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DS results in multiple phenotypes, including craniofacial dysmorphology, which is characterised by midfacial hypoplasia, brachycephaly and micrognathia. The genetic and developmental causes of this are poorly understood. Using morphometric analysis of the Dp1Tyb mouse model of DS and an associated mouse genetic mapping panel, we demonstrate that four Hsa21-orthologous regions of mouse chromosome 16 contain dosage-sensitive genes that cause the DS craniofacial phenotype, and identify one of these causative genes as Dyrk1a. We show that the earliest and most severe defects in Dp1Tyb skulls are in bones of neural crest (NC) origin, and that mineralisation of the Dp1Tyb skull base synchondroses is aberrant. Furthermore, we show that increased dosage of Dyrk1a results in decreased NC cell proliferation and a decrease in size and cellularity of the NC-derived frontal bone primordia. Thus, DS craniofacial dysmorphology is caused by an increased dosage of Dyrk1a and at least three other genes.<\/jats:p>","DOI":"10.1242\/dev.201077","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T10:01:28Z","timestamp":1682503288000},"source":"Crossref","is-referenced-by-count":33,"title":["Craniofacial dysmorphology in Down syndrome is caused by increased dosage of Dyrk1a and at least three other genes"],"prefix":"10.1242","volume":"150","author":[{"given":"Yushi","family":"Redhead","sequence":"first","affiliation":[{"name":"Centre for Craniofacial Biology and Regenerative Biology, King's College London 1 , London SE1 9RT , UK"},{"name":"The Francis Crick Institute 2 , London NW1 1AT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"Gibbins","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute 2 , London NW1 1AT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Lana-Elola","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute 2 , London NW1 1AT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheona","family":"Watson-Scales","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute 2 , London NW1 1AT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Dobson","sequence":"additional","affiliation":[{"name":"Centre for Craniofacial Biology and Regenerative Biology, King's College London 1 , London SE1 9RT , UK"},{"name":"Randall Centre for Cell and Molecular Biophysics, King's College London 3 , London SE1 1UL , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3200-3199","authenticated-orcid":false,"given":"Matthias","family":"Krause","sequence":"additional","affiliation":[{"name":"Randall Centre for Cell and Molecular Biophysics, King's College London 3 , London SE1 1UL , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2483-2165","authenticated-orcid":false,"given":"Karen J.","family":"Liu","sequence":"additional","affiliation":[{"name":"Centre for Craniofacial Biology and Regenerative Biology, King's College London 1 , London SE1 9RT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2850-9936","authenticated-orcid":false,"given":"Elizabeth M. 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