Schaake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selin","family":"\u00d6zcakir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Westenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"M\u00fcnchau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn","family":"Knappe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Trinh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5969-6899","authenticated-orcid":false,"given":"Norbert","family":"Br\u00fcggemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Lohmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,4,22]]},"reference":[{"issue":"9","key":"1557_CR1","first-page":"164","volume":"10","author":"J Chapman","year":"2020","unstructured":"Chapman J, Ng YS, Nicholls TJ. 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