{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:48:25Z","timestamp":1791600505621,"version":"4.3.4"},"reference-count":76,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2019,12,11]],"date-time":"2019-12-11T00:00:00Z","timestamp":1576022400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DE011931"],"award-info":[{"award-number":["R01DE011931"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Nonsyndromic cleft lip and palate (NSCLP) is one of the most common craniofacial anomalies in humans, affecting more than 135,000 newborns worldwide. NSCLP has a multifactorial etiology with more than 50 genes postulated to play an etiologic role. The genetic pathway comprised of<jats:italic>Pbx<\/jats:italic>\u2010<jats:italic>Wnt<\/jats:italic>\u2010<jats:italic>p63<\/jats:italic>\u2010<jats:italic>Irf6<\/jats:italic>genes was shown to control facial morphogenesis in mice and proposed as a regulatory pathway for NSCLP. Based on these findings, we investigated whether variation in<jats:italic>PBX1<\/jats:italic>,<jats:italic>PBX2<\/jats:italic>, and<jats:italic>TP63<\/jats:italic>, and their proposed interactions were associated with NSCLP. Fourteen single nucleotide variants (SNVs) in\/nearby<jats:italic>PBX1<\/jats:italic>,<jats:italic>PBX2<\/jats:italic>, and<jats:italic>TP63<\/jats:italic>were genotyped in 780 NSCLP families of nonHispanic white (NHW) and Hispanic ethnicities. Family\u2010based association tests were performed for individual SNVs stratified by ethnicity and family history of NSCLP. Gene\u2013gene interactions were also tested. A significant association was found for<jats:italic>PBX2<\/jats:italic>rs3131300 and NSCLP in combined Hispanic families (<jats:italic>p<\/jats:italic>= .003) while nominal association was found for<jats:italic>TP63<\/jats:italic>rs9332461 in multiplex Hispanic families (<jats:italic>p<\/jats:italic>= .005). Significant haplotype associations were observed for<jats:italic>PBX2<\/jats:italic>in NHW (<jats:italic>p<\/jats:italic>= .0002) and Hispanic families (<jats:italic>p<\/jats:italic>= .003), and for<jats:italic>TP63<\/jats:italic>in multiplex Hispanic families (.003). An independent case\u2013control group was used to validate findings, and significant associations were found with<jats:italic>PBX1<\/jats:italic>rs6426870 (<jats:italic>p<\/jats:italic>= .007) and<jats:italic>TP63<\/jats:italic>rs9332461 (<jats:italic>p<\/jats:italic>= .03). Gene\u2013gene interactions were detected between<jats:italic>PBX1\/PBX2\/TP63<\/jats:italic>with<jats:italic>IRF6<\/jats:italic>in NHW families, and between<jats:italic>PBX1<\/jats:italic>with<jats:italic>WNT9B<\/jats:italic>in both NHW and Hispanic families (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.0018). This study provides the first evidence for a role of<jats:italic>PBX1<\/jats:italic>and<jats:italic>PBX2<\/jats:italic>, additional evidence for the role of<jats:italic>TP63<\/jats:italic>, and support for the proposed<jats:italic>PBX<\/jats:italic>\u2010<jats:italic>WNT<\/jats:italic>\u2010<jats:italic>TP63<\/jats:italic>\u2010<jats:italic>IRF6<\/jats:italic>regulatory pathway in the etiology of NSCLP.<\/jats:p>","DOI":"10.1002\/bdr2.1630","type":"journal-article","created":{"date-parts":[[2019,12,11]],"date-time":"2019-12-11T12:36:01Z","timestamp":1576067761000},"page":"234-244","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["<i>PBX\u2010WNT\u2010P63\u2010IRF6<\/i>pathway in nonsyndromic cleft lip and palate"],"prefix":"10.1002","volume":"112","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7695-4319","authenticated-orcid":false,"given":"Lorena","family":"Maili","sequence":"first","affiliation":[{"name":"Department of Pediatrics University of Texas Health Science Center McGovern Medical School at Houston Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7197-6735","authenticated-orcid":false,"given":"Ariadne","family":"Letra","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Biomedical Sciences University of Texas Health Science Center School of Dentistry at Houston Houston Texas"},{"name":"Center for Craniofacial Research University of Texas Health Science Center School of Dentistry at Houston Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato","family":"Silva","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Research University of Texas Health Science Center School of Dentistry at Houston Houston Texas"},{"name":"Department of Endodontics University of Texas Health Science Center School of Dentistry at Houston Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward P.","family":"Buchanan","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery Texas Children's Hospital Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John B.","family":"Mulliken","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R.","family":"Greives","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery University of Texas Health Science Center McGovern Medical School at Houston Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Teichgraeber","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery University of Texas Health Science Center McGovern Medical School at Houston Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J.","family":"Blackwell","sequence":"additional","affiliation":[{"name":"Shriners Hospital for Children Houston Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohit","family":"Ummer","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Research University of Texas Health Science Center School of Dentistry at Houston Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Weber","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Research University of Texas Health Science Center School of Dentistry at Houston Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"Chiquet","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Research University of Texas Health Science Center School of Dentistry at Houston Houston Texas"},{"name":"Department of Pediatric Dentistry University of Texas Health Science Center School of Dentistry at Houston Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan H.","family":"Blanton","sequence":"additional","affiliation":[{"name":"Dr. John T. 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