Dataset Information

Phenotypic and Genotypic Features of Thai Patients With Nonsyndromic Tooth Agenesis and WNT10A Variants.

ABSTRACT: 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.

SUBMITTER: Kanchanasevee C

PROVIDER: S-EPMC7710930 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Phenotypic and Genotypic Features of Thai Patients With Nonsyndromic Tooth Agenesis and <i>WNT10A</i> Variants.

Kanchanasevee Charinya C Sriwattanapong Kanokwan K Theerapanon Thanakorn T Thaweesapphithak Sermporn S Chetruengchai Wanna W Porntaveetus Thantrira T Shotelersuk Vorasuk V

Frontiers in physiology 20201119

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 <i>WNT10A</i> 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 20 ...[more]

PMID: 33329022

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Project description:BackgroundSex dimorphism has been implicated in oral health differences and the pathogenesis of oral diseases, such as tooth agenesis, periodontal disease, dental caries, and tooth loss. Tooth agenesis (TA) is one of the most common developmental anomalies in humans, and its prevalence and patterns are different across ethnic groups. The aim of this study was to investigate the phenotypes and sex-associated patterns of nonsyndromic tooth agenesis (TA) in Thai dental patients.MethodsOne thousand ninety panoramic radiographs were examined. One hundred and one subjects (37 males, 64 females, 15-20 years-old) with nonsyndromic TA were evaluated. Differences in TA prevalence between groups were analyzed using the chi-square or Fisher exact test.ResultsThe TA prevalence, excluding third molars, was 9.3% and more frequently found in the mandible compared with the maxilla. The maxilla demonstrated a higher prevalence of first premolar agenesis than the mandible (P = 0.012), while the mandible had a higher prevalence of second premolar agenesis than the maxilla (P = 0.031). There were significantly more males missing one tooth than females, however, there were more females missing two or more teeth than males (P = 0.042). A missing maxillary left lateral incisor was significantly more frequent in males (P = 0.019), while a missing mandibular right lateral incisor was more frequent in females (P = 0.025). In females, the pattern of two mandibular lateral incisors agenesis was the most common and significantly present in females more than males (P = 0.015). In contrast, the pattern of one mandibular left lateral incisor agenesis was only observed in males and significantly found in males more than females (P = 0.047).ConclusionsWe demonstrate sex-associated differences in nonsyndromic tooth agenesis. The prevalence of single tooth agenesis was higher in males, while that of two or more teeth agenesis was higher in females. We found different patterns of lateral incisor agenesis between males and females.

Project description:Since MSX1 and PAX9 are linked to the pathogenesis of nonsyndromic tooth agenesis, we performed detailed mutational analysis of these two genes sampled from Japanese patients. We identified two novel MSX1 variants with an amino acid substitution within the homeodomain; Thr174Ile (T174I) from a sporadic hypodontia case and Leu205Arg (L205R) from a familial oligodontia case. Both the Thr174 and Leu205 residues in the MSX1 homeodomain are highly conserved among different species. To define possible roles of mutations at these amino acids in the pathogenesis of nonsyndromic tooth agenesis, we performed several functional analyses. It has been demonstrated that MSX1 plays a pivotal role in hard tissue development as a suppressor for mesenchymal cell differentiation. To evaluate the suppression activity of the variants in mesenchymal cells, we used the myoD-promoter, which is one of convenient reporter assay system for MSX1. Although the gene products of these MSX1 variants are stable and capable of normal nuclear localization, they do not suppress myoD-promoter activity in differentiated C2C12 cells. To clarify the molecular mechanisms underlying our results, we performed further analyses including electrophoretic mobility shift assays, and co-immunoprecipitation assays to survey the molecular interactions between the mutant MSX1 proteins and the oligonucleotide DNA with MSX1 consensus binding motif or EZH2 methyltransferase. Since EZH2 is reported to interact with MSX1 and regulate MSX1 mediated gene suppression, we hypothesized that the T174I and L205R substitutions would impair this interaction. We conclude from the results of our experiments that the DNA binding ability of MSX1 is abolished by these two amino acid substitutions. This illustrates a causative role of the T174I and L205R MSX1 homeodomain mutations in tooth agenesis, and suggests that they may influence cell proliferation and differentiation resulting in lesser tooth germ formation in vivo.

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.

Dataset Information

Phenotypic and Genotypic Features of Thai Patients With Nonsyndromic Tooth Agenesis and WNT10A Variants.

Publications

Phenotypic and Genotypic Features of Thai Patients With Nonsyndromic Tooth Agenesis and <i>WNT10A</i> Variants.

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