{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T11:25:28Z","timestamp":1791804328683,"version":"4.3.4"},"reference-count":62,"publisher":"SAGE Publications","issue":"11","license":[{"start":{"date-parts":[[2020,7,1]],"date-time":"2020-07-01T00:00:00Z","timestamp":1593561600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["DE019471"],"award-info":[{"award-number":["DE019471"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"schweizerischer nationalfonds zur f\u04e7rderung der wissenschaftlichen forschung","doi-asserted-by":"publisher","award":["310030A_176356"],"award-info":[{"award-number":["310030A_176356"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Dent Res"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:p>Orofacial clefts and their management impose a substantial burden on patients, on their families, and on the health system. Under the current standard of care, affected patients are subjected to a lifelong journey of corrective surgeries and multidisciplinary management to replace bone and soft tissues, as well as restore esthetics and physiologic functions while restoring self-esteem and psychological health. Hence, a better understanding of the dynamic interplay of molecular signaling pathways at critical phases of palate development is necessary to pioneer novel prenatal interventions. Such pathways include transforming growth factor\u2013\u03b2 ( Tgf\u03b2), sonic hedgehog ( Shh), wingless-integrated site ( Wnt)\/\u03b2-catenin, bone morphogenetic protein ( Bmp), and fibroblast growth factor ( Fgf) and its associated receptors, among others. Here, we summarize commonly used surgical methods used to correct cleft defects postnatally. We also review the advances made in prenatal diagnostics of clefts through imaging and genomics and the various in utero surgical corrections that have been attempted thus far. An overview of how key mediators of signaling that drive palatogenesis are emphasized in the context of the framework and rationale for the development and testing of therapeutics in animal model systems and in humans is provided. The pros and cons of in utero therapies that can potentially restore molecular homeostasis needed for the proper growth and fusion of palatal shelves are presented. The theme advanced throughout this review is the need to develop preclinical molecular therapies that could ultimately be translated into human trials that can correct orofacial clefts at earlier stages of development.<\/jats:p>","DOI":"10.1177\/0022034520936245","type":"journal-article","created":{"date-parts":[[2020,7,1]],"date-time":"2020-07-01T14:47:12Z","timestamp":1593614832000},"page":"1221-1227","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":17,"title":["Molecular Diagnostics and In Utero Therapeutics for Orofacial Clefts"],"prefix":"10.1177","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3387-5770","authenticated-orcid":false,"given":"J.D.","family":"Oliver","sequence":"first","affiliation":[{"name":"School of Medicine and School of Dentistry, University of Utah Health, Salt Lake City, UT, USA"},{"name":"Department of Biomedical Engineering, College of Engineering, University of Utah, Salt Lake City, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.C.","family":"Turner","sequence":"additional","affiliation":[{"name":"University of Western Australia Dental School, Perth, Western Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.R.","family":"Halpern","sequence":"additional","affiliation":[{"name":"School of Medicine and School of Dentistry, University of Utah Health, Salt Lake City, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Jia","sequence":"additional","affiliation":[{"name":"School of Medicine and School of Dentistry, University of Utah Health, Salt Lake City, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0677-9409","authenticated-orcid":false,"given":"P.","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Lausanne, Epalinges, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1505-5173","authenticated-orcid":false,"given":"R.N.","family":"D\u2019Souza","sequence":"additional","affiliation":[{"name":"School of Medicine and School of Dentistry, University of Utah Health, Salt Lake City, UT, USA"},{"name":"Department of Biomedical Engineering, College of Engineering, University of Utah, Salt Lake City, UT, USA"},{"name":"University of Utah, Departments of Neurobiology and Anatomy, Pathology, and Surgery, Salt Lake City, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2020,7,1]]},"reference":[{"issue":"9","key":"bibr1-0022034520936245","volume":"9","author":"Alfirevic Z","year":"2017","journal-title":"Cochrane Database Syst Rev"},{"key":"bibr2-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2019.02.015"},{"key":"bibr3-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1111\/ppe.12131"},{"key":"bibr4-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2829"},{"key":"bibr5-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.22214"},{"key":"bibr6-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1038\/srep19248"},{"issue":"1","key":"bibr7-0022034520936245","first-page":"72","volume":"81","author":"Cheng EY","year":"1993","journal-title":"Obstet Gynecol"},{"key":"bibr8-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1038\/s41525-018-0053-8"},{"key":"bibr9-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1016\/j.fsc.2016.06.005"},{"key":"bibr10-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2017.226"},{"key":"bibr11-0022034520936245","doi-asserted-by":"publisher","DOI":"10.4331\/wjbc.v6.i3.121"},{"key":"bibr12-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1002\/pd.5407"},{"key":"bibr13-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1155\/1998\/624810"},{"key":"bibr14-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2014.264"},{"key":"bibr15-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz234"},{"key":"bibr16-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1111\/ors.12117"},{"key":"bibr17-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1242\/dev.157750"},{"key":"bibr18-0022034520936245","doi-asserted-by":"publisher","DOI":"10.4161\/org.4.2.5851"},{"key":"bibr19-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198510033131401"},{"key":"bibr20-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31381"},{"key":"bibr21-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1177\/0022034517719865"},{"key":"bibr22-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1205015109"},{"key":"bibr23-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1597\/05-058"},{"key":"bibr24-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1038\/nature05557"},{"key":"bibr25-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-199104000-00003"},{"key":"bibr26-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-199401000-00011"},{"key":"bibr27-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31940-8"},{"key":"bibr28-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1002\/uog.7472"},{"key":"bibr29-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-090711-163729"},{"issue":"1","key":"bibr30-0022034520936245","first-page":"60","volume":"55","author":"Milunsky A","year":"1980","journal-title":"Obstet Gynecol"},{"key":"bibr31-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1002\/wdev.309"},{"key":"bibr32-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1002\/pd.4047"},{"key":"bibr33-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw171"},{"key":"bibr34-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-018-0582-x"},{"key":"bibr35-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1054\/bjps.2000.3460"},{"key":"bibr36-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1021\/jm9014197"},{"key":"bibr37-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1097\/GOX.0000000000001635"},{"key":"bibr38-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.037051"},{"key":"bibr39-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1597\/12-209"},{"key":"bibr40-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0116963"},{"key":"bibr41-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.038851"},{"key":"bibr42-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1714322"},{"issue":"3","key":"bibr43-0022034520936245","first-page":"233","volume-title":"J Med Genet","volume":"36","author":"Schuffenhauer S","year":"1999"},{"key":"bibr44-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1267\/ahc.18038"},{"key":"bibr45-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.10.016"},{"key":"bibr46-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.39458.563611.AE"},{"key":"bibr47-0022034520936245","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2013.1617"},{"key":"bibr48-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1016\/j.jamcollsurg.2007.06.229"},{"key":"bibr49-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1097\/00006534-199909010-00001"},{"key":"bibr50-0022034520936245","doi-asserted-by":"crossref","unstructured":"Thevenon J, Duffourd Y, Masurel-Paulet A, Lefebvre M, Feillet F, El Chehadeh-Djebbar S, St-Onge J, Steinmetz A, Huet F, Chouchane M, et al. 2016. Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test. Clin Genet. 89(6):700\u2013707.","DOI":"10.1111\/cge.12732"},{"key":"bibr51-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410780200"},{"key":"bibr52-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1002\/pd.5499"},{"key":"bibr53-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2016.97"},{"key":"bibr54-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-017-0845-1"},{"key":"bibr55-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2014.11.041"},{"key":"bibr56-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-0825.2009.01587.x"},{"key":"bibr57-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007438"},{"key":"bibr58-0022034520936245","doi-asserted-by":"publisher","DOI":"10.12659\/MSM.882117"},{"key":"bibr59-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2011.11.042"},{"key":"bibr60-0022034520936245","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00154"},{"key":"bibr61-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.304"},{"key":"bibr62-0022034520936245","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33113"}],"container-title":["Journal of Dental Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/0022034520936245","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/0022034520936245","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/0022034520936245","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T21:08:46Z","timestamp":1777496926000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/0022034520936245"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,1]]},"references-count":62,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2020,10]]}},"alternative-id":["10.1177\/0022034520936245"],"URL":"https:\/\/doi.org\/10.1177\/0022034520936245","relation":{},"ISSN":["0022-0345","1544-0591"],"issn-type":[{"value":"0022-0345","type":"print"},{"value":"1544-0591","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,1]]}}}