Prevalence of WNT10A gene mutations in non-syndromic oligodontia
Non-syndromic oligodontia is an infrequent clinical condition whose etiology is not yet completely understood being a wide spectrum of gene mutations described in concomitance with this severe form of tooth agenesis. Recently, multiple observations have linked up to 50% of cases with isolated hypodontia to mutations in the WNT10A gene. Here, we hypothesized that mutations in the WNT10A gene could also be present in families affected by non-syndromic oligodontia.
Material and methods
All available patients with non-syndromic oligodontia (n = 20) treated at the Department of Orthodontics, University of Giessen, Germany between 1986 and 2013 as well as their family members were analyzed for mutations in the WNT10A gene.
Mutation screening was positive in 50% of the 20 patients. The analysis revealed that the mutations 2:219755011(c.682T>TA)(p.F228I), 2:219754822(c.493G>GA)(p.G165R), 2:219754816(c.487C>CT)(p.R163W), and 2:219747090(c.321C>CA)(p.C107*), the novel missense mutation 2:219757676(c.937G/GT)(p.G313C), and the novel synonym variant 2:219754854(c.525C>CT)(p.H175H) were present.
Multiple phenotypes are found in individuals presenting mutations in the WNT10A gene. Among them, the stop codon p.C107* as well as the biallelic p.F228I variants correlate with the most severe oligodontia phenotypes. In addition, we diagnosed the monoallelic mutations p.F228I, p.G165R, and p.G313C in healthy relatives with normal dentitions.
A correct diagnosis of non-syndromic oligodontia is fundamental to discard a possible underlying pathology in which multiple tooth agenesis could be the most evidential clinical sign. Due to the wide spectrum of pathologies that are associated to mutations in the WNT10A gene, an extended genetic analysis of these individuals’ relatives is also essential.
KeywordsNon-syndromic oligodontia WNT10A Gene Mutation Pedigree Analysis
We sincerely thank the patients and their family members for their participation in the study; the German Orthodontic Society (DGKFO) for funding our research; Prof. D. Nolte, Department of Human Genetics, Justus-Liebig University, Giessen; and Dr. C. Grünig, Microsynth AG, Balgach, Switzerland, for the helpful discussions during the analysis of results.
The work was supported by the German Orthodontic Society (DGKFO).
Compliance with ethical standards
Conflict of interest
Author A declares that she has no conflict of interest. Author B declares that she has no conflict of interest. Author C declares that he has no conflict of interest. Author D declares that she has no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Medical Faculty, University of Giessen, Germany, file number 122/12) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Written informed consent was obtained from all individual participants or, in case of minors, from their parents.
- 6.Ockeloen CW, Khandelwal KD, Dreesen K, Ludwig KU, Sullivan R, van Rooij IA, Thonissen M, Swinnen S, Phan M, Conte F, Ishorst N, Gilissen C, Roa Fuentes L, van de Vorst M, Henkes A, Steehouwer M, van Beusekom E, Bloemen M, Vankeirsbilck B, Berge S, Hens G, Schoenaers J, Van der Poorten V, Roosenboom J, Verdonck A, Devriendt K, Roeleveldt N, Jhangiani SN, Vissers LE, Lupski JR, de Ligt J, Von den Hoff JW, Pfundt R, Brunner HG, Zhou H, Dixon J, Mangold E, van Bokhoven H, Dixon MJ, Kleefstra T, Hoischen A, Carels CE (2016) Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis. Genetics in Medicine 18:1158–1162. https://doi.org/10.1038/gim.2016.10 CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Liu F, Chu EY, Watt B, Zhang Y, Gallant NM, Andl T, Yang SH, Lu MM, Piccolo S, Schmidt-Ullrich R, Taketo MM, Morrisey EE, Atit R, Dlugosz AA, Millar SE (2008) Wnt/beta-catenin signaling directs multiple stages of tooth morphogenesis. Dev Biol 313:210–224. https://doi.org/10.1016/j.ydbio.2007.10.016 CrossRefPubMedGoogle Scholar
- 10.Yamashiro T, Zheng L, Shitaku Y, Saito M, Tsubakimoto T, Takada K, Takano- Yamamoto T, Thesleff I (2007) Wnt10a regulates dentin sialophosphoprotein mRNA expression and possibly links odontoblast differentiation and tooth morphogenesis. Differentiation 75:452–462. https://doi.org/10.1111/j.1432-0436.2006.00150.x CrossRefPubMedGoogle Scholar
- 12.Bohring A, Stamm T, Spaich C, Haase C, Spree K, Hehr U, Hoffmann M, Ledig S, Sel S, Wieacker P, Ropke A (2009) WNT10A mutations are a frequent cause of a broad spectrum of ectodermal dysplasias with sex-biased manifestation pattern in heterozygotes. Am J Hum Genet 85:97–105. https://doi.org/10.1016/j.ajhg.2009.06.001 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Cluzeau C, Hadj-Rabia S, Jambou M, Mansour S, Guigue P, Masmoudi S, Bal E, Chassaing N, Vincent MC, Viot G, Clauss F, Maniere MC, Toupenay S, Le Merrer M, Lyonnet S, Cormier-Daire V, Amiel J, Faivre L, de Prost Y, Munnich A, Bonnefont JP, Bodemer C, Smahi A (2011) Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases. Hum Mutat 32:70–72. https://doi.org/10.1002/humu.21384 CrossRefPubMedGoogle Scholar
- 23.Machida J, Goto H, Tatematsu T, Shibata A, Miyachi H, Takahashi K, Izumi H, Nakayama A, Shimozato K, Tokita Y (2017) WNT10A variants isolated from Japanese patients with congenital tooth agenesis. Human Genome Variation 4:17047. https://doi.org/10.1038/hgv.2017.47 CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Vink CP, Ockeloen CW, ten Kate S, Koolen DA, Ploos van Amstel JK, Kuijpers-Jagtman AM, van Heumen CC, Kleefstra T, Carels CE (2014) Variability in dentofacial phenotypes in four families with WNT10A mutations. Eur J Hum Genet 22:1063–1070. https://doi.org/10.1038/ejhg.2013.300 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Yuan Q, Zhao M, Tandon B, Maili L, Liu X, Zhang A, Baugh EH, Tran T, Silva RM, Hecht JT, Swindell EC, Wagner DS, Letra A (2017) Role of WNT10A in failure of tooth development in humans and zebrafish. Molecular Genetics & Genomic Medicine 5:730–741. https://doi.org/10.1002/mgg3.332 CrossRefGoogle Scholar
- 32.Yang J, Wang SK, Choi M, Reid BM, Hu Y, Lee YL, Herzog CR, Kim-Berman H, Lee M, Benke PJ, Lloyd KC, Simmer JP, Hu JC (2015) Taurodontism, variations in tooth number, and misshapened crowns in Wnt10a null mice and human kindreds. Molecular Genetics & Genomic Medicine 3:40–58. https://doi.org/10.1002/mgg3.111 CrossRefGoogle Scholar
- 35.Dinckan N, Du R, Petty LE, Coban-Akdemir Z, Jhangiani SN, Paine I, Baugh EH, Erdem AP, Kayserili H, Doddapaneni H, Hu J, Muzny DM, Boerwinkle E, Gibbs RA, Lupski JR, Uyguner ZO, Below JE, Letra A (2018) Whole-exome sequencing identifies novel variants for tooth agenesis. Journal of Dent Research 97:49–59. https://doi.org/10.1177/0022034517724149 CrossRefGoogle Scholar
- 36.Haddaji Mastouri M, De Coster P, Zaghabani A, Jammali F, Raouahi N, Ben Salem A, Saad A, Coucke P, H’Mida Ben Brahim D (2018) Genetic study of non-syndromic tooth agenesis through the screening of paired box 9, msh homeobox 1, axin 2, and Wnt family member 10A genes: a case-series. European Journal of Oral Sciences 126:24–32. https://doi.org/10.1111/eos.12391 CrossRefPubMedGoogle Scholar
- 37.Tardieu C, Jung S, Niederreither K, Prasad M, Hadj-Rabia S, Philip N, Mallet A, Consolino E, Sfeir E, Noueiri B, Chassaing N, Dollfus H, Manière MC, Bloch-Zupan A, Clauss F (2017) Dental and extra-oral clinical features in 41 patients with WNT10A gene mutations: a multicentric genotype-phenotype study. Clin Genet 92:477–486. https://doi.org/10.1111/cge.12972 CrossRefPubMedGoogle Scholar
- 39.Salvi A, Giacopuzzi E, Bardellini E, Amadori F, Ferrari L, De Petro G, Borsani G, Majorana A (2016) Mutation analysis by direct and whole exome sequencing in familial and sporadic tooth agenesis. Int J Mol Med 38:1338–1348. https://doi.org/10.3892/ijmm.2016.2742 CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Plaisancie J, Bailleul-Forestier I, Gaston V, Vaysse F, Lacombe D, Holder- Espinasse M, Abramowicz M, Coubes C, Plessis G, Faivre L, Demeer B, Vincent- Delorme C, Dollfus H, Sigaudy S, Guillen-Navarro E, Verloes A, Jonveaux P, Martin- Coignard D, Colin E, Bieth E, Calvas P, Chassaing N (2013) Mutations in WNT10A are frequently involved in oligodontia associated with minor signs of ectodermal dysplasia. Am J Med Genet A 161A:671–678. https://doi.org/10.1002/ajmg.a.35747. CrossRefPubMedGoogle Scholar
- 41.Castori M, Castiglia D, Brancati F, Foglio M, Heath S, Floriddia G, Madonna S, Fischer J, Zambruno G (2011) Two families confirm Schopf-Schulz-Passarge syndrome as a discrete entity within the WNT10A phenotypic spectrum. Clin Genet 79:92–95. https://doi.org/10.1111/j.1399-0004.2010.01513.x CrossRefPubMedGoogle Scholar
- 42.Kroigard AB, Clemmensen O, Gjorup H, Hertz JM, Bygum A (2016) Odonto-onycho-dermal dysplasia in a patient homozygous for a WNT10A nonsense mutation and mild manifestations of ectodermal dysplasia in carriers of the mutation. BMC Dermatol 16:3. https://doi.org/10.1186/s12895-016-0040-7 CrossRefPubMedPubMedCentralGoogle Scholar
- 45.Dhamo B, Fennis W, Creton M, Vucic S, Cune M, Ploos van Amstel HK, Wolvius EB, van den Boogaard MJ, Ongkosuwito EM (2016) The association between WNT10A variants and dental development in patients with isolated oligodontia. Eur J Hum Genet 25:59–65. https://doi.org/10.1038/ejhg.2016.117 CrossRefPubMedPubMedCentralGoogle Scholar