{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T19:34:43Z","timestamp":1786649683711,"version":"build-2736575974"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,1]]},"abstract":"Abstract<\/jats:title>\n \n Introduction:<\/jats:title>\n \n Non-syndromic cleft lip and\/or palate (NSCL\/P) is a common congenital deformity, influenced by both genetic and environmental factors. The thymocyte selection-associated high-mobility group box-3 (\n TOX3<\/jats:italic>\n ) gene is suggested to influence NSCL\/P development, though its role remains unclear. This study investigates environmental factors associated with NSCL\/P and explores the association between\n TOX3<\/jats:italic>\n mutations and these factors.\n <\/jats:p>\n <\/jats:sec>\n \n Materials and Methods:<\/jats:title>\n \n A cross-sectional retrospective study was conducted amongst 50 Malay patients with NSCL\/P who underwent surgery at Hospital Universiti Sains Malaysia (January 2022\u2013January 2023). Participants were selected based on inclusion criteria from electronic medical records. Data on environmental and familial risk factors were obtained using validated pro formas, and\n TOX3<\/jats:italic>\n gene copy number was analysed using quantitative polymerase chain reaction.\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n Cleft lip and palate (CL\/P) were the most common deformity, accounting for 74% of cases, and 56% of patients were male. Significant risk factors for NSCL\/P included consanguineous marriage, family history of clefts, maternal radiation exposure, traditional medicine use, allergies, paternal smoking and infant heart anomalies (\n P<\/jats:italic>\n \u2264 0.05). Maternal pregnancy age was inversely correlated with\n TOX3<\/jats:italic>\n expression in CL\/P cases (\n r<\/jats:italic>\n = \u22120.387,\n P<\/jats:italic>\n = 0.018).\n <\/jats:p>\n <\/jats:sec>\n \n Discussion:<\/jats:title>\n \n The findings highlight complex gene\u2013environment interactions in NSCL\/P aetiology. Genetic predisposition, parental exposures and maternal factors jointly increase risk. Larger studies are needed to confirm these findings and further investigate gene\u2013environment interactions in NSCL\/P. The study underscores the role of\n TOX3<\/jats:italic>\n and environmental influences in NSCL\/P pathogenesis, supporting targeted prevention and genetic counselling in the Malay population.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.4103\/ams.ams_180_25","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T14:00:10Z","timestamp":1776261610000},"page":"46-53","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Validation of Thymocyte Selection-associated High-mobility Group Box-3 Gene Mutation and Risk Identification in Non-syndromic Cleft Lip and Palate Deformities in Malay Patients - A Retrospective Study"],"prefix":"10.4103","volume":"16","author":[{"given":"Izzeddin Jameel","family":"Abualjubain","sequence":"first","affiliation":[{"name":"Reconstructive Sciences Unit, School of Medical Sciences, Health Campus, Universiti Sains Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nurul Syazana Binti Mohamad","family":"Shah","sequence":"additional","affiliation":[{"name":"Reconstructive Sciences Unit, School of Medical Sciences, Health Campus, Universiti Sains Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan Azman Wan","family":"Sulaiman","sequence":"additional","affiliation":[{"name":"Reconstructive Sciences Unit, School of Medical Sciences, Health Campus, Universiti Sains Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noor Areefa Ameera Mohd","family":"Ma\u2019amor","sequence":"additional","affiliation":[{"name":"Reconstructive Sciences Unit, School of Medical Sciences, Health Campus, Universiti Sains Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba Mohammed","family":"Arafat","sequence":"additional","affiliation":[{"name":"Department of Chemical Pathology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"R1-20260703","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.3390\/jcm13072090","article-title":"Diagnostic methods for the prenatal detection of cleft lip and palate: A systematic review","volume":"13","author":"Baeza-Pagador","year":"2024","journal-title":"J Clin Med"},{"key":"R2-20260703","doi-asserted-by":"crossref","first-page":"2","DOI":"10.21037\/fomm-21-85","article-title":"A narrative review of craniofacial deformities","volume":"6","author":"Stanbouly","year":"2024","journal-title":"Front Oral Maxillofac Med"},{"key":"R3-20260703","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1053\/j.sodo.2025.03.007","article-title":"Prevalence, causes and characteristics of orthodontic patients with cleft lip with or without palate","volume":"31","author":"Baek","year":"2025","journal-title":"Semin Orthod"},{"key":"R4-20260703","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.3390\/genes14101859","article-title":"Genetic inheritance models of non-syndromic cleft lip with or without palate: From monogenic to polygenic","volume":"14","author":"Cheng","year":"2023","journal-title":"Genes (Basel)"},{"key":"R5-20260703","doi-asserted-by":"crossref","first-page":"e0215931","DOI":"10.1371\/journal.pone.0215931","article-title":"Epidemiology and clinical profile of individuals with cleft lip and palate utilising specialised academic treatment centres in South Africa","volume":"14","author":"Hlongwa","year":"2019","journal-title":"PLoS One"},{"key":"R7-20260703","first-page":"578","article-title":"Analysis of environmental exposures for nonsyndromic cleft lip and\/or Palate: A case-control study","volume":"51","author":"Ahmed Sakran","year":"2022","journal-title":"Iran J Public Health"},{"key":"R8-20260703","doi-asserted-by":"crossref","first-page":"108373","DOI":"10.1016\/j.mrrev.2021.108373","article-title":"Orofacial clefts embryology, classification, epidemiology, and genetics","volume":"787","author":"Nasreddine","year":"2021","journal-title":"Mutat Res Rev Mutat Res"},{"key":"R9-20260703","doi-asserted-by":"crossref","first-page":"429","DOI":"10.4103\/ams.ams_134_20","article-title":"Parental age and the risk of cleft lip and palate in a Nigerian population \u2013 A case-control study","volume":"10","author":"James","year":"2020","journal-title":"Ann Maxillofac Surg"},{"key":"R10-20260703","doi-asserted-by":"crossref","first-page":"e635","DOI":"10.1002\/mgg3.635","article-title":"Two novel genes TOX3 and COL21A1 in large extended Malay families with nonsyndromic cleft lip and\/or palate","volume":"7","author":"Mohamad Shah","year":"2019","journal-title":"Mol Genet Genomic Med"},{"key":"R11-20260703","doi-asserted-by":"crossref","first-page":"7656","DOI":"10.3390\/ijms25147656","article-title":"Structure and functions of HMGB3 protein","volume":"25","author":"Chikhirzhina","year":"2024","journal-title":"Int J Mol Sci"},{"key":"R12-20260703","doi-asserted-by":"crossref","first-page":"9","DOI":"10.25301\/JPDA.271.9","article-title":"Evaluating occurrence of variable cleft lip and palate types among ethnic groups of Malaysia","volume":"27","author":"Shah","year":"2018","journal-title":"J Pak Dent Assoc"},{"key":"R13-20260703","doi-asserted-by":"crossref","first-page":"68","DOI":"10.4103\/0970-0358.53004","article-title":"Current concepts in genetics of nonsyndromic clefts","volume":"42","author":"Murthy","year":"2009","journal-title":"Indian J Plast Surg"},{"key":"R14-20260703","doi-asserted-by":"crossref","first-page":"e114912","DOI":"10.5812\/ijhrba.114912","article-title":"Consanguineous marriage and the risk of parents having children with cleft lip and palate","volume":"10","author":"Bakhshani","year":"2021","journal-title":"Int J High Risk Behav Addict"},{"key":"R15-20260703","doi-asserted-by":"crossref","first-page":"e34419","DOI":"10.1097\/MD.0000000000034419","article-title":"Cleft lip and palate risk factors among otorhinolaryngology: Head and neck surgery patients in two hospitals","volume":"102","author":"Darjazini Nahas","year":"2023","journal-title":"Medicine (Baltimore)"},{"key":"R16-20260703","first-page":"e19579","article-title":"A cross-sectional study: Are myths on cleft lip and palate still prevalent?","volume":"13","author":"Turlapati","year":"2021","journal-title":"Cureus"},{"key":"R17-20260703","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/S0007-1226(03)00044-4","article-title":"Congenital heart disease and associated malformations in children with cleft lip and palate in Pakistan","volume":"56","author":"Shafi","year":"2003","journal-title":"Br J Plast Surg"},{"key":"R18-20260703","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s40902-020-00270-7","article-title":"Assessment of the correlation between various risk factors and orofacial cleft disorder spectrum: A retrospective case-control study","volume":"42","author":"Cheshmi","year":"2020","journal-title":"Maxillofac Plast Reconstr Surg"},{"key":"R20-20260703","first-page":"75","article-title":"Intermarriage in Malaysia","volume":"46","author":"Nagaraj","year":"2009","journal-title":"Malays J Econ Stud"},{"key":"R21-20260703","first-page":"279","article-title":"Prevalence and evaluation of environmental risk factors associated with cleft lip and palate in a central Indian population","volume":"35","author":"Kalaskar","year":"2013","journal-title":"Pediatr Dent"},{"key":"R22-20260703","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1002\/bdra.23417","article-title":"Parental risk factors for oral clefts among central Africans, Southeast Asians, and Central Americans","volume":"103","author":"Figueiredo","year":"2015","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"key":"R23-20260703","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s40368-020-00522-0","article-title":"Nonsyndromic oral clefts and associated risk factors in the state of Bahia, Brazil","volume":"22","author":"Maranh\u00e3o","year":"2021","journal-title":"Eur Arch Paediatr Dent"},{"key":"R24-20260703","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.jdent.2011.10.002","article-title":"Parental age as a risk factor for non-syndromic oral clefts: A meta-analysis","volume":"40","author":"Herkrath","year":"2012","journal-title":"J Dent"},{"key":"R26-20260703","first-page":"78","article-title":"Family history and risk factors for cleft lip and palate patients and their associated anomalies","volume":"19","author":"Jamilian","year":"2017","journal-title":"Stomatologija"},{"key":"R27-20260703","doi-asserted-by":"crossref","first-page":"e54726","DOI":"10.1371\/journal.pone.0054726","article-title":"A survey of congenital heart disease and other organic malformations associated with different types of orofacial clefts in Eastern China","volume":"8","author":"Sun","year":"2013","journal-title":"PLoS One"},{"key":"R28-20260703","first-page":"472","article-title":"Risk factors of non-syndromic orofacial clefts in Sudan during 2016-2017","volume":"9","author":"Ali","year":"2019","journal-title":"Ann Med Health Sci Res"},{"key":"R29-20260703","doi-asserted-by":"crossref","first-page":"e07957","DOI":"10.1016\/j.heliyon.2021.e07957","article-title":"Distribution and risk factors of cleft lip and palate on patients from a sample of Damascus hospitals \u2013 A case-control study","volume":"7","author":"Nahas","year":"2021","journal-title":"Heliyon"},{"key":"R30-20260703","doi-asserted-by":"crossref","first-page":"118","DOI":"10.4183\/aeb.2019.118","article-title":"Gestational diabetes mellitus and the development of cleft lip\/palate in newborns","volume":"5","author":"Kozma","year":"2019","journal-title":"Acta Endocrinol (Buchar)"},{"key":"R31-20260703","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1111\/j.1601-0825.2011.01810.x","article-title":"Maternal malnutrition, environmental exposure during pregnancy and the risk of non-syndromic orofacial clefts","volume":"17","author":"Jia","year":"2011","journal-title":"Oral Dis"},{"key":"R32-20260703","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.mrrev.2004.02.001","article-title":"Genotoxicity of tobacco smoke and tobacco smoke condensate: A review","volume":"567","author":"DeMarini","year":"2004","journal-title":"Mutat Res"},{"key":"R33-20260703","doi-asserted-by":"crossref","first-page":"e66","DOI":"10.1542\/peds.104.6.e66","article-title":"Dose-dependent effect of folic acid on the prevention of orofacial clefts","volume":"104","author":"Czeizel","year":"1999","journal-title":"Pediatrics"},{"key":"R34-20260703","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1002\/pds.2179","article-title":"Maternal use of antibiotics and the risk of orofacial clefts: A nationwide cohort study","volume":"21","author":"M\u00f8lgaard-Nielsen","year":"2012","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"R37-20260703","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1016\/j.jcms.2018.05.006","article-title":"Non-syndromic cleft lip and\/or cleft palate: Epidemiology and risk factors in Lubumbashi (DR Congo), a case-control study","volume":"46","author":"Mbuyi-Musanzayi","year":"2018","journal-title":"J Craniomaxillofac Surg"},{"key":"R38-20260703","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.bbi.2021.03.025","article-title":"Maternal allergic inflammation in rats impacts the offspring perinatal neuroimmune milieu and the development of social play, locomotor behavior, and cognitive flexibility","volume":"95","author":"Breach","year":"2021","journal-title":"Brain Behav Immun"}],"container-title":["Annals of Maxillofacial Surgery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.4103\/ams.ams_180_25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T18:56:54Z","timestamp":1786647414000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.4103\/ams.ams_180_25"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.4103\/ams.ams_180_25","relation":{},"ISSN":["2231-0746","2249-3816"],"issn-type":[{"value":"2231-0746","type":"print"},{"value":"2249-3816","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"2025-09-03","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-29","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}