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The WNT10A gene in ectodermal dysplasias and selective tooth agenesis.

ABSTRACT: Mutations in the WNT10A gene were first detected in the rare syndrome odonto-onycho-dermal dysplasia (OODD, OMIM257980) but have now also been found to cause about 35-50% of selective tooth agenesis (STHAG4, OMIM150400), a common disorder that mostly affects the permanent dentition. In our random sample of tooth agenesis patients, 40% had at least one mutation in the WNT10A gene. The WNT10A Phe228Ile variant alone reached an allele frequency of 0.21 in the tooth agenesis cohort, about 10 times higher than the allele frequency reported in large SNP databases for Caucasian populations. Patients with bi-allelic WNT10A mutations have severe tooth agenesis while heterozygous individuals are either unaffected or have a mild phenotype. Mutations in the coding areas of the WNT10B gene, which is co-expressed with WNT10A during odontogenesis, and the WNT6 gene which is located at the same chromosomal locus as WNT10A in humans, do not contribute to the tooth agenesis phenotype.

SUBMITTER: Mues G

PROVIDER: S-EPMC4167166 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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The WNT10A gene in ectodermal dysplasias and selective tooth agenesis.

Mues Gabriele G Bonds John J Xiang Lilin L Vieira Alexandre R AR Seymen Figen F Klein Ophir O D'Souza Rena N RN

American journal of medical genetics. Part A 20140403 10

Mutations in the WNT10A gene were first detected in the rare syndrome odonto-onycho-dermal dysplasia (OODD, OMIM257980) but have now also been found to cause about 35-50% of selective tooth agenesis (STHAG4, OMIM150400), a common disorder that mostly affects the permanent dentition. In our random sample of tooth agenesis patients, 40% had at least one mutation in the WNT10A gene. The WNT10A Phe228Ile variant alone reached an allele frequency of 0.21 in the tooth agenesis cohort, about 10 times h ...[more]

PMID: 24700731

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Project description:Tooth agenesis is one of the most common orodental anomalies that demonstrate phenotypic and genotypic heterogeneity with a prevalence of 2.5%-7%. Mutations in WNT10A have been proposed to be the most common cause of nonsyndromic tooth agenesis (NSTA). The aim of this study was to characterize the dental features and genetic variants of NSTA in a Thai population. We recruited 13 unrelated patients with NSTA who attended the Faculty of Dentistry, Chulalongkorn University, Thailand, from 2017 to 2019. All 13 underwent whole exome sequencing that identified likely pathogenic genetic variants, all in WNT10A, in five patients. All five patients had second premolar agenesis, while three also had absent or peg-shaped upper lateral incisors. Patient 1 possessed a novel heterozygous duplication, c.916_918dupAAC (p.Asn306dup) in WNT10A. Patients 2 and 3 harbored a heterozygous and homozygous c.637G > A (p.Gly213Ser) in WNT10A, respectively. Patients 4 possessed a heterozygous c.511C > T (p.Arg171Cys) in WNT10A. Patient 5 harbored a homozygous c.511C > T (p.Arg171Cys) in WNT10A and a novel heterozygous c.413A > T (p.Asn138Ile) in EDARADD, suggesting digenic inheritance. We recruited another 18 family members of these five patients. Out of 23 participants, homozygous WNT10A variants were identified in 2 patients and heterozygous variants in 17 individuals. Both homozygous patients had NSTA. Eight out of 17 heterozygous individuals (8/17) had NSTA or a peg-shaped lateral incisor, indicating a 47% penetrance of the heterozygous variants or 53% (10/19) penetrance of either homozygous or heterozygous variants in WNT10A. The frequencies of the c.511C > T in our in-house 1,876 Thai exome database, Asian populations, and non-Asian populations were 0.016, 0.005-0.033, and 0.001, respectively; while those of the c.637G > A were 0.016, 0.004-0.029, and 0.000, respectively. In conclusion, our study reports two novel variants with one each in WNT10A and EDARADD, expanding the genotypic spectra of NSTA. Second premolar agenesis is a common phenotype in affected individuals with variants in WNT10A; however, its penetrance is incomplete. Lastly, the different frequencies of WNT10A variants, c.511C > T and c.637G > A, in diverse populations might contribute to the prevalence range of NSTA between continents.

Project description:The dental abnormalities are the typical features of many ectodermal dysplasias along with congenital malformations of nails, skin, hair, and sweat glands. However, several reports of non-syndromic/isolated tooth agenesis have also been found in the literature. The characteristic features of hypohidrotic ectodermal dysplasia (HED) comprise of hypodontia/oligodontia, along with hypohidrosis/anhidrosis, and hypotrichosis. Pathogenic variants in EDA, EDAR, EDARADD, and TRAF6, cause the phenotypic expression of HED. Genetic alterations in EDA and WNT10A cause particularly non-syndromic/isolated oligodontia. In the current project, we recruited 57 patients of 17 genetic pedigrees (A-Q) from different geographic regions of the world, including Pakistan, Egypt, Saudi Arabia, and Syria. The molecular investigation of different syndromic and non-syndromic dental conditions, including hypodontia, oligodontia, generalized odontodysplasia, and dental crowding was carried out by using exome and Sanger sequencing. We have identified a novel missense variant (c.311G>A; p.Arg104His) in WNT10A in three oligodontia patients of family A, two novel sequence variants (c.207delinsTT, p.Gly70Trpfs*25 and c.1300T>G; p.Try434Gly) in EDAR in three patients of family B and four patients of family C, respectively. To better understand the structural and functional consequences of missense variants in WNT10A and EDAR on the stability of the proteins, we have performed extensive molecular dynamic (MD) simulations. We have also identified three previously reported pathogenic variants (c.1076T>C; p.Met359Thr), (c.1133C>T; p.Thr378Met) and (c.594_595insC; Gly201Argfs*39) in EDA in family D (four patients), E (two patients) and F (one patient), correspondingly. Presently, our data explain the genetic cause of 18 syndromic and non-syndromic tooth agenesis patients in six autosomal recessive and X-linked pedigrees (A-F), which expand the mutational spectrum of these unique clinical manifestations.

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The WNT10A gene in ectodermal dysplasias and selective tooth agenesis.

Publications

The WNT10A gene in ectodermal dysplasias and selective tooth agenesis.

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