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Here, we present a pluripotent-stem-cell-based 3D ectodermal organoid model that faithfully recapitulates early ectodermal patterning of future central nervous system, epidermis and cranial and trunk NC, as well as a diverse selection of NC derivatives \u2014offering a comprehensive platform to study neurocristopathies from early induction of pluripotent-like stem cells at the neural plate border to differentiated cells. DiGeorge syndrome (DGS) is caused by a hemizygous microdeletion of \u223cfifty genes, many of which play broad roles during embryogenesis. While DGS is traditionally considered to originate from all germ layers, its clinical manifestations\u2014including craniofacial anomalies, cardiac outflow tract defects, thymic hypoplasia and thyroid dysfunction\u2014are consistent with tissues requiring NC contributions. This raises the question why DGS mainly manifest in organs of NC origin? Using patient-derived iPSCs, we show that DGS organoids display reduced pluripotency gene expression and impaired maintenance of ectodermal stem cells, leading to defective NC specification, posteriorization of cranial NC, and failure to form cartilage. We identify a small subset of genes within the DGS deletion as potential drivers of these early NC defects. Consequently, impaired NC cells are further affected during cranial and vagal mesenchyme maturation, likely worsened by hemizygosity of additional DGS genes that individually, without the initial NC defect, are insufficient to cause the disease. We hypothesize that DGS is primarily, or possibly entirely, a neurocristopathy.<\/jats:p>","DOI":"10.1101\/2025.08.08.669417","type":"posted-content","created":{"date-parts":[[2025,8,9]],"date-time":"2025-08-09T08:00:10Z","timestamp":1754726410000},"source":"Crossref","is-referenced-by-count":2,"title":["Human ectodermal organoids reveal the cellular origin of DiGeorge Syndrome"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0873-4901","authenticated-orcid":false,"given":"Ed Zandro M.","family":"Taroc","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4827-9242","authenticated-orcid":false,"given":"Surangi","family":"Perera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8670-4353","authenticated-orcid":false,"given":"Tunde","family":"Berecz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1751-7028","authenticated-orcid":false,"given":"Jenny","family":"Hsin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9259-2861","authenticated-orcid":false,"given":"Karla","family":"Barbosa-Sabanero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7795-5524","authenticated-orcid":false,"given":"Sravya","family":"Pailla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3982-8123","authenticated-orcid":false,"given":"Zarin","family":"Zainul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3248-8859","authenticated-orcid":false,"given":"Ceren","family":"Pajanoja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0380-8139","authenticated-orcid":false,"given":"Agota","family":"Apati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8880-9087","authenticated-orcid":false,"given":"Daniel","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6710-3512","authenticated-orcid":false,"given":"Laura","family":"Kerosuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025081204000680000_2025.08.08.669417v1.1","unstructured":"Torres B.S. , F.C., Abrams S ., Kerosuo L. 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