The molecular basis of non-syndromic orofacial clefts and tooth agenesis


  • Agnieszka Danuta Gaczkowska Śląski Uniwersytet Medyczny w Katowicach; Wydział Lekarski z Oddziałem Lekarsko-Dentystycznym w Zabrzu; Katedra Anestezjologii, Intensywnej Terapii i Medycyny Ratunkowej
  • Paweł Piotr Jagodziński
  • Adrianna Mostowska



orofacial clefts, tooth agenesis, etiology, candidate genes


Non-syndromic orofacial clefts and tooth agenesis are two of the most common craniofacial birth defects. Both of them have a complex etiology, with genetic and environmental factors involved. Additionally, the epigenetic modifications have been implicated in the pathogenesis of these structural malformations. Despite an increasing number of research studies, using a variety of methodological approaches, the role of genetic factors in the etiology of orofacial clefts and tooth agenesis is still not well elucidated. The most consistent findings across studies concerning the genetic factors influencing the risk to orofacial clefts include the association of polymorphic variants of the IRF6 gene and the chromosomal locus 8q24.21. The major candidate gene for tooth agenesis in the European populations is WNT10A; its pathogenic mutations are present in more than 50% of patients with this dental anomaly. It has been found that both orofacial clefts and tooth agenesis, which co-occurrence is often reported, may share common candidate genes.


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Mossey PA, Little J, Munger RG, Dixon MJ, Shaw WC. Cleft lip and palate. Lancet. 2009 Nov 21;374(9703):1773–1785.

Polder BJ, Van't Hof MA, Van der Linden FP, Kuijpers-Jagtman AM. A meta-analysis of the prevalence of dental agenesis of permanent teeth. Community Dent Oral Epidemiol. 2004 Jun;32(3):217–226.

Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet. 2011 Mar;12(3):167–178.

Vieira AR. Oral clefts and syndromic forms of tooth agenesis as models for genetics of isolated tooth agenesis. J Dent Res. 2003 Mar;82(3):162–165.

Phan M, Conte F, Khandelwal KD, Ockeloen CW, Bartzela T, Kleefstra T, et al. Tooth agenesis and orofacial clefting: genetic brothers in arms? Hum Genet. 2016 Dec;135(12):1299–1327.

Tannure PN, Oliveira CA, Maia LC, Vieira AR, Granjeiro JM, Costa Mde C. Prevalence of dental anomalies in nonsyndromic individuals with cleft lip and palate: a systematic review and meta-analysis. Cleft Palate Craniofac J. 2012 Mar;49(2):194–200.

Bartzela TN, Carels CE, Bronkhorst EM, Kuijpers-Jagtman AM. Tooth agenesis patterns in unilateral cleft lip and palate in humans. Arch Oral Biol. 2013 Jun;58(6):596–602.

Slayton RL, Williams L, Murray JC, Wheeler JJ, Lidral AC, Nishimura CJ. Genetic association studies of cleft lip and/or palate with hypodontia outside the cleft region. Cleft Palate Craniofac J. 2003 May;40(3):274–279.

Yin W, Bian Z. The Gene Network Underlying Hypodontia. J Dent Res. 2015 Jul;94(7):878–885.

Wang J, Sun K, Shen Y, Xu Y, Xie J, Huang R, et al. DNA methylation is critical for tooth agenesis: implications for sporadic non-syndromic anodontia and hypodontia. Sci Rep. 2016 Jan 13;6:19162.

Leslie EJ, Marazita ML. Genetics of cleft lip and cleft palate. Am J Med Genet C Semin Med Genet. 2013 Nov;163C(4):246–258.

Rahimov F, Marazita ML, Visel A, Cooper ME, Hitchler MJ, Rubini M, et al. Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip. Nat Genet. 2008 Nov;40(11):1341–1347.

Mostowska A, Hozyasz KK, Wojcicki P, Biedziak B, Paradowska P, Jagodzinski PP. Association between genetic variants of reported candidate genes or regions and risk of cleft lip with or without cleft palate in the polish population. Birth Defects Res A Clin Mol Teratol. 2010 Jul;88(7):538–545.

Thieme F, Ludwig KU. The Role of Noncoding Genetic Variation in Isolated Orofacial Clefts. J Dent Res. 2017 Oct;96(11):1238–1247.

Richardson RJ, Dixon J, Jiang R, Dixon MJ. Integration of IRF6 and Jagged2 signalling is essential for controlling palatal adhesion and fusion competence. Hum Mol Genet. 2009 Jul 15;18(14):2632–2642.

Krasone K, Lace B, Akota I, Care R, Deeley K, Küchler EC, et al. IRF6 AP-2a binding site promoter polymorphism is associated with oral clefts in Latvia. Stomatologija. 2014;16(4):132–136.

Vieira AR, Modesto A, Meira R, Barbosa AR, Lidral AC, Murray JC. Interferon regulatory factor 6 (IRF6) and fibroblast growth factor receptor 1 (FGFR1) contribute to human tooth agenesis. Am J Med Genet A. 2007 Mar 15;143A(6):538–545.

Vieira AR, McHenry TG, Daack-Hirsch S, Murray JC, Marazita ML. Candidate gene/loci studies in cleft lip/palate and dental anomalies finds novel susceptibility genes for clefts. Genet Med. 2008 Sep;10(9):668–674.

Birnbaum S, Ludwig KU, Reutter H, Herms S, Steffens M, Rubini M, et al. Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24. Nat Genet. 2009 Apr;41(4):473–477.

Murray T, Taub MA, Ruczinski I, Scott AF, Hetmanski JB, Schwender H, et al. Examining markers in 8q24 to explain differences in evidence for association with cleft lip with/without cleft palate between Asians and Europeans. Genet Epidemiol. 2012 May;36(4):392–399.

Uslu VV, Petretich M, Ruf S, Langenfeld K, Fonseca NA, Marioni JC, et al. Long-range enhancers regulating Myc expression are required for normal facial morphogenesis. Nat Genet. 2014 Jul;46(7):753–758.

Yildirim M, Seymen F, Deeley K, Cooper ME, Vieira AR. Defining predictors of cleft lip and palate risk. J Dent Res. 2012 Jun;91(6):556–561.

van den Boogaard MJ, Créton M, Bronkhorst Y, van der Hout A, Hennekam E, Lindhout D, et al. Mutations in WNT10A are present in more than half of isolated hypodontia cases. J Med Genet. 2012 May;49(5):327–331.

Mostowska A, Biedziak B, Zadurska M, Dunin-Wilczynska I, Lianeri M, Jagodzinski PP. Nucleotide variants of genes encoding components of the Wnt signalling pathway and the risk of non-syndromic tooth agenesis. Clin Genet. 2013 Nov;84(5):429–440.

MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009 Jul;17(1):9–26.

Feng C, Duan W, Zhang D, Zhang E, Xu Z, Lu L. C392T polymorphism of the Wnt10a gene in non-syndromic oral cleft in a northeastern Chinese population. Br J Oral Maxillofac Surg. 2014 Oct;52(8):751–755.

Chiquet BT, Blanton SH, Burt A, Ma D, Stal S, Mulliken JB, et al. Variation in WNT genes is associated with non-syndromic cleft lip with or without cleft palate. Hum Mol Genet. 2008 Jul 15;17(14):2212–2218.

Mostowska A, Hozyasz KK, Biedziak B, Wojcicki P, Lianeri M, Jagodzinski PP. Genotype and haplotype analysis of WNT genes in non-syndromic cleft lip with or without cleft palate. Eur J Oral Sci. 2012 Feb;120(1):1–8.

Jezewski PA, Vieira AR, Nishimura C, Ludwig B, Johnson M, O'Brien SE, et al. Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate. J Med Genet. 2003 Jun;40(6):399–407.

Nakatomi M, Wang XP, Key D, Lund JJ, Turbe-Doan A, Kist R, et al. Genetic interactions between Pax9 and Msx1 regulate lip development and several stages of tooth morphogenesis. Dev Biol. 2010 Apr 15;340(2):438–449.

Satokata I, Maas R. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat Genet. 1994 Apr;6(4):348–356.

Peters H, Neubüser A, Kratochwil K, Balling R. Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes Dev. 1998 Sep 1;12(17):2735–2747.

Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F. Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol. 2002 Feb;22(4):1172–1183.

Letra A, Menezes R, Granjeiro JM, Vieira AR. Defining subphenotypes for oral clefts based on dental development. J Dent Res. 2007 Oct;86(10):986–991.




How to Cite

Gaczkowska AD, Jagodziński PP, Mostowska A. The molecular basis of non-syndromic orofacial clefts and tooth agenesis. JMS [Internet]. 2017 Dec. 30 [cited 2024 Jun. 21];86(4):321-4. Available from:



Thousand words about...
Received 2017-11-25
Accepted 2017-12-07
Published 2017-12-30