UNASSIGNED: To analyse the pathogenic genes in a patient with hypohidrotic ectodermal dysplasia (HED) and explore the relationship between pathogenic genes and the oligodontia phenotype.
UNASSIGNED: Clinical data and peripheral blood were collected from a patient with HED. Pathogenic genes were analysed by whole-exon sequencing (WES) and verified by Singer sequencing. The secondary and tertiary structures of the variant proteins were predicted to analyse their toxicity.
UNASSIGNED: The patient exhibited a severe oligodontia phenotype, wherein only two deciduous canines were left in the upper jaw. WES revealed a hemizygous EDA variant c.466C > T p.(Arg156Cys) and a novel heterozygous EVC2 variant c.1772T > C p.(Leu591Ser). Prediction of the secondary and tertiary structures of the EDA variant p.(Arg156Cys) and EVC2 variant p.(Leu591Ser) indicated impaired function of both molecules.
UNASSIGNED: The patient demonstrated a more severe oligodontia phenotype when compared with the other patients caused by the EDA variant c.466C > T. Since Evc2 is a positive regulator of the Sonic Hedgehog (Shh) signal pathway, we speculated that the EVC2 variant p.(Leu591Ser) may play a synergistic role in the oligodontia phenotype of HED, thereby exacerbating the oligodontia phenotype. Knowledge of oligodontia caused by multiple gene variants is of great significance for understanding individual differences in oligodontia phenotypes.

OBJECTIVE: The purpose of this study was to identify associations between PAX9 mutations and clinical features of non-syndromic tooth agenesis patients.
METHODS: Non-syndromic tooth agenesis patients were found to have mutations by whole exome sequencing (WES). Additionally, conservation analysis and three-dimensional structure prediction were also applied to identify mutated proteins.
RESULTS: Eight non-syndromic tooth agenesis probands were identified with PAX9 mutations (c.C112T; C.131_134del; c.G151A; c.189delG; c.305delT; c.C365A; c.394delG; c.A679C). All of the probands were missing more than six teeth (oligodontia). The mutations (c.131_134del,p.R44fs; c.189delG,p.T63fs; c.305delT,p.I102fs and c.394delG,p.G123fs) caused premature termination of the PAX9 protein. The c.C112T(p.R38X) mutation created a truncated protein. Bioinformatic prediction demonstrated that the three missense mutations change the PAX9 structure suggesting the corresponding functional impairments.
CONCLUSIONS: We reported that eight mutations of PAX9 caused non-syndromic tooth agenesis and analyzed the relationship between PAX9 mutations and non-syndromic tooth agenesis.
CONCLUSIONS: Our study revealed that PAX9 mutations might be the mutations most associated with non-syndromic tooth agenesis in humans, which greatly broadened the mutation spectrum of PAX9-related non-syndromic tooth agenesis.

OBJECTIVE: To investigate the pathogenic gene of a patient with nonsyndromic oligodontia, and analyze its possible pathogenic mechanism.
METHODS: The variant was detected by whole exome sequencing (WES) and Sanger sequencing in a family with oligodontia. Bioinformatic and structural analyses were used to analyze variant. Functional studies including western blotting and immunofluorescent analyses and luciferase reporter assay were conducted to explore the functional effects.
RESULTS: We identified a novel frameshift variant of PAX9 (c.491-510delGCCCT-ATCACGGCGGCGGCC, p.P165Qfs*145) outside the DNA-binding domain causing an autosomal-dominant nonsyndromic oligodontia in a Chinese family. Bioinformatic and structural analyses revealed that the variant is pathogenic and conserved evolutionarily, and the changes might affect protein stability or folding. Functional studies demonstrate dramatically reduced ability in activating transcription activity of BMP4 promoter and a marked decrease in protein production, as evaluated by western blotting and immunofluorescent analyses.
CONCLUSIONS: We found a novel frameshift variant of PAX9 causing nonsyndromic oligodontia in a Chinese family. Our findings indicate that frameshift variants cause loss of function of PAX9 protein during the patterning of the dentition and the subsequent tooth agenesis, providing new molecular insights into the role of frameshift variant of PAX9 and broaden the pathogenic spectrum of PAX9 variants.

UNASSIGNED: The congenital oligodontia in maxilla could result in a significant skeletal jaw malformation such as atrophic maxilla and severe skeletal class III malocclusion. Since there is no referable dentition in anterior maxilla, the orthognathic surgery and oral rehabilitation for those patients becomes more challenging and less predictable.
UNASSIGNED: We hereby present a new sequencing of interdisciplinary treatments, including calvarial bone grafting, installation of implant-supported provisional prosthesis, bimaxillary orthognathic surgery, and the final installation of dental implants and the fixed prosthesis.
UNASSIGNED: The facial esthetics and function of the permanent prosthesis were satisfactory, with a remarkable improvement in the maxillomandibular relation, adequate horizontal and vertical repositioning of the maxilla, and appropriate incisor exposure.
UNASSIGNED: Although more surgeries and longer treatment period may be required due to the interdisciplinary treatment plan, better aesthetic and functional outcomes may be acquired by this reported procedure in the long-term for young patients.

OBJECTIVE: To identify potentially pathogenic mutations for tooth agenesis by whole-exome sequencing.
METHODS: Ten Chinese families including five families with ectodermal dysplasia (syndromic tooth agenesis) and five families with selective tooth agenesis were included. Whole-exome sequencing was performed using genomic DNA. Potentially pathogenic mutations were identified after data filtering and screening. The pathogenicity of novel variants was investigated by segregation analysis, in silico analysis, and functional studies.
RESULTS: One novel mutation (c.441_442insACTCT) and three reported mutations (c.252delT, c.463C>T, and c.1013C>T) in EDA were identified in families with ectodermal dysplasia. The novel EDA mutation was co-segregated with phenotype. A functional study revealed that NF-κB activation was compromised by the identified mutations. The secretion of active EDA was also compromised detection by western blotting. Novel Wnt10A mutations (c.521T>C and c.653T>G) and EVC2 mutation (c.1472C>T) were identified in families with selective tooth agenesis. The Wnt10A c.521T>C mutation and the EVC2 c.1472C>T mutation were considered as pathogenic for affecting highly conserved amino acids, co-segregated with phenotype and predicted to be disease-causing by SIFT and PolyPhen2. Moreover, several reported mutations in PAX9, Wnt10A, and FGFR3 were also detected.
CONCLUSIONS: Our study expanded our knowledge on tooth agenesis spectrum by identifying novel variants.

Tooth agenesis (TA) is one of the most common developmental anomalies that affects the number of teeth. An extensive analysis of publicly accessible databases revealed 15 causative genes responsible for nonsyndromic TA, along with their signaling pathways in Wnt/β-catenin, TGF-β/BMP, and Eda/Edar/NF-κB. However, genotype-phenotype correlation analysis showed that most of the causal genes are also responsible for syndromic TA or other conditions. In a total of 198 different mutations of the 15 genes responsible for nonsyndromic TA, 182 mutations (91.9%) are derived from seven genes (AXIN2, EDA, LRP6, MSX1, PAX9, WNT10A, and WNT10B) compared with the remaining 16 mutations (8.1%) identified in the remaining eight genes (BMP4, DKK1, EDAR, EDARADD, GREM2, KREMEN1, LTBP3, and SMOC2). Furthermore, specificity analysis in terms of the ratio of nonsyndromic TA mutations versus syndromic mutations in each of the aforementioned seven genes showed a 98.2% specificity rate in PAX9, 58.9% in WNT10A, 56.6% in MSX1, 41.2% in WNT10B, 31.4% in LRP6, 23.8% in AXIN2%, and 8.4% in EDA. These findings underscore an important role of the Wnt and Wnt-associated pathways in the genetic etiology of this heterozygous disease and shed new lights on the discovery of novel molecular mechanisms associated with tooth agenesis.

Tooth agenesis is one of the most common developmental anomalies affecting function and esthetics. The paired-domain transcription factor, Pax9, is critical for patterning and morphogenesis of tooth and taste buds. Mutations of PAX9 have been identified in patients with tooth agenesis. Despite significant progress in the genetics of tooth agenesis, many gaps in knowledge exist in refining the genotype-phenotype correlation between PAX9 and tooth agenesis. In the present study, we complete genetic and phenotypic characterization of multiplex Chinese families with nonsyndromic (NS) tooth agenesis. Direct sequencing of polymerase chain reaction products revealed 9 novel (c.140G>C, c.167T>A, c.332G>C, c.194C>A, c.271A>T, c.146delC, c.185_189dup, c.256_262dup, and c.592delG) and 2 known heterozygous mutations in the PAX9 gene among 120 probands. Subsequently, pedigrees were extended, and we confirmed that the mutations co-segregated with the tooth agenesis phenotype (with exception of families in which DNA analysis was not available). In 1 family ( n = 6), 2 individuals harbored both the PAX9 c.592delG mutation and a heterozygous missense mutation (c.739C>T) in the MSX1 gene. Clinical characterization of families segregating a PAX9 mutation reveal that all affected individuals were missing the mandibular second molar and their maxillary central incisors are most susceptible to microdontia. A significant reduction of bitter taste perception was documented in individuals harboring PAX9 mutations ( n = 3). Functional studies revealed that PAX9 haploinsufficiency or a loss of function of the PAX9 protein underlies tooth agenesis.

Human dentition development is a long and complex process which involves a series of reciprocal and sequential interactions between the embryonic stomodeal epithelium and the underlying neural crest-derived mesenchyme. Despite environment disturbances, tooth development is predominantly genetically controlled. To date, more than 200 genes have been identified in tooth development. These genes implied in various signaling pathways such as the bone morphogenetic protein, fibroblast growth factor, sonic hedgehog homolog, ectodysplasin A, wingless-type MMTV integration site family (Wnt), and transform growth factor pathways. Mutations in any of these strictly balanced signaling cascades may cause arrested odontogenesis and/or other dental defects. This article aims to review current knowledge about the genetic mechanisms responsible for selective nonsyndromic tooth agenesis in humans and to present a detailed summary of syndromes with hypodontia as regular features and their causative genes.

OBJECTIVE: Recent studies have attributed non-syndromic tooth agenesis to mutations in several genes, including MSX1, PAX9, AXIN2, WNT10A and EDA. In this study, mutation of PAX9gene was investigated in a four-generation Chinese family with oligodontia.
METHODS: Genomic DNA was isolated from the blood samples of all the available family members. Candidate genes MSX1 and PAX9 were amplified using polymerase chain reaction and then directly sequenced.
RESULTS: A novel initiation codon mutation was identified; it consisted of a heterozygous c.2T>G mutation in the PAX9 gene which changed the ATG initiation codon to AGG. Restriction-enzyme analysis was performed to verify this mutation, which was segregated amongst the members with the oligodontia phenotype.
CONCLUSIONS: Our results demonstrate a new initiation codon mutation in the PAX9 gene. This mutation probably caused the oligodontia in the investigated Chinese family through haplo-insufficiency.

OBJECTIVE: Oligodontia is defined as the congenital absence of 6 or more permanent teeth excluding the third molar. Tooth agenesis may be classified as syndromic/non-syndromic and as familial/sporadic. To date, more than 300 genes have been found to be involved in tooth development, but only a few of these genes, such as MSX1, PAX9 and AXIN2, are related to the condition of non-syndromic oligodontia. The objective of the present work was to investigate the disease-causing gene of non-syndromic oligodontia in a Han Chinese family and analyse the pathogenesis of mutations that result in oligodontia.
METHODS: We examined all individuals of the oligodontia family by clinical and radiographic examinations. Based on the clinical manifestations, the candidate genes MSX, PAX9 and AXIN2 were selected to analyse and screen for mutations.
RESULTS: The clinical evaluation suggested that the family might show non-syndromic oligodontia. DNA sequencing of the MSX1 gene revealed two mutations in the two patients with oligodontia: a heterozygotic silent mutation, c.348C>T (P.Gly116=), in exon 1 and a homozygotic deletion of 11 nucleotides (c.469+56delins GCCGGGTGGGG) in the intron. However, the silent mutation and the deletion mutation were thought to be known polymorphisms (rs34165410 and rs34341187) by bioinformatics analysis. We did not detect any mutations in the PAX9 and AXIN2 genes of oligodontia patients.
CONCLUSIONS: Our finding suggests that identified polymorphisms (c.348C>T and c.469+56delins GCCGGGTGGGG) may be responsible for the oligodontia phenotype in this Chinese family, but the association requires further study.