Non-syndromic Hypodontia Research Articles

What could be the role of genetic tests and machine learning of AXIN2 variant dominance in non-syndromic hypodontia? A case-control study in orthodontically treated patients

BackgroundHypodontia is the most prevalent dental anomaly in humans, and is primarily attributed to genetic factors. Although genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNP) associated with hypodontia, genetic risk assessment remains challenging due to population-specific SNP variants. Therefore, we aimed to conducted a genetic analysis and developed a machine-learning-based predictive model to examine the association between previously reported SNPs and hypodontia in the Saudi Arabian population. Our case–control study included 106 participants (aged 8–50 years; 64 females and 42 males), comprising 54 hypodontia cases and 52 controls. We utilized TaqManTM Real-Time Polymerase Chain Reaction and allelic genotyping to analyze three selected SNPs (AXIN2: rs2240308, PAX9: rs61754301, and MSX1: rs12532) in unstimulated whole saliva samples. The chi-square test, multinomial logistic regression, and machine-learning techniques were used to assess genetic risk by using odds ratios (ORs) for multiple target variables.ResultsMultivariate logistic regression indicated a significant association between homozygous AXIN2 rs2240308 and the hypodontia phenotype (ORs [95% confidence interval] 2.893 [1.28–6.53]). Machine-learning algorithms revealed that the AXIN2 homozygous (A/A) genotype is a genetic risk factor for hypodontia of teeth #12, #22, and #35, whereas the AXIN2 homozygous (G/G) genotype increases the risk for hypodontia of teeth #22, #35, and #45. The PAX9 homozygous (C/C) genotype is associated with an increased risk for hypodontia of teeth #22 and #35.ConclusionsOur study confirms a link between AXIN2 and hypodontia in Saudi orthodontic patients and suggests that combining machine-learning models with SNP analysis of saliva samples can effectively identify individuals with non-syndromic hypodontia.

Patterns and sexual dimorphism of non-syndromic hypodontia among a French orthodontic population

ObjectivesThis retrospective study aimed to estimate the prevalence of non-syndromic congenitally missing teeth (CMT) and to explore the frequency of CMT patterns in a French orthodontic population. In addition, the study sought to assess sex-based differences in CMT patterns. DesignPanoramic radiographs of 4569 orthodontic patients between 9 and 21 years-old performed over a 16-year period (2006–2022) were examined to identify non-syndromic tooth agenesis, excluding third molars. A chi-square test or a Fisher exact test were used to determine the difference in the prevalence of tooth agenesis between sex and between arches. ResultsTooth agenesis was observed in 7.3% of the sample (7.9% for females and 6.6% for males). Approximately 86% of the included subjects presented 1 or 2 missing teeth. Single tooth agenesis was significantly more frequent in females than males (p = 0.002, χ2). In total, 23 of the 67 different patterns of CMT observed, were present more than once. 75.5% of male patients and 79.5% of female patients presented one or both missing lateral incisors or second premolars, rarely affected at the same time. This study showed no sex difference in the patterns of tooth agenesis. LimitationsThis study has limitations due to its retrospective nature and our findings apply solely to an orthodontic population from a white ethnic background. ConclusionsClinicians should be aware of this particular incisor/premolar phenotype regardless of biological sex. Issues associated with congenitally missing teeth can be managed more effectively with early teenage diagnosis.

The genetic basis of hypodontia in dental development.

Dental agenesis is one of the most common developmental anomalies in humans, characterised by the developmental absence of one or more teeth. It can present as an isolated condition (non-syndromic hypodontia) or associated with a syndrome (syndromic hypodontia). This paper aims to review the genetic basis of hypodontia with reference to aetiology, classification and the subsequent clinical features.Significant progress has been made to identify the developmental basis of tooth formation, though there is still a lack of knowledge within the literature of the aetiological basis of inherited tooth loss.Gene anomalies or mutations in WNT10A, MSX1, PAX9, AXIN2 and EDA appear to be most critical during tooth development, leading to various forms of tooth agenesis.

A SCOPING REVIEW: GENE MUTATIONS OF NONSYNDROMIC HYPODONTIA AND ITS PREVALENCE IN GENDER AND TYPE OF TEETH

Non-syndromic hypodontia is a developmental anomaly characterized by the absence of one to six of permanent teeth. The goal of this review was to identify all known gene mutations, prevalence of gender and type of teeth, to review current research and identify knowledge gaps on the topic of nonsyndromic hypodontia. Three electronic databases were performed (Science Direct, PubMed, and Scopus) and restricted to English papers published after 2012 until 2019. Search terms were combined as follows: Hypodontia or 'non-syndromic hypodontia' and 'genes' or 'tooth anomaly' and 'mutation' or 'genes' and were checked against the inclusion criteria independently by two investigators. From 16 studies, five genes currently known caused non-syndromic hypodontia: WNT10A (37 variants, 256 patients), MSX1 (9 variants, 112 patients), PAX9 (17 variants, 79 patients), AXIN2 (8 variants, 60 patients) and EDA (2 variants, 11 patients). It was demonstrated that females exhibited a higher prevalence of hypodontia with 89.3% as compared to males with 84.2%. The most commonly missing teeth was a lateral incisor, followed by second premolar and central incisor. Five genes, including WNT10A, PAX9, MSX1, AXIN2 and EDA, are currently considered to have the ability to cause nonsyndromic hypodontia. Lateral incisor was found to be commonly missing teeth and there was an increased risk for females to have hypodontia than males.

Non syndromic hypodontia with retained natal teeth-a rare case report

Teeth that erupt prematurely have been designated with various terms such as natal teeth, neonatal teeth, congenital teeth, pre-deciduous teeth and dentitio praecox. Tooth agenesis is one of very common finding in a person. Developmental or congenital absence of one or more teeth excluding the third molars is a highly prevalent condition referred to as hypodontia. The incidence of hypodontia usually varies from 1.6-6.9% while the incidence of natal teeth on the other hand is noted to be approximately 1:2,000-1:3,000. Lower primary central incisors are the most affected tooth. The occurrence of retained natal teeth and that too with hypodontia is not found in the literature. This case report presents a rare occurrence of hypodontia with presence of retained natal teeth in a 14-year-old male child. Diagnosis made as non-syndromic hypodontia and retained natal teeth.

Non-syndromic hypodontia of maxillary lateral incisors and its association with other dental anomalies

BackgroundTooth agenesis (TA) is the developmental absence of one or more teeth and is the most common craniofacial disorder in humans. Maxillary lateral incisor agenesis (MLIA) is a specific subtype of TA and can have esthetic, functional, and psychosocial implications for patients. The aim of this study was to evaluate the prevalence of MLIA amongst patients with non-syndromic tooth agenesis, as well as its association with other dental anomalies.Materials and methodsThe dental records of 240 patients with non-syndromic congenitally missing teeth treated at the University of Alabama at Birmingham Department of Orthodontics were reviewed. Dolphin Imaging software was used to identify missing teeth, microdonts, peg laterals, impactions, and transpositions. Data were analyzed using chi-square or Fisher’s exact test. All the tests were two-sided at the significance level of 0.05 (SAS 9.4).ResultsIn the patient cohort, MLIA prevalence was 37.5% (second most common) and no gender or ethnic differences were identified. We also observed the bilaterally missing lateral incisors more frequently than the unilateral presentation (p = 0.0006). Additionally, 62.5% of patients with unilateral MLIA displayed a contralateral tooth that was a peg (p = 0.0001); however, no association was found with other microdonts. Furthermore, of the 90 patients missing at least one maxillary lateral incisor, 42.2% were missing another tooth type and 10% of MLIA patients also had an impacted tooth (mainly maxillary canines). However, these were not statistically significant. Finally, no transposed teeth were found in our patients.ConclusionsThis study found that maxillary lateral incisors were the second most frequently missing teeth. When clinicians diagnose congenital absence of a maxillary lateral incisor, the patient should be evaluated for other missing teeth, peg lateral incisors, or potential impactions, especially maxillary canines.

Detection of a rare AXIN2 variant in an Iranian family with hypodontia and oligodontia.

Background. Hypodontia, or the absence of one or more teeth during tooth formation, is a highly prevalent dental anomaly. Nevertheless, the main causes are still unknown. Mutations in PAX9, MSX1, WNT10A, and AXIN2 genes are most commonly associated with non-syndromic tooth agenesis in the literature. This study investigated these candidate genes in an Iranian family with non-syndromic hypodontia and oligodontia. Methods. Peripheral blood samples of the proband and her family members were collected, and DNA extractions using the salting-out method were carried out. In addition, polymerase chain reaction (PCR) and Sanger sequencing for candidate genes were performed. Results. A missense variant (rs4904210) was identified in the PAX9 gene, with one heterozygous missense variant (rs2240308) and one stop-gained variant (rs121908568) in the AXIN2 gene. Conclusion. By surveying similar studies and analyzing the variant in bioinformatics websites, we concluded that the heterozygous stop-gained variant rs121908568 in exon 8 of the AXIN2 gene could be responsible for tooth agenesis in the Iranian population.

PRKG1 mutation identified by whole-exome sequencing: a potential genetic etiology for He-Zhao deficiency

Objective: He-Zhao deficiency was originally described as a severe type of nonsyndromic hypodontia, and the causative gene locus was mapped to chromosome 10q11.2. The aim of this study was to identify potential genetic mutations that could cause He-Zhao deficiency. Methods: Patients with He-Zhao deficiency and their unaffected relatives of the large pedigree were investigated. The whole-exome sequencing using next-generation sequencing was employed to identify genetic variants. The data generated from the whole-exome sequencing using the Illumina Novaseq 6000 system were further analyzed by Burrows–Wheeler Aligner software, Sequence Alignment/Map tools and ANNOVAR tool. In vitro luciferase assay was used to investigate the effect of the detected mutation on gene expression. R environment was used to conduct t-tests. The study protocol was approved by the Research Ethics Committee of Bio-X Institutes, Shanghai Jiao Tong University (M2011004). Results: The exomes of five patients with He-Zhao deficiency and two of their unaffected relatives identified a mutation in PRKG1α as the molecular etiology of the disease. The variant c.-144 C>A of PRKG1 isoform 1 cosegregated with permanent tooth agenesis in 93 family members who were older than 12, at which time the primary teeth should have been replaced with permanent teeth. Functional studies suggested that the mutant allele promotes gene transcription by increasing its promoter activity. Conclusion: c.-144 C>A variant of PRKG1α involving odontoclast-associated root resorption is responsible for He-Zhao deficiency, unlike other forms of hypodontia, which typically involve odontoblast dysfunction.

Association of Non-Syndromic Hypodontia with Skeletal Malocclusion in Orthodontic Patients

Background: Hypodontia is one of the frequently observed dental anomalies in which dentofacial esthetics, phonetics, mastication, self-esteem and quality of life can be adversely affected. Awareness of disproportionate tooth number is important and must be considered by orthodontists while making treatment plans to achieve proper occlusion, overbite, and overjet, in order to restrain oral health deterioration. The aim of this study was to determine the frequency of non-syndromic hypodontia in orthodontic patients and its association with skeletal malocclusion. Methods: This retrospective case-series was conducted at the department of Orthodontics, Sharif Medical & Dental College. It involved screening the records of orthodontic patients from last 5 years from October 2017 – October 2021, consisting of standardized good quality orthopantomograms and lateral cephalograms. Patient files with incomplete records, any craniofacial syndrome and/or previous history of tooth loss were excluded. Non-syndromic hypodontia and skeletal malocclusion was recorded along with demographic data, in predesigned proforma. Results: Out of 244 orthodontic patients, 18 patients (7.37%) had non-syndromic hypodontia. Moreover, 63 teeth were missing in 18 patients of NSH. Maxillary arch (52.4%) and upper left quadrant (28.6%) were found to be more frequently affected. The difference of non-syndromic hypodontia among dental arches, quadrants and skeletal malocclusion was statistically significant while for genders it was insignificant. Conclusion: Non-syndromic hypodontia was significantly associated with skeletal malocclusion, highlighting their genetic etiology. Most commonly absent tooth was maxillary lateral incisor followed by mandibular second premolar and lateral incisor. Keywords: congenitally missing tooth, dental anomaly, dentofacial esthetics, genetic etiology, skeletal malocclusion

An Overview of Syndromic Hypodontia

Hypodontia is collectively used to describe the developmental absence of primary or secondary teeth. A number of causes like alterations in the dental lamina development, lack of maturation of tooth germ at the appropriate time, space constraints, systemic and genetic factors may result in missing teeth. With the exception of the third molars, hypodontia is most frequently encountered in lower second bicuspids and upper lateral incisors. Hypodontia is most commonly categorized into two categories: syndromic and non-syndromic hypodontia. Syndromic hypodontia constitutes cases where agenesis of one or more teeth occurs as a result of underlying diagnosable syndromic conditions like ectodermal dysplasia. The more extreme phenotypes of hypodontia include oligodontia with the agenesis of canines, first molars, and second molars and anodontia, and are generally seen in syndromic hypodontia, accompanying and underlying developmental disease. over 200 cleft lip and palate syndromes present with differing extent of hypodontia as a component of their clinical phenotype. The number of missing teeth increases with the extent of cleft. Ectodermal dysplasia consists of a varied group of syndromic presentations resulting from mutations influencing a range of vital congenital pathways such as connection between the overlaying ectoderm and the underlying mesoderm during embryonic growth. Many of these cases present with dental dysplasia and agenesis. In general, dental agenesis may be caused by the arrest of tooth development in the initial bud or cap phase. Care guidelines for such individuals include tooth replacement therapy through fixed and removable prostheses with optional implant support in skeletally mature individuals.

Prevalence of nonsyndromic hypodontia in a south-east Transylvanian region.

Abstract Introduction. Clinicians claim that the prevalence of hypodontia has skyrocketed in recent years. However, there is no clear evidence whether it is really a change in dentition in Homo Sapiens or a purely hypothetical observation, due to the advanced modern technology used in the diagnosis of dento-maxillary anomalies. The aim of this study was to establish the prevalence and distribution of nonsyndromic hypodontia in young patients from the South-East Transylvanian region of Romania. Material and methods. A number of 325 dental charts were selected. The patients who needed orthodontic treatment were treated in the Pedodontics Department and Orthodontic Department of UMFST “George Emil Palade“ Targu Mures and two private dental offices during 2017-2019. The age of the patients was between 12 and 25 at the moment when the clinical and paraclinical examination were performed. Results. From a total number of 275 cases investigated, 78 patients were diagnosed with hypodontia in permanent dentition, not taking into consideration the third molars. Hypodontia’s prevalence is 6.47% for patients which seek orthodontic treatment, without taking into consideration the third molars. This value is found in the range of 2.8%-11.3% reported in studies in the literature. The present study showed that hypodontia affects a greater proportion of females (6.83%) than males (5.74%), without statistically significant differences. Conclusions. The prevalence of non-syndromic hypodontia in permanent dentition, compared to the total number of patients who requested orthodontic treatment, is 6.47%, being higher than the data reported in the literature of our country, but falls within the range reported in the international literature in general.

Prevalence and Pattern of Non-syndromic Hypodontia among Adolescents in Southern Part of India.

BackgroundNon-syndromic hypodontia is the most common developmental dental anomaly, but there is a paucity of literature on its prevalence and severity in the Indian population.Aim and objectivesTo estimate the prevalence of non-syndromic hypodontia among adolescent schoolchildren in the southern part of India.Settings and designThis cross-sectional study was conducted in 20 schools from two states of southern India, named—Andhra Pradesh and Telangana. A total of 5,458 children in the age-group 13 to 15 years were selected.Materials and methodsClinical examination was carried out to check the absence of a permanent tooth and was confirmed by radiographic findings. The inclusion criterion was children with all the permanent teeth erupted (except third molars) and exclusion criteria were teeth missing due to reasons other than congenital agenesis. A Chi-square test was applied to check the significance.ResultsThe total prevalence of hypodontia in the study sample was 1.4%. Girls displayed a higher prevalence value (1.9%) than boys (1.1%). Maxillary lateral incisor was the most commonly congenitally missing tooth, followed by mandibular incisors and mandibular second premolar. Overall, hypodontia with a predominance of unilateral pattern and a predilection for the left side was observed.ConclusionThe most common missing permanent tooth (except third molars) was the maxillary lateral incisor. Hypodontia was more prevalent in females and had a predominance of unilateral patterns with a predilection toward the left side.How to cite this articleManasa Devi TL, Dutta B, Dwijendra KS, et al. Prevalence and Pattern of Non-syndromic Hypodontia among Adolescents in Southern Part of India. Int J Clin Pediatr Dent 2021;14(4):492–496.

Functional Analysis of Ectodysplasin-A Mutations in X-Linked Nonsyndromic Hypodontia and Possible Involvement of X-Chromosome Inactivation.

Background Mutations of the Ectodysplasin-A (EDA) gene are generally associated with syndrome hypohidrotic ectodermal dysplasia or nonsyndromic tooth agenesis. The influence of EDA mutations on dentinogenesis and odontoblast differentiation has not been reported. The aim of this study was to identify genetic clues for the causes of familial nonsyndromic oligodontia and explore the underlying mechanisms involved, while focusing on the role of human dental pulp stem cells (hDPSCs). Materials and Methods Candidate gene sequences were obtained by PCR amplification and Sanger sequencing. Functional analysis was conducted, and the pathogenesis associated with EDA mutations in hDPSCs was investigated to explore the impact of the identified mutation on the phenotype. Capillary electrophoresis (CE) was used to detect X-chromosome inactivation (XCI) in the blood of female carriers. Results In this study, we identified an EDA mutation in a Chinese family: the missense mutation c.1013C>T (Thr338Met). Transfection of hDPSCs with a mutant EDA lentivirus decreased the expression of EDA and dentin sialophosphoprotein (DSPP) compared with transfection of control EDA lentivirus. Mechanistically, mutant EDA inhibited the activation of the NF-κB pathway. The CE results showed that symptomatic female carriers had a skewed XCI with a preferential inactivation of the X chromosome that carried the normal allele. Conclusions In summary, we demonstrated that EDA mutations result in nonsyndromic tooth agenesis in heterozygous females and that, mechanistically, EDA regulates odontogenesis through the NF-κB signalling pathway in hDPSCs. Due to the large heterogeneity of tooth agenesis, this study provided a genetic basis for individuals who exhibit similar clinical phenotypes.

Genetic Basis of Dental Agenesis: Non-Syndromic Hypodontia

Tooth agenesis or hypodontia is one of the most prevalent developmental anomalies of the human dentition which affects up to 8% of the Caucasian population. It is a quite heterogenous condition which describes the congenital absence of one or more teeth and can occur either with a syndrome (syndromic hypodontia) or without (non-syndromic hypodontia). Hypodontia still constitutes a challenging clinical problem. Our insight on the cause of tooth agenesis is increasing as a result of recent advances in the field of molecular biology and human genetics. Further research is needed to establish a genotype phenotype correlation and to fully understand the pathogenesis of tooth agenesis. This review presents the genes and signaling pathways associated with nonsyndromic hypodontia, based on the most current literature and provides an overview of novel genes that seem to contribute to dental agenesis.

Early Management of Non-Syndromic Hypodontia in a Child: Three-Year Follow-Up

Hypodontia is the congenital absence of few teeth. The early multidisciplinary management of hypodontia assures the reestablishment of the disturbed psychological, aesthetic and oral functions. In this study, the clinical case of a child presenting a non-syndromic hypodontia with three agenesis teeth was described. No evidence of maxillary and mandibular third molars bud formation was noted on the orthopantomograph. To replace the two missing permanent mandibular central incisors, two mini-implants in the mandibular symphyseal region were placed and then restored by individually fixed prostheses. In the maxilla, the permanent canine in a complete transposition, was reshaped with composite resin restoration to replace the missing right permanent lateral incisor. Clinical and radiological reassessments were done 3 years later. The aesthetic and functional evaluations were satisfactory. The marginal bone level was stable with no bone loss. The periodontal health around the mini-implants were confirmed in conjunction with mechanical function.

Common variants of EDA are associated with non-syndromic hypodontia.

The aim of this case-control study was to investigate the association between non-syndromic hypodontia and nineteen common variants of candidate genes ectodysplasin A (EDA), paired box 9 (PAX9), msh homeobox 1 (MSX1) and axis inhibition protein 2 (AXIN2). Sixty-one hypodontia cases were frequency-matched to 253 controls with no missing teeth (excluding the third molars). Self-report data and DNA samples were collected from each participant. The sample had a mean age of 16.6years (SD=7.3), with most participants being female (59.6%), and of New Zealand European origin (75.4%). Using multiple logistic regression analysis, it was found that the T-allele of rs12853659 (EDA) and the G-allele of rs2428151 (EDA) were both associated with a higher risk of hypodontia (odds ratio, OR=2.79, 95% CI=1.11-7.01; and OR=2.87, 95% CI=1.04-7.94, respectively). The G-allele of rs2520378 (EDA) showed a protective effect with an OR of 0.61 (95% CI=0.38-0.99). The EDA SNP findings were consistent with previous reports included in a meta-analysis. No associations were found with the PAX9, AXIN2 and MSX1 genes, after adjusting for sex and ethnicity. Common variants of the EDA genes are associated with specific phenotypes of non-syndromic hypodontia, thus confirming their role in the regulatory pathways of normal tooth development. However, larger samples are needed to investigate the association further.

Study of rs12532, rs8670 Polymorphism of Msh Homeobox 1 (MSX1), rs61754301, rs4904155 Polymorphism of Paired Box Gene 9 (PAX9), and rs2240308 Polymorphism of Axis Inhibitor Protein 2 (AXIN2) Genes in Nonsyndromic Hypodontia.

The etiology of hypodontia is complex, in which both genetic and environmental factors can be related. The main objective of our study was to contribute to elucidating the genetic background of nonsyndromic hypodontia (NSH). In this order, we selected 97 NSH subjects (70 females and 27 males) from patients referred to orthodontic treatment, and we matched to each NSH subject a control by age and sex. DNA was obtained from epithelial cells from the oral mucosa. Genotyping of the PAX9 (rs4904155 and rs61754301), MSX1 (rs8670 and rs12532), and AXIN2 (rs2240308) SNPs was performed by using TaqMan SNP Genotyping Assays on a real-time PCR system. Single-nucleotide polymorphisms (SNPs) were studied for the whole NSH group and for frontal and lateral agenesis NSH subjects separately. Our results showed that the variant genotype (p=0.0008, OR = 2.9, 95% CI = 1.58–5.3) and variant T allele (p=0.0002, OR = 2.65, 95% CI = 1.6–4.39) of the MSX1 rs8670 SNP increased the risk of hypodontia in the studied population when the whole NSH group was compared with controls. The variant genotype of the MSX1 rs8670 SNP was the most frequent in frontal agenesis; meanwhile in the lateral agenesis NSH group, the AXIN2 rs2240308 SNP showed a higher frequency of the variant genotype, with a trend towards statistical significance. In conclusion, the results of the present study showed that the variant genotype and variant T allele of the MSX1 rs8670 SNP increased the risk of hypodontia in the studied population. The presence of the variant A allele of AXIN2 rs2240308 is associated with frontal agenesis but not with lateral agenesis.

Ectodermal dysplasias: Classification and organization by phenotype, genotype and molecular pathway.

An international advisory group met at the National Institutes of Health in Bethesda, Maryland in 2017, to discuss a new classification system for the ectodermal dysplasias (EDs) that would integrate both clinical and molecular information. We propose the following, a working definition of the EDs building on previous classification systems and incorporating current approaches to diagnosis: EDs are genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. Genetic variations in genes known to be associated with EDs that affect only one derivative of the ectoderm (attenuated phenotype) will be grouped as non-syndromic traits of the causative gene (e.g., non-syndromic hypodontia or missing teeth associated with pathogenic variants of EDA "ectodysplasin"). Information for categorization and cataloging includes the phenotypic features, Online Mendelian Inheritance in Man number, mode of inheritance, genetic alteration, major developmental pathways involved (e.g., EDA, WNT "wingless-type," TP63 "tumor protein p63") or the components of complex molecular structures (e.g., connexins, keratins, cadherins).

A novel PAX9 mutation found in a Chinese patient with hypodontia via whole exome sequencing.

To investigate a novel gene mutation in a Chinese patient with non-syndromic hypodontia. Mutation analysis was carried out by whole exome sequencing. Bioinformatics tools were used for the biophysical predictions of the mutative protein. Luciferase reporter assay was performed to analyse the effects of mutation on protein function. PAX9 and BMP4 gene expression from mutant cells was detected by qRT-PCR. A novel heterozygous mutation (c.G1057A) was detected in the patient but was not found in the controls. The novel missense mutation led to a Val111Met substitution in the paired box domain which was completely conserved evolutionarily, as analysed by dbNSFP. The mutation was predicted to be disease-causing and harmful using MutationTaster and CADD, respectively. Protean of Lasergene showed that this mutation may lead to β-region shortening in the mutant protein compared to the wild type. Luciferase reporter assay indicated that the mutated protein reduced the transactivation activity of PAX9. This mutation led to increased levels of PAX9 transcript and reduced levels of BMP4 transcript, likely due to compensatory activation and lower transactivation activity of mutant PAX9. This novel mutation (c.G1057A) in PAX9 caused hypodontia by altering PAX9 gene function and downregulating BMP4 gene expression.

WNT10A variants in relation to nonsyndromic hypodontia in eastern Slovak population

Nonsyndromic hypodontia is a congenital absence of less than six permanent teeth, with a most common subtype maxillary lateral incisor agenesis (MLIA). Mutations in several genes have been described in severe tooth agenesis. The aim of this study was to search for the variants in wingless-type MMTV-integration site family member (WNT10A), paired box 9 (PAX9) and axis inhibitor 2 (AXIN2) genes, and investigate their potential role in the pathogenesis of non-syndromic hypodontia. Clinical examination and panoramic radiograph were performed in the cohort of 60 unrelated Slovak patients of Caucasian origin with nonsyndromic hypodontia including 37 MLIA cases and 48 healthy controls. Genomic DNA was isolated from buccal swabs and Sanger sequencing of WNT10A, PAX9 and AXIN2 was performed. Altogether, we identified 23 single-nucleotide variants, of which five were novel. We have found three rare nonsynonymous variants in WNT10A (p.Gly165Arg; p.Gly213Ser and p.Phe228Ile) in eight (13.33%) of 60 patients. Analysis showed potentially damaged WNT10A variant p.Phe228Ile predominantly occurred only in MLIA patients, and with a dominant form of tooth agenesis (odds ratio (ORdom) = 9.841; P = 0.045; 95% confidence interval (CI) 0.492-196.701;ORrec = 0.773; P = 1.000; 95% CI 0.015-39.877). In addition, the WNT10A variant p.Phe228Ile showed a trend associated with familial nonsyndromic hypodontia (P = 0.024; OR= 1.20; 95% CI 0.97-1.48). After Bonferroni correction, these effects remained with borderline tendencies. Using a 3D WNT10A protein model, we demonstrated that the variant Phe228Ile changes the proteinsecondary structure. In PAX9 and AXIN2, common variants were detected. Our findings suggest that the identified WNT10A variant p.Phe228Ile could represent risk for the inherited nonsyndromic hypodontia underlying MLIA. However, further study in different populations is required.