{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T05:31:25Z","timestamp":1778045485153,"version":"3.51.4"},"reference-count":34,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T00:00:00Z","timestamp":1681776000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01 DE014581"],"award-info":[{"award-number":["R01 DE014581"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["U01 DE020073"],"award-info":[{"award-number":["U01 DE020073"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Oral clefts and ectrodactyly are common, heterogeneous birth defects. We performed whole\u2010exome sequencing (WES) analysis in a Syrian family. The proband presented with both orofacial clefting and ectrodactyly but not ectodermal dysplasia as typically seen in ectrodactyly, ectodermal dysplasia, and cleft lip\/palate syndrome\u20103. A paternal uncle with only an oral cleft was deceased and unavailable for analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Variant annotation, Mendelian inconsistencies, and novel variants in known cleft genes were examined. Candidate variants were validated using Sanger sequencing, and pathogenicity assessed by knocking out the\n                      <jats:italic>tp63<\/jats:italic>\n                      gene in zebrafish to evaluate its role during zebrafish development.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Twenty\u2010eight candidate de novo events were identified, one of which is in a known oral cleft and ectrodactyly gene,\n                      <jats:italic>TP63<\/jats:italic>\n                      (c.956G\u2009&gt;\u2009T, p.Arg319Leu), and confirmed by Sanger sequencing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>TP63<\/jats:italic>\n                      mutations are associated with multiple autosomal dominant orofacial clefting and limb malformation disorders. The p.Arg319Leu mutation seen in this patient is de novo but also novel. Two known mutations in the same codon (c.956G\u2009&gt;\u2009A, p.(Arg319His; rs121908839, c.955C\u2009&gt;\u2009T), p.Arg319Cys) cause ectrodactyly, providing evidence that mutating this codon is deleterious. While this\n                      <jats:italic>TP63<\/jats:italic>\n                      mutation is the best candidate for the patient's clinical presentation, whether it is responsible for the entire phenotype is unclear. Generation and characterization of\n                      <jats:italic>tp63<\/jats:italic>\n                      knockout zebrafish showed necrosis and rupture of the head at 3\u2009days post\u2010fertilization (dpf). The embryonic phenotype could not be rescued by injection of zebrafish or human messenger RNA (mRNA). Further functional analysis is needed to determine what proportion of the phenotype is due to this mutation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mgg3.2179","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T07:58:26Z","timestamp":1681804706000},"source":"Crossref","is-referenced-by-count":3,"title":["A novel de novo\n                    <i>TP63<\/i>\n                    mutation in whole\u2010exome sequencing of a Syrian family with Oral cleft and ectrodactyly"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2244-7690","authenticated-orcid":false,"given":"Claire L.","family":"Simpson","sequence":"first","affiliation":[{"name":"Computational and Statistical Genomics Branch, National Human Genome Research Institute National Institutes of Health  Baltimore Maryland 21224 USA"},{"name":"Department of Genetics, Genomics and Informatics University of Tennessee Health Science Center  Memphis Tennessee 38163 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danielle C.","family":"Kimble","sequence":"additional","affiliation":[{"name":"Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute National Institutes of Health  Bethesda Maryland 20814 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Settara C.","family":"Chandrasekharappa","sequence":"additional","affiliation":[{"name":"Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute National Institutes of Health  Bethesda Maryland 20814 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"NISC Comparative Sequencing Program","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khalid","family":"Alqosayer","sequence":"additional","affiliation":[{"name":"Prime Health Clinic  Jeddah Riyadh 21511 Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Holzinger","sequence":"additional","affiliation":[{"name":"Computational and Statistical Genomics Branch, National Human Genome Research Institute National Institutes of Health  Baltimore Maryland 21224 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blake","family":"Carrington","sequence":"additional","affiliation":[{"name":"Zebrafish Core, National Human Genome Research Institute National Institutes of Health  Bethesda Maryland 20892 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"McElderry","sequence":"additional","affiliation":[{"name":"Zebrafish Core, National Human Genome Research Institute National Institutes of Health  Bethesda Maryland 20892 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raman","family":"Sood","sequence":"additional","affiliation":[{"name":"Zebrafish Core, National Human Genome Research Institute National Institutes of Health  Bethesda Maryland 20892 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ghiath","family":"Al\u2010Souqi","sequence":"additional","affiliation":[{"name":"Hejazi Clinic  P.O. 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