{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T20:28:22Z","timestamp":1790368102346,"version":"4.1.0"},"reference-count":26,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,2,26]],"date-time":"2020-02-26T00:00:00Z","timestamp":1582675200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2020,2,26]],"date-time":"2020-02-26T00:00:00Z","timestamp":1582675200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["320030_160200"],"award-info":[{"award-number":["320030_160200"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Agnathia\u2010otocephaly is a rare and lethal anomaly affecting craniofacial structures derived from the first pharyngeal arch. It is characterized by agnathia, microstomia, aglossia, and abnormally positioned auricles with or without associated anomalies. Variants affecting function of\n                      <jats:italic>OTX2<\/jats:italic>\n                      and\n                      <jats:italic>PRRX1,<\/jats:italic>\n                      which together regulate the neural crest cells and the patterning of the first pharyngeal arch as well as skeletal and limb development, were identified to be causal for the anomaly in a few patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Family\u2010based exome sequencing (ES) on a fetus with severe agnathia\u2010otocephaly, cheilognathopalatoschisis, laryngeal hypoplasia, fused lung lobes and other organ abnormalities and mRNA expression analysis were performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Exome sequencing detected a de novo\n                      <jats:italic>SMAD3<\/jats:italic>\n                      missense variant in exon 6 (c.860G&gt;A) associated with decreased mRNA expression. Variants in\n                      <jats:italic>SMAD3<\/jats:italic>\n                      cause Loeys\u2013Dietz syndrome 3 presenting with craniofacial anomalies such as mandibular hypoplasia, micro\u2010 or retro\u2010gnathia, bifid uvula and cleft palate as well as skeletal anomalies and arterial tortuosity.\n                    <\/jats:p>\n                    <jats:p>The SMAD3 protein acts as a transcriptional regulator in the transforming growth factor \u03b2 (TGFB) and bone morphogenetic (BMP) signaling pathways, which play a key role in the development of craniofacial structures originating from the pharyngeal arches.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Agnathia\u2010otocephaly with or without associated anomalies may represent the severe end of a phenotypic spectrum related to variants in genes in the interacting SMAD\/TGFB\/BMP\/SHH\/FGF developmental pathways.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mgg3.1178","type":"journal-article","created":{"date-parts":[[2020,2,26]],"date-time":"2020-02-26T07:40:49Z","timestamp":1582702849000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Expanding the spectrum of\n                    <i>SMAD3<\/i>\n                    \u2010related phenotypes to agnathia\u2010otocephaly"],"prefix":"10.1002","volume":"8","author":[{"given":"Nicole","family":"Meier","sequence":"first","affiliation":[{"name":"Medical Genetics Institute of Medical Genetics and Pathology University Hospital Basel University of Basel Basel Switzerland"},{"name":"Department of Clinical Research University Hospital Basel Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Bruder","sequence":"additional","affiliation":[{"name":"Pathology Institute of Medical Genetics and Pathology University 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