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Whole-exome sequencing revealed homozygous missense mutations affecting exostosin-like 3 (EXTL3), a glycosyltransferase involved in heparan sulfate (HS) biosynthesis. Patient-derived fibroblasts showed abnormal HS composition and altered fibroblast growth factor 2 signaling, which was rescued by overexpression of wild-type EXTL3 cDNA. Interleukin-2\u2013mediated STAT5 phosphorylation in patients\u2019 lymphocytes was markedly reduced. Interbreeding of the extl3-mutant zebrafish (box) with Tg(rag2:green fluorescent protein) transgenic zebrafish revealed defective thymopoiesis, which was rescued by injection of wild-type human EXTL3 RNA. Targeted differentiation of patient-derived induced pluripotent stem cells showed a reduced expansion of lymphohematopoietic progenitor cells and defects of thymic epithelial progenitor cell differentiation. These data identify EXTL3 mutations as a novel cause of severe immune deficiency with skeletal dysplasia and developmental delay and underline a crucial role of HS in thymopoiesis and skeletal and brain development.<\/jats:p>","DOI":"10.1084\/jem.20161525","type":"journal-article","created":{"date-parts":[[2017,2,1]],"date-time":"2017-02-01T10:10:09Z","timestamp":1485943809000},"page":"623-637","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":87,"title":["<i>EXTL3<\/i>\n                    mutations cause skeletal dysplasia, immune deficiency, and developmental delay"],"prefix":"10.1084","volume":"214","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7129-868X","authenticated-orcid":true,"given":"Stefano","family":"Volpi","sequence":"first","affiliation":[{"name":"Unita\u2019 Operativa Pediatria 2, Istituto Giannina Gaslini, 16148 Genoa, Italy 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