{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:14:59Z","timestamp":1753892099881,"version":"3.41.2"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T00:00:00Z","timestamp":1614297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Nonsyndromic cleft lip and or without cleft palate (NSCL\/P) with the hypodontia is a common developmental abnormality in humans and animals. This study identified the genetic aberration involved in both NSCL\/P and hypodontia pathogenesis. A cross-sectional study using genome-wide study copy number variation-targeted CytoScan 750K array carried out on salivary samples from 61 NSCL\/P and 20 noncleft with and without hypodontia Malay subjects aged 7\u201313 years old. Copy number variations (CNVs) of <jats:italic>SKI<\/jats:italic> and fragile histidine triad (<jats:italic>FHIT<\/jats:italic>) were identified in NSCL\/P and noncleft children using quantitative polymerase chain reaction (qPCR) as a validation analysis. Copy number calculated (CNC) for each gene determined with Applied Biosystems CopyCaller Software v2.0. The six significant CNVs included gains (12q14.3, 15q26.3, 1p36.32, and 1p36.33) and losses (3p14.2 and 4q13.2) in NSCL\/P with hypodontia patients compared with the NSCL\/P only. The genes located in these regions encoded <jats:italic>LEMD3<\/jats:italic>, <jats:italic>IGF1R<\/jats:italic>, <jats:italic>TP73<\/jats:italic>, <jats:italic>SKI<\/jats:italic>, <jats:italic>FHIT<\/jats:italic>, and <jats:italic>UGT2\u03b215<\/jats:italic>. There were a significant gain and loss of both <jats:italic>SKI<\/jats:italic> and <jats:italic>FHIT<\/jats:italic> copy number in NSCL\/P with hypodontia compared with the noncleft group (<jats:italic>p<\/jats:italic> &amp;lt; 0.05). The results supported that CNVs significantly furnish to the development of NSCL\/P with hypodontia.<\/jats:p>","DOI":"10.3389\/fphys.2021.637306","type":"journal-article","created":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T05:44:04Z","timestamp":1614318244000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification of Copy Number Variation Among Nonsyndromic Cleft Lip and or Without Cleft Palate With Hypodontia: A Genome-Wide Association Study"],"prefix":"10.3389","volume":"12","author":[{"given":"Norliana","family":"Ghazali","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Normastura","family":"Abd Rahman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Azlina","family":"Ahmad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarina","family":"Sulong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thirumulu Ponnuraj","family":"Kannan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,26]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"75","DOI":"10.9790\/0853-1601057585.","article-title":"Aetiological factors article in IOSR","volume":"16","author":"Abdulgani","year":"2017","journal-title":"J. Dent. Med. Sci."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"9378325","DOI":"10.1155\/2017\/9378325","article-title":"Hypodontia: an update on its etiology, classification, and clinical management","volume":"2017","author":"Al-Ani","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.sdentj.2014.11.007","article-title":"The prevalence of specific dental anomalies in a group of Saudi cleft lip and palate patients","volume":"27","author":"Al-Kharboush","year":"2015","journal-title":"Saudi Dent. J."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2029","DOI":"10.1101\/gad.11.16.2029","article-title":"Mice lacking the ski proto-oncogene have defects in neurulation, craniofacial patterning, and skeletal muscle development","volume":"11","author":"Berk","year":"1997","journal-title":"Genes Dev."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1002\/bdra.20488","article-title":"Genome-wide pathway analysis of folate-responsive genes to unravel the pathogenesis of orofacial clefting in man","volume":"82","author":"Bliek","year":"2008","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1593\/neo.03442","article-title":"Amplification of SKI is a prognostic marker in early colorectal cancer","volume":"6","author":"Buess","year":"2004","journal-title":"Neoplasia"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1111\/j.1365-263X.2010.01063.x","article-title":"Maxillary dental anomalies in children with cleft lip and palate: a controlled study","volume":"20","author":"Camporesi","year":"2010","journal-title":"Int. J. Paediatr. Dent."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s00439-015-1606-x","article-title":"Systematic analysis of copy number variants of a large cohort of orofacial cleft patients identifies candidate genes for orofacial clefts","volume":"135","author":"Conte","year":"2016","journal-title":"Hum. Genet."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/cr.2008.324","article-title":"Ski and SnoN, potent negative regulators of TGF-\u03b2 signaling","volume":"19","author":"Deheuninck","year":"2009","journal-title":"Cell Res."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1097\/GIM.0b013e318197a49a","article-title":"Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome","volume":"11","author":"de Lima","year":"2009","journal-title":"Genet. Med."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1159\/000184688","article-title":"Human genes involved in copy number variation: mechanisms of origin, functional effects and implications for disease","volume":"123","author":"De Smith","year":"2008","journal-title":"Cytogenet. Genome Res."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"34","DOI":"10.5195\/D3000.2016.57","article-title":"Association of AXIN2 gene polymorphisms with non-syndromic oligodontia in Turkish families","volume":"3000","author":"Dinckan","year":"2016","journal-title":"Dentistry"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1038\/ng.2421","article-title":"Mutations in the TGF-\u03b2 repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm","volume":"44","author":"Doyle","year":"2012","journal-title":"Nat. Genet."},{"key":"ref52","first-page":"55","article-title":"Common dental anomalies in cleft lip and palate patients","volume":"22","author":"Haque","year":"2015","journal-title":"Malays. J. Med. Sci."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"3128","DOI":"10.1242\/dev.139907","article-title":"Wnt\/\u03b2-catenin signaling via Axin 2 is required for myogenesis and, together with YAP\/Taz and Tead1, active in IIa\/IIx muscle fibers","volume":"143","author":"Huraskin","year":"2016","journal-title":"Development"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"325947","DOI":"10.4061\/2011\/325947","article-title":"Multiple patterns of FHIT gene homozygous deletion in Egyptian breast cancer patients","volume":"2011","author":"Ismail","year":"2011","journal-title":"Int. J. Breast Cancer"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1111\/j.1601-0825.2011.01806.x","article-title":"The mechanism of TGF-\u03b2 signaling during palate development","volume":"17","author":"Iwata","year":"2011","journal-title":"Oral Dis."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"a008425","DOI":"10.1101\/cshperspect.a008425","article-title":"Signaling networks regulating tooth organogenesis and regeneration, and the specification of dental mesenchymal and epithelial cell lineages","volume":"4","author":"Jussila","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1186\/s12943-017-0749-x","article-title":"Impact of FHIT loss on the translation of cancer-associated mRNAs","volume":"16","author":"Kiss","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1002\/ajmg.c.31382","article-title":"Developmental disorders of the dentition: an update","volume":"163","author":"Klein","year":"2013","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/ng985","article-title":"Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes","volume":"32","author":"Kondo","year":"2002","journal-title":"Nat. Genet."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"636","DOI":"10.5167\/uzh-50358","article-title":"The genetic basis of craniofacial and dental abnormalities","volume":"121","author":"Kouskoura","year":"2011","journal-title":"Schweiz. Monatsschr. Zahnmed."},{"key":"ref21","first-page":"1","article-title":"Genetics of cleft lip and palate\u2013is it still patchy","volume":"2","author":"Lakhanpal","year":"2014","journal-title":"JSM Dent."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1002\/ajmg.c.31381","article-title":"Genetics of cleft lip and cleft palate","author":"Leslie","year":"2013","journal-title":"Am. J. Med. Genet. C: Semin. Med. Genet."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"e45441","DOI":"10.1371\/journal.pone.0045441","article-title":"Interaction between IRF6 and TGFA genes contribute to the risk of nonsyndromic cleft lip\/palate","volume":"7","author":"Letra","year":"2012","journal-title":"PLoS One"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1002\/bdra.20489","article-title":"AXIN2 and CDH1 polymorphisms, tooth agenesis, and oral clefts","volume":"85","author":"Letra","year":"2009","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1111\/j.1600-0722.2012.00965.x","article-title":"Novel nonsense mutation in MSX 1 causes tooth agenesis with cleft lip in a Chinese family","volume":"120","author":"Liang","year":"2012","journal-title":"Eur. J. Oral Sci."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/ng1511","article-title":"A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2","volume":"37","author":"Loeys","year":"2005","journal-title":"Nat. Genet."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1016\/j.ymgme.2005.06.003","article-title":"Genetic variation in the proto-oncogene SKI and risk for orofacial clefting","volume":"86","author":"Lu","year":"2005","journal-title":"Mol. Genet. Metab."},{"key":"ref26","first-page":"968","article-title":"Genome-wide meta-analyses of non-syndromic cleft lip with or without cleft palate identify six new risk loci","volume-title":"Nat. Genet.","author":"Ludwig","year":"2012"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"8197","DOI":"10.7314\/APJCP.2015.16.18.8197","article-title":"FHIT gene expression in acute lymphoblastic leukemia and its clinical significance","volume":"16","author":"Malak","year":"2016","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1016\/j.ydbio.2010.01.031","article-title":"Genetic interactions between Pax9 and Msx1 regulate lip development and several stages of tooth morphogenesis","volume":"340","author":"Nakatomi","year":"2010","journal-title":"Dev. Biol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-018-22823-7","article-title":"The dynamics of TGF-\u03b2 in dental pulp, odontoblasts and dentin","volume":"8","author":"Niwa","year":"2018","journal-title":"Sci. Rep."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41405-019-0022-z","article-title":"Variations in AXIN2 predict risk and prognosis of colorectal cancer","volume":"5","author":"Otero","year":"2019","journal-title":"BDJ open"},{"key":"ref31","first-page":"60","article-title":"Roles of BMP signaling pathway in lip and palate development","volume-title":"Frontiers of oral biology.","author":"Parada","year":"2012"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"232","DOI":"10.4161\/cbt.73","article-title":"FHIT as tumor suppressor: mechanisms and therapeutic opportunities","volume":"1","author":"Pekarsky","year":"2002","journal-title":"Cancer Biol. Ther."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1007\/s00439-016-1733-z","article-title":"Tooth agenesis and orofacial clefting: genetic brothers in arms?","volume":"135","author":"Phan","year":"2016","journal-title":"Hum. Genet."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1186\/gb-2010-11-8-216","article-title":"Dosage compensation and the global re-balancing of aneuploid genomes","volume":"11","author":"Prestel","year":"2010","journal-title":"Genome Biol."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1164\/rccm.201712-2553OC","article-title":"FHIT, a novel modifier gene in pulmonary arterial hypertension","volume":"199","author":"Prosseda","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref51","first-page":"41","article-title":"Dental anomalies and facial profile abnormality of the non-syndromic cleft lip and palate children in kelantan","volume":"11","author":"Rahman","year":"2004","journal-title":"Malays. J. Med. Sci."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4103\/1735-3327.150286","article-title":"Congenitally missing teeth (hypodontia): a review of the literature concerning the etiology, prevalence, risk factors, patterns and treatment","volume":"12","author":"Rakhshan","year":"2015","journal-title":"Dent. Res. J."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1038\/nature05329","article-title":"Global variation in copy number in the human genome","volume":"444","author":"Redon","year":"2006","journal-title":"Nature"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"dmm037051","DOI":"10.1242\/dmm.037051","article-title":"Wnt signaling in orofacial clefts: crosstalk, pathogenesis and models","volume":"12","author":"Reynolds","year":"2019","journal-title":"Dis. Model. Mech."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1002\/ajmg.a.33164","article-title":"Ectodermal dysplasia-like syndrome with mental retardation due to contiguous gene deletion: further clinical and molecular delineation of del(2q32) syndrome","volume":"152","author":"Rifai","year":"2010","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"345","DOI":"10.31486\/toj.18.0060","article-title":"Diagnosis of tooth agenesis in childhood and risk for neoplasms in adulthood","volume":"18","author":"Ritwik","year":"2018","journal-title":"Ochsner J."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1038\/ejhg.2014.61","article-title":"The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen\u2013Goldberg syndrome","volume":"23","author":"Schepers","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1111\/j.1399-0004.1980.tb00890.x","article-title":"Interstitial deletion of the long arm of chromosome 1, del (1)(q21-q25) in a profoundly retarded 8-year-old girl with multiple anomalies","volume":"18","author":"Schinzel","year":"1980","journal-title":"Clin. Genet."},{"key":"ref56","first-page":"81","article-title":"A preliminary gene map for the Van der Woude syndrome critical region derived from 900 kb of genomic sequence at 1q32-q41","volume":"10","author":"Schutte","year":"2000","journal-title":"Genome Res."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/jhg.2014.96","article-title":"Investigation of genetic factors underlying typical orofacial clefts: mutational screening and copy number variation","volume":"60","author":"Simioni","year":"2015","journal-title":"J. Hum. Genet."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.archoralbio.2018.08.014","article-title":"Non-syndromic tooth agenesis patterns and their association with other dental anomalies: a retrospective study","volume":"96","author":"Souza-Silva","year":"2018","journal-title":"Arch. Oral Biol."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1126\/science.1136678","article-title":"Relative impact of nucleotide and copy number variation on gene expression phenotypes","volume":"315","author":"Stranger","year":"2007","journal-title":"Science"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.jdsr.2016.04.001","article-title":"Role of the Wnt signaling molecules in the tooth","volume":"52","author":"Tamura","year":"2016","journal-title":"Jpn. Dent. Sci. Rev."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"e64","DOI":"10.1371\/journal.pgen.0010064","article-title":"Medical sequencing of candidate genes for non-syndromic cleft lip and palate","volume":"1","author":"Vieira","year":"2005","journal-title":"PLoS Genet."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1002\/ajmg.a.31620","article-title":"Interferon regulatory factor 6 (IRF6) and fibroblast growth factor receptor 1 (FGFR1) contribute to human tooth agenesis","author":"Vieira","year":"2007","journal-title":"Am. J. Med. Genet. A"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"4577","DOI":"10.1007\/s00018-014-1722-0","article-title":"The FHIT gene product: tumor suppressor and genome \"caretaker.\"","volume":"71","author":"Waters","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"20344","DOI":"10.1073\/pnas.0703664105","article-title":"The tumor suppressor Fhit acts as a repressor of \u03b2-catenin transcriptional activity","volume":"104","author":"Weiske","year":"2007","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1080\/000163599428931","article-title":"Clinical and genetic studies of Van der Woude syndrome in Sweden","volume":"57","author":"Wong","year":"1999","journal-title":"Acta Odontol. Scand."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3892\/or.2015.3961","article-title":"Ski prevents TGF-\u03b2-induced EMT and cell invasion by repressing SMAD-dependent signaling in non-small cell lung cancer","volume":"34","author":"Yang","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"14364","DOI":"10.1038\/ncomms14364","article-title":"Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity","volume":"8","author":"Yu","year":"2017","journal-title":"Nat. Commun."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.637306\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T05:44:11Z","timestamp":1614318251000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.637306\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,26]]},"references-count":59,"alternative-id":["10.3389\/fphys.2021.637306"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.637306","relation":{},"ISSN":["1664-042X"],"issn-type":[{"type":"electronic","value":"1664-042X"}],"subject":[],"published":{"date-parts":[[2021,2,26]]},"article-number":"637306"}}