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In a recent population\u2010based study by our group, 84% of the syndromic CS cases had a genetically verified diagnosis after targeted analyses. A number of different genetic causes were detected, confirming that syndromic CS is highly heterogeneous. In this study, we performed whole\u2010exome sequencing of 10 children and parents from the same cohort where previous genetic results were negative. We detected pathogenic, or likely pathogenic, variants in four additional genes (<jats:italic>NFIA<\/jats:italic>, <jats:italic>EXTL3<\/jats:italic>, <jats:italic>POLR2A<\/jats:italic>, and <jats:italic>FOXP2)<\/jats:italic> associated with rare conditions. In two of these (<jats:italic>POLR2A<\/jats:italic> and <jats:italic>FOXP2<\/jats:italic>), CS has not previously been reported. We further detected a rare predicted damaging variant in <jats:italic>SH3BP4<\/jats:italic>, which has not previously been related to human disease. All findings were clustered in genes involved in the pathways of osteogenesis and suture patency. We conclude that whole\u2010exome sequencing expands the list of genes associated with syndromic CS, and provides new candidate genes in osteogenic signaling pathways.<\/jats:p>","DOI":"10.1002\/ajmg.a.62663","type":"journal-article","created":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T03:18:16Z","timestamp":1643167096000},"page":"1464-1475","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Whole\u2010exome sequencing in syndromic craniosynostosis increases diagnostic yield and identifies candidate genes in osteogenic signaling pathways"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3547-9280","authenticated-orcid":false,"given":"Elin","family":"T\u00f8nne","sequence":"first","affiliation":[{"name":"Faculty of Medicine University of Oslo  Oslo Norway"},{"name":"Department of Medical Genetics Oslo University Hospital  Oslo Norway"},{"name":"Norwegian National Unit for Craniofacial Surgery Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernt Johan","family":"Due\u2010T\u00f8nnessen","sequence":"additional","affiliation":[{"name":"Norwegian National Unit for Craniofacial Surgery Oslo University Hospital  Oslo Norway"},{"name":"Department of Neurosurgery Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus Dehli","family":"Vigeland","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Oslo  Oslo Norway"},{"name":"Department of Medical Genetics Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silja Svanstr\u00f8m","family":"Amundsen","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodora","family":"Ribarska","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Oslo  Oslo Norway"},{"name":"Department of Medical Genetics Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela Marika","family":"\u00c5sten","sequence":"additional","affiliation":[{"name":"TAKO Centre, Lovisenberg Diakonale Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirik","family":"Helseth","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Oslo  Oslo Norway"},{"name":"Department of Neurosurgery Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregor Duncan","family":"Gilfillan","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Oslo  Oslo Norway"},{"name":"Department of Medical Genetics Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inger\u2010Lise","family":"Mero","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ketil Riddervold","family":"Heimdal","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Oslo University Hospital  Oslo Norway"},{"name":"Norwegian National Unit for Craniofacial Surgery Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,1,25]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpbi.27"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.01.110"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61518"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1159\/000320668"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(04)00058-9"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-020-0817-2"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gep.2016.03.001"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3651"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1159\/000318841"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1159\/000066311"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0197-42"},{"key":"e_1_2_10_13_1","unstructured":"EllardS Baple E. 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