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This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a\n                    <jats:italic>Cux1<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in\n                    <jats:italic>Cux1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In\n                    <jats:italic>Cux1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/<\/jats:italic>\n                      \u2212\n                    <\/jats:sup>\n                    mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In\n                    <jats:italic>Cux1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/<\/jats:italic>\n                      \u2212\n                    <\/jats:sup>\n                    brains, the expression of\n                    <jats:italic>Cux1<\/jats:italic>\n                    transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing\n                    <jats:italic>CUX1<\/jats:italic>\n                    variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.\n                  <\/jats:p>","DOI":"10.1038\/s41431-023-01445-2","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T23:25:14Z","timestamp":1693351514000},"page":"1251-1260","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying 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There is no conflicted of interest for all other authors.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All experiments complied with ethical animal testing and research regulations and European Commission guidelines (2010\/63\/E.U.) and were approved by the CSIC and the Community of Madrid Ethics Committees on Animal Experimentation (PROEX 395\/15, 236.7\/20). This study was approved by the ethics committees of the University of Leipzig (402\/16-ek), Cambridge South REC (14\/EE\/1112), JKU Linz (ECS 1253\/2021). When carried out in a research setting, testing was approved by the ethics committees of the respective centers. Research data from additional contributing centers are covered by their own Research Ethics protocols and boards. For some individuals, genetic testing was carried out as part of routine clinical care. Institutional ethics approval was not required. All individuals or their legal guardians provided informed written consent for genetic testing and publication of clinical details and images.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}]}}