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TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in\n                    <jats:italic>TOP3A<\/jats:italic>\n                    can cause a disorder similar to Bloom syndrome, which results from bi\u2010allelic pathogenic variants in\n                    <jats:italic>BLM<\/jats:italic>\n                    , encoding a nuclear\u2010binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult\u2010onset mitochondrial disease resulting from bi\u2010allelic\n                    <jats:italic>TOP3A<\/jats:italic>\n                    gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory\u2010motor neuropathy. We present a comprehensive characterisation of the effect of\n                    <jats:italic>TOP3A<\/jats:italic>\n                    variants, from individuals with mitochondrial disease and Bloom\u2010like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult\u2010onset mitochondrial disease and more severe variants causing a Bloom\u2010like syndrome with mitochondrial dysfunction in childhood.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202216775","type":"journal-article","created":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T03:41:37Z","timestamp":1680579697000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5830-9911","authenticated-orcid":false,"given":"Direnis","family":"Erdinc","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3989-1317","authenticated-orcid":false,"given":"Alejandro","family":"Rodr\u00edguez\u2010Luis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud R","family":"Fassad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Mackenzie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2371-1844","authenticated-orcid":false,"given":"Christopher 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