{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:53:41Z","timestamp":1792785221245,"version":"4.5.0"},"reference-count":37,"publisher":"National Academy of Sciences","issue":"30","license":[{"start":{"date-parts":[[2019,7,10]],"date-time":"2019-07-10T00:00:00Z","timestamp":1562716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Yale Center for Mendelian Genomics","award":["NIH M#UM1HG006504-05"],"award-info":[{"award-number":["NIH M#UM1HG006504-05"]}]},{"name":"NIH Medical Scientist Training Program","award":["NIH\/NIGMS T32GM007205"],"award-info":[{"award-number":["NIH\/NIGMS T32GM007205"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,7,23]]},"abstract":"<jats:p>\n                    Craniosynostosis (CS) is a frequent congenital anomaly featuring the premature fusion of 1 or more sutures of the cranial vault. Syndromic cases, featuring additional congenital anomalies, make up 15% of CS. While many genes underlying syndromic CS have been identified, the cause of many syndromic cases remains unknown. We performed exome sequencing of 12 syndromic CS cases and their parents, in whom previous genetic evaluations were unrevealing. Damaging de novo or transmitted loss of function (LOF) mutations were found in 8 genes that are highly intolerant to LOF mutation (\n                    <jats:italic>P<\/jats:italic>\n                    = 4.0 \u00d7 10\n                    <jats:sup>\u22128<\/jats:sup>\n                    ); additionally, a rare damaging mutation in\n                    <jats:italic>SOX11<\/jats:italic>\n                    , which has a lower level of intolerance, was identified. Four probands had rare damaging mutations (2 de novo) in\n                    <jats:italic>TFAP2B<\/jats:italic>\n                    , a transcription factor that orchestrates neural crest cell migration and differentiation; this mutation burden is highly significant (\n                    <jats:italic>P<\/jats:italic>\n                    = 8.2 \u00d7 10\n                    <jats:sup>\u221212<\/jats:sup>\n                    ). Three probands had rare damaging mutations in\n                    <jats:italic>GLI2<\/jats:italic>\n                    ,\n                    <jats:italic>SOX11<\/jats:italic>\n                    , or\n                    <jats:italic>GPC4<\/jats:italic>\n                    , which function in the Hedgehog, BMP, and Wnt signaling pathways; other genes in these pathways have previously been implicated in syndromic CS. Similarly, damaging de novo mutations were identified in genes encoding the chromatin modifier\n                    <jats:italic>KAT6A<\/jats:italic>\n                    , and\n                    <jats:italic>CTNNA1<\/jats:italic>\n                    , encoding catenin \u03b1-1. These findings establish\n                    <jats:italic>TFAP2B<\/jats:italic>\n                    as a CS gene, have implications for assessing risk to subsequent children in these families, and provide evidence implicating other genes in syndromic CS. This high yield indicates the value of performing exome sequencing of syndromic CS patients when sequencing of known disease loci is unrevealing.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1902041116","type":"journal-article","created":{"date-parts":[[2019,7,10]],"date-time":"2019-07-10T19:26:53Z","timestamp":1562786813000},"page":"15116-15121","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":31,"title":["Mutations in\n                    <i>TFAP2B<\/i>\n                    and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis"],"prefix":"10.1073","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8926-9692","authenticated-orcid":false,"given":"Andrew T.","family":"Timberlake","sequence":"first","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine, New Haven, CT 06510;"},{"name":"Hansj\u00f6rg Wyss Department of Plastic Surgery, 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