Oligodontia Phenotype Research Articles

Clinical analysis of nonsyndromic oligodontia phenotypes.

To provide references, this study investigated the clinical characteristics of patients with nonsyndromic oligodontia. The information of 178 patients with oligodontia was collected, including histories, oral examinations, and panoramic radiographs. Tooth agenesis characteristics were calculated and evaluated. All the data were statistically analyzed with SPSS 24.0 software. No significant difference in the number of missing teeth was found between sexes nor between the right and left sides, and congenitally missing teeth affected the maxillary arch (P<0.05). The highest prevalence of tooth agenesis was observed in the mandibular second premolars. In the maxillary arch, the most common pattern of tooth agenesis was agenesis of the bilateral first and second premolars. The agenesis of the bilateral second premolars was observed in the mandibular arch. The prevalence of a symmetric pattern between the right and left quadrants was significantly higher than that of matched patterns between the maxillary and mandibular antagonistic quadrants. Approximately 16.85% of patients with nonsyndromic oligodontia were affected by other tooth-related anomalies. The common patterns of tooth agenesis were successfully identified in patients with nonsyndromic oligodontia. Dentists need to provide multidisciplinary treatments for patients with nonsyndromic oligodontia because of variations in occluding and full-mouth tooth agenesis patterns.

The oligodontia phenotype in a X-linked hypohidrotic ectodermal dysplasia patient with a novel EVC2 variant

ObjectivesTo analyse the pathogenic genes in a patient with hypohidrotic ectodermal dysplasia (HED) and explore the relationship between pathogenic genes and the oligodontia phenotype. MethodsClinical 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. ResultsThe 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. ConclusionThe 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.

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. 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.

Nonsyndromic oligodontia : Does the Tooth Agenesis Code (TAC) enable prediction of the causative mutation?

The literature suggests an association between phenotype and causative mutation in nonsyndromic oligodontia. Thus, the present study was designed to verify this hypothesis in a consecutive cohort of patients. All patients with nonsyndromic oligodontia who had been treated at the study center (Department of Orthodontics, University of Giessen, Germany) over the period 1986-2013 were contacted. Candidates were included only if at least one more family member had hypo- or oligodontia (i.e., without regard to the number of congenitally missing teeth). A total of 20 patients were included. After evaluating the dental status of each participant, the Tooth Agenesis Code (TAC) was applied. On this basis, a tentative diagnosis was made to predict which gene (MSX1, AXIN2, EDA, or PAX9) was likely to show mutation. Afterwards this hypothesis was confirmed or rejected by analyzing a saliva sample for mutation of the predicted gene. If confirmed, any available family members were also genetically analyzed. Based on their TAC scores and sums, gene mutations were predicted for MXS1 in 11, AXIN2 in 3, EDA in 6, and PAX9 in none of the patients. The evaluation of MSX1 yielded variants in 4 of 11 cases, all of which were classified as nonpathogenic since they were not considered as functional mutations. The evaluation of EDA yielded a pathogenic exon-7 mutation in 2 of 6 patients, both being brothers with different TAC scores; the same mutation, which represents a novel missense mutation, was also found in other members of the same family. The evaluation of AXIN2 yielded variants in 3 of 3 cases, all of which were classified as nonpathogenic. Our findings obtained in consecutive patients with nonsyndromic oligodontia did not reveal any clinically relevant associations between oligodontia phenotype (based on TAC) and causative mutations for nonsyndromic oligodontia.

A novel initiation codon mutation of PAX9 in a family with oligodontia

ObjectiveRecent 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. DesignGenomic 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. ResultsA 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. ConclusionsOur 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.

Axis inhibition protein 2 polymorphisms may be a risk factor for families with isolated oligodontia.

The objective of the present study was to search for Msh homeobox 1 (MSX1), paired box gene 9 (PAX9), ectodysplasin‑A (EDA) and axis inhibition protein 2 (AXIN2) variants in a family with isolated oligodontia and analyse the pathogenesis of mutations that result in oligodontia phenotypes. Members of a single family (but of different descent) with oligodontia and unrelated healthy controls were enrolled in our study. Genomic DNA was isolated from blood samples. Mutation analysis was performed by amplifying MSX1, PAX9, EDA and AXIN2 exons as well as their exon‑intron boundaries and sequencing the products. DNA sequencing of the AXIN2 gene revealed three mutations in the two patients with oligodontia: a homozygotic silent mutation c.1365A>G (p.Pro455=) in exon 3, two c.956+16A>G mutations (II‑1: homozygosis; III‑1: heterozygosis) and c.1200+71A>G (homozygosis) in the intron, which possibly contributed to structural and functional changes in proteins. The heterozygotic mutations c.1365A>G and c.1200+71A>G were identified in the proband's mother (II‑2). No mutations were detected in the MSX1, PAX9 and EDA genes of oligodontia patients. The findings suggest that the c.956+16A>G, c.1365A>G and c.1200+71A>G mutations of AXIN2 may be responsible for the oligodontia phenotype in this family, but these findings require further study.

Genetic background of nonsyndromic oligodontia: a systematic review and meta-analysis

The goal of this work was to identify all known gene mutations that have been associated with the development of nonsyndromic oligodontia. A systematic literature search was performed electronically in two databases (PubMed, Medpilot) supplemented by a hand search. Articles published up to March 2012 were considered. Search terms were combined as follows: oligodontia and genes, oligodontia and mutations, tooth agenesis and genes, and tooth agenesis and mutations. A meta-analysis of the data was conducted based on the Tooth Agenesis Code (TAC). Seven genes are currently known to have a potential for causing nonsyndromic oligodontia. All these genes vary both in terms of number of identified mutations and in terms of number of documented patients: 33 mutations and 93 patients are on record for PAX9, 10 mutations and 51 patients for EDA, 12 mutations and 33 patients for MSX1, 6 mutations and 17 patients for AXIN2, and 1 mutation in 1 patient for EDARADD, NEMO, and KRT17 each. A total TAC score of 250 was found to have cutoff properties, as 100% of MSX1 and 80% of EDA patients exhibited TAC ≤ 250, whereas 96.9% of PAX9 and 90% of AXIN2 patients exhibited TAC >250. Furthermore, 94.3% of EDA patients but only 28.6% of MSX1 patients exhibited odd-numbered TAC scores in at least one quadrant, and 72.7% of PAX9 but none of the AXIN2 patients were found to show TAC scores of 112 in at least one quadrant. In order of decreasing frequency, PAX9, EDA, MSX1, AXIN2, EDARADD, NEMO, and KRT17 are the seven genes currently known to have a potential for causing nonsyndromic oligodontia. TAC scores enabled us to identify an association between oligodontia phenotypes and genotypes in the patients covered by this meta-analysis.

Clinical and genetic evaluation of a Chinese family with isolated oligodontia

ObjectivesOligodontia 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. DesignWe 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. ResultsThe 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. ConclusionOur 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.

Tooth agenesis patterns and phenotype variation in a cohort of Belgian patients with hypodontia and oligodontia clustered in 79 families with their pedigrees

Even though tooth agenesis is the most common developmental anomaly of the human dentition, its genetic background and pathogenic mechanism(s) still remain poorly understood. Syndromic and isolated forms of hypodontia have been described and can occur sporadically or in families. We describe and analyse the hypo-/oligodontia phenotype variations in families. The index patient suffers from severe or mild hypodontia; case-parents/sib records are available. Furthermore, we aim to evaluate whether the different agenesis patterns in the pedigrees are predictive of mutations in specific genes based on reported genotype-phenotype associations. Dental records and pedigrees were collected from 79 families. In 67 families, the index patient presented with oligodontia while in 12 families with hypodontia. The phenotype data of 66 oligodontia index patients were analysed with the Tooth Agenesis Code software. Nine families counted two members; one family counted three members affected with oligodontia. Twenty-four oligodontia families respectively had one (n = 17), two (n = 4), three (n = 2) or four (n = 1) additional family members presenting with hypodontia. Of the 77 oligodontia cases, two showed the same tooth agenesis pattern, while 75 patients showed unique tooth agenesis patterns. Despite familial aggregation and expected Mendelian segregation, the number of missing teeth in the familial hypo-/oligodontia phenotypes and the tooth agenesis patterns are highly variable between the affected family members. Therefore, we hypothesize that tooth agenesis is not (always) a simple monogenic condition, but additional genetic or environmental factors can modify the expression of the phenotype.

Sequence analysis of PAX9, MSX1 and AXIN2 genes in a Chinese oligodontia family

ObjectivesThe goal of our research was to look into the clinical traits and genetic mutations in nonsyndromic oligodontia in a Chinese family and to gain insight into the role of mutations of PAX9, MSX1 and AXIN2 in oligodontia phenotypes. Materials and methods6 subjects from a family underwent complete oral examination, including panoramic radiographs. Retrospective data were reviewed and blood samples were collected. PCR primers for PAX9, MSX1, and AXIN2 were designed through the Oligo Primer Analysis Software. PCR products were purified and sequenced using the BigDye Terminator Kit and analysed by the 3730 DNA Analyzer. ResultsThe proband missed 4 permanent canines, 2 permanent maxillary lateral incisors, 2 permanent mandibular lateral incisors, and 2 permanent mandibular central incisors, whilst his maternal grandfather lacked only 2 permanent mandibular central incisors. Moreover, the size of some permanent teeth appeared smaller than normal values of crown width of Chinese people. Oligodontia and abnormalities of teeth were not present in other family members. Radiographic examination showed that the proband and the rest of family members retained all germs of the third molars. There was one known mutation A240P (rs4904210) of PAX9 in the coding region in the proband and the maternal family members (II-2, II-3, and II-4), which possibly contributed to structural and functional changes of proteins. No mutations were identified in MSX1 and AXIN2. ConclusionsOur findings may imply that the PAX9 A240P mutation is a risk factor for oligodontia in the Chinese population. A240P is likely to be a genetic cause of oligodontia though previous literature suggested it as a polymorphism only.

Clinical and functional data implicate the Arg(151)Ser variant of MSX1 in familial hypodontia

Multiple previous reports confirm that several missense alleles of MSX1 exhibit Mendelian inheritance of an oligodontia phenotype (agenesis of more than six secondary teeth besides third molars). However, the extent to which missense MSX1 alleles contribute to common, multifactorial disorders is less certain. It is still not yet clear whether multiple non-synonomous MSX1-coding variants identified among patients with oral clefting are merely neutral polymorphisms or whether any of these might represent real mutations with mild effects. The present work steps toward resolving these issues for at least one MSX1 allele: R151S, previously identified in a single Japanese proband with unilateral cleft lip and palate. Candidate gene sequencing within a patient cohort demonstrating mild tooth agenesis (loss of six or less secondary teeth besides third molars, hypodontia), secondarily identified this same MSX1 variant, functioning as a mildly deleterious, moderately penetrant allele. Four of five heterozygous R151S individuals from one Japanese family exhibited the hypodontia phenotype. The in vitro functional assays of the variant protein display partial repression activity with normal nuclear localization. These data establish that the MSX1-R151S allele is a low-frequency, mildly deleterious allele for familial hypodontia that alone is insufficient to cause oral facial clefting. Yet, as this work also establishes its hypomorphic nature, it suggests that it may in fact contribute to the likelihood of common birth disorder phenotypes, such as partial tooth agenesis and oral facial clefting. Nevertheless, the exact mechanism in which differential pleiotropy is manifested will need further and deeper clinical and functional analyses.

Identification of a novel missense mutation of MSX1 gene in Chinese family with autosomal-dominant oligodontia

Objectives Oligodontia is defined as the congenital absence of 6 or more permanent teeth excluding the third molar. The occurrence of non-syndromic still remains poorly understood, but in recent years some cases have been reported where mutations or polymorphisms of PAX9 and MSX1 had been associated with non-syndromic oligodontia. The objective of the present work was to study the phenotype and genotype of three generations of a Han Chinese family affected by non-syndromic autosomal-dominant oligodontia. Design We examined all individuals of the oligodontia family by clinical and radiographic examinations. Based on clinical manifestations, candidate genes MSX1 and PAX9 were picked up to analyse and screen mutations. Results Dental evaluation showed that the most commonly missing teeth are the mandibular second premolars, followed by the maxillary second premolars and maxillary lateral incisors, and subsequently the maxillary first premolars. The probability of missing a particular type of tooth is not always bilaterally symmetrical, and differences exist between maxilla and mandible. PCR-SSCP analysis and DNA sequencing revealed a novel missense mutation c.662C>A in a highly conserved homeobox sequence of MSX1 and a known polymorphisms c.347C>G. Conclusion Our finding suggests the missense transversion (c.662C>A) and the polymorphisms (c.347C>G) may be responsible for oligodontia phenotype in this Chinese family.

Investigating the etiology of multiple tooth agenesis in three sisters with severe oligodontia

To describe the dentofacial phenotypes of three sisters with severe non-syndromic oligodontia, to report on the mutation analysis in three genes, previously shown to cause various phenotypes of non-syndromic oligodontia and in two other suspected genes. Based on the phenotypes in the pedigree of this family, the different possible patterns of transmission are discussed. Anamnestic data and a panoramic radiograph were taken to study the phenotype of the three sisters and their first-degree relatives. Blood samples were also taken to obtain their karyotypes and DNA samples. Mutational screening was performed for the MSX1, PAX9, AXIN2, DLX1 and DLX2 genes. The probands' pedigree showed evidence for a recessive or multifactorial inheritance pattern. Normal chromosomal karyotypes were found and - despite the severe oligodontia present in all three sisters - no mutation appeared to be present in the five genes studied so far in these patients. In the three sisters reported, their common oligodontia phenotype is not caused by mutations in the coding regions of MSX1, PAX9, AXIN2, DLX1 or DLX2 genes, but genetic factors most probably play a role as all three sisters were affected. Environmental and epigenetic factors as well as genes regulating odontogenesis need further in vivo and in vitro investigation to explain the phenotypic heterogeneity and to increase our understanding of the odontogenic processes.

A novel missense mutation in the paired domain of human PAX9 causes oligodontia

PAX9 and MSX1 are transcription factors that play essential roles in craniofacial and limb development. In humans, mutations in both genes are associated with nonsyndromic and syndromic oligodontia, respectively. We screened one family with nonsyndromic oligodontia for mutations in PAX9 and MSX1. Single stranded conformational polymorphism (SSCP) analysis and sequencing revealed a novel heterozygous C139T transition in PAX9 in the affected members of the family. There were no mutations detected in the entire coding sequence of MSX1. The C139T mutation, predicted to result in the substitution of an arginine by a tryptophan (R47W) in the N-terminal subdomain, affected conserved residues in the PAX9 paired domain. To elucidate the pathogenic mechanism producing oligodontia phenotype caused by this mutation, we analyzed the binding of wild-type and mutant PAX9 paired domain protein to double-stranded DNA targets. The R47W mutation dramatically reduced DNA binding suggesting that the mutant protein with consequent haploinsufficiency results in a clinical phenotype.

Exclusion of coding region mutations inMSX1,PAX9andAXIN2in eight patients with severe oligodontia phenotype

This paper describes the screening of eight patients with severe oligodontia for PAX9 and AXIN2 mutations. Anamnestic data and a panoramic radiograph were collected to study the phenotype of eight patients with oligodontia and their first-degree relatives. A blood sample was taken for a mutational screening for PAX9 and AXIN2 mutations. No mutations were discovered, but a unique nucleotide change in a conserved 5' flanking region of PAX9 was revealed. Earlier screening of the same patients for MSX1 mutations also had a negative outcome. Considering the discrepancy between the high incidence rate of agenesis and the relatively small number of reported causative mutations in PAX9, MSX1 and AXIN2 genes, the genetic contribution to oligodontia probably is much more heterogeneous than expected so far. Therefore negative results, like the present exclusion data, should be published more often in order to get a better appreciation of the relative contribution of these specific mutations causing oligodontia. In this context the exact number of tested probands also should be mentioned at all cases. Recent evidence of PAX9-MSX1 protein interactions in odontogenesis as well as other genes and developmental factors should receive more attention.

A missense mutation in PAX9 in a family with distinct phenotype of oligodontia.

Mutations in PAX9 have been described for families in which inherited oligodontia characteristically involves permanent molars. Our study analysed one large family with dominantly inherited oligodontia clinically and genetically. In addition to permanent molars, some teeth were congenitally missing in the premolar, canine, and incisor regions. Measurements of tooth size revealed the reduced size of the proband's and his father's deciduous and permanent teeth. This phenotype is distinct from oligodontia phenotypes associated with mutations in PAX9. Sequencing of the PAX9 gene revealed a missense mutation in the beginning of the paired domain of the molecule, an arginine-to-tryptophan amino-acid change occurring in a position absolutely conserved in all sequenced paired box genes. A mutation of the homologous arginine of PAX6 has been shown to affect the target DNA specificity of PAX6. We suggest that a similar mechanism explains these distinct oligodontia phenotypes.