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To study the molecular pathology of this essential eukaryotic gene, we generated a mouse model based on a hypomorphic <jats:italic>Thoc2<\/jats:italic> exon 37\u201338 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The <jats:italic>Thoc2<\/jats:italic> exon 37\u201338 deletion male (<jats:italic>Thoc2<\/jats:italic><jats:sup><jats:italic>\u0394\/Y<\/jats:italic><\/jats:sup>) mice recapitulate the core phenotypes of <jats:italic>THOC2<\/jats:italic> syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The <jats:italic>Thoc2<\/jats:italic><jats:sup><jats:italic>\u0394\/Y<\/jats:italic><\/jats:sup> mouse brain development is significantly impacted by compromised THOC2\/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Overall, we suggest that perturbed R-loop homeostasis, in stem cells and\/or differentiated cells in mice and the patient, and DNA damage-associated functional alterations are at the root of <jats:italic>THOC2<\/jats:italic> syndrome.<\/jats:p>","DOI":"10.1038\/s41467-024-45121-5","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T18:02:26Z","timestamp":1707415346000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2740-6986","authenticated-orcid":false,"given":"Rudrarup","family":"Bhattacharjee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lachlan A.","family":"Jolly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9298-3072","authenticated-orcid":false,"given":"Mark A.","family":"Corbett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1181-7791","authenticated-orcid":false,"given":"Ing Chee","family":"Wee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sushma R.","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison E.","family":"Gardner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2951-6820","authenticated-orcid":false,"given":"Tarin","family":"Ritchie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eline J. 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