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While a genetic risk factor for neuropsychiatric disorders, the role of <jats:italic>CSMD1<\/jats:italic> in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic <jats:italic>CSMD1<\/jats:italic> variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled <jats:italic>CSMD1<\/jats:italic> loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from <jats:italic>CSMD1<\/jats:italic> knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic <jats:italic>CSMD1<\/jats:italic> variants as the molecular basis of a previously undefined neurodevelopmental disorder.<\/jats:p>","DOI":"10.1038\/s41419-024-06768-6","type":"journal-article","created":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T14:03:24Z","timestamp":1717077804000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Biallelic variants in CSMD1 are implicated in a neurodevelopmental disorder with intellectual disability and variable cortical malformations"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0151-2564","authenticated-orcid":false,"given":"Elizabeth A.","family":"Werren","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily R.","family":"Peirent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henna","family":"Jantti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alba","family":"Guxholli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinshuk Raj","family":"Srivastava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naama","family":"Orenstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinodh","family":"Narayanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojciech","family":"Wiszniewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateusz","family":"Dawidziuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawel","family":"Gawlinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Umair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4149-9544","authenticated-orcid":false,"given":"Amjad","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahid Niaz","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6928-6287","authenticated-orcid":false,"given":"David","family":"Genevi\u00e8ve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daphn\u00e9","family":"Lehalle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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