Genetic epidemiology of tooth agenesis in Japan: a population- and family-based study

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1 Clin Genet 2015: 88: Printed in Singapore. All rights reserved Short Report 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: /cge Genetic epidemiology of tooth agenesis in Japan: a population- and family-based study Machida J, Nishiyama T, Kishino H, Yamaguchi S, Kimura M, Shibata A, Tatematsu T, Kamamoto M, Yamamoto K, Makino S, Miyachi H, Shimozato K, Tokita Y. Genetic epidemiology of tooth agenesis in Japan: a populationand family-based study. Clin Genet 2015: 88: John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2014 Tooth agenesis is one of the most common congenital anomalies in humans. However, the etiology of tooth agenesis remains largely unclear, as well as evidence base useful for genetic counseling. Therefore, we estimated the prevalence and sibling recurrence risk, and investigated agenetic patterns systematically. Tooth agenesis was classified into two subtypes: hypodontia (one to five missing teeth) and oligodontia (six or more missing teeth). The prevalence of these two subtypes were 6.8% [95% confidence interval (CI): %] and 0.1% (95% CI: %), respectively, and sibling recurrence risk of these were 24.5% (95% CI: %) and 43.8% (95% CI: %), respectively. This result suggests that the severe phenotype, oligodontia, might be mostly transmitted in a dominant fashion. Using a simple statistical modeling approach, our data were found to be consistent with a bilateral symmetry model, meaning that there was equal probability of missing teeth from the right and left sides. Conflictofinterest This study was not supported by any financial sources nor do the authors have any financial relationships to disclose. J. Machida a, T. Nishiyama b, H. Kishino c, S. Yamaguchi d, M. Kimura d,a.shibata d, T. Tatematsu d, M. Kamamoto e, K. Yamamoto d, S. Makino d, H. Miyachi d,k.shimozato d and Y. Tokita f a Department of Oral and Maxillofacial Surgery, Toyota Memorial Hospital, Toyota, Japan, b Department of Public Health, Aichi Medical University School of Medicine, Nagakute, Japan, c Laboratory of Biometry and Bioinformatics, Graduate School of Agriculture and Life Sciences, University of Tokyo, Tokyo, Japan, d Department of Maxillofacial Surgery, Aichi-Gakuin University, Nagoya, Japan, e Department of oral and maxillofacial surgery, Himeji Red Cross Hospital, Himeji, Japan, and f Department of Perinatology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan Key words: hypodontia oligodontia prevalence sibling recurrence risk tooth agenesis Corresponding author: Takeshi Nishiyama, MD, DPH, PhD, Department of Public Health, Aichi Medical University School of Medicine, 1-1 Yazako, Nagakute, Aichi , Japan. Tel.: ; fax: ; nishiyama@minos.ocn.ne.jp Received 25 March 2014, revised and accepted for publication 2 July 2014 Although non-syndromic tooth agenesis is one of the most common developmental anomalies in humans, the etiology is largely unknown (1). When the third molars, the most commonly missing teeth are excluded, reported prevalence of nonsyndromic tooth agenesis vary enormously, from 2.2 to 10.1% (2). However, previous studies on this matter have relied on various methodologies for detecting tooth agenesis, many of which are unreliable. The sibling recurrence risk is also an important measure, especially for advising families of the likelihood of disease recurrence. Surprisingly, however, there are no published studies addressing recurrence risk for tooth agenesis. Because the prevalence and sibling recurrence risk only relate to the number of missing teeth, they are not sufficient for describing patterns of tooth agenesis. Studies examining frequencies of missing teeth have 167

2 Machida et al. been limited in that they examine only one tooth at a time and not combinations of missing teeth (2). The identification of specific patterns of tooth agenesis would be valuable for understanding this complicated disease. In this study, therefore, we estimated the prevalence and sibling recurrence risk of tooth agenesis using population- and family-based samples, respectively. In addition, we clarified patterns of missing teeth using a simple statistical modeling approach. Methods Prevalence The prevalence of tooth agenesis was estimated using a regular dental checkup system in the west Mikawa region of the Aichi Prefecture in Japan. In 2012, 27 well-trained school dentists examined oral conditions of students according to the predefined format. The subjects for estimating the prevalence of tooth agenesis were all the third-grade students in the junior high schools except for one private school in this catchment area. The participation rate for dental checkups was 95.0%. Of 4088 enrolled students, 3875 remained in this study after excluding subjects without Japanese ancestry, those with a history of extraction or orthodontic treatments, or those with syndromic form of tooth ageneisis such as ectodermal dysplasia. Agenesis of all permanent teeth except third molars was investigated. The number of missing teeth was counted by checking both the absence of permanent teeth or persistence of primary dentition clinically. Consistency between agenesis findings and dental checkup records from the previous year were also checked. As a validation subset of the population-based sample, 25 subjects with and without tooth agenesis were recruited from seven dental clinics in the catchment area which they had visited. The gold standard diagnoses in the subsample were conducted by two researchers (J. M. and K. Y.) independently based on panoramic radiograph, and any disagreements were resolved by discussions. The resulting criterion validity of regular dental checkups was excellent as shown by κ=0.80 [95% confidence interval (CI): ] (3). of tooth agenesis was estimated using 71 probands, who visited the outpatient clinic at Aichi Gakuin University, Nagoya, from April 2006 to March 2012, and their siblings. The diagnoses of the probands and their siblings were based on radiographic examination during this study period, and familial history of tooth agenesis was confirmed by medical records or radiographic examination if possible. All subjects were of Japanese ancestry with no history of major medical disorders likely to be associated with missing or extra teeth, including oral clefts and ectodermal dysplasia. Table 1 shows the family data used to estimate sibling recurrence risk. was estimated using the proband method (4). Table 1. Summary of data pertaining to the 71 families with tooth agenesis Age Median 21.0 (IQR 8.5, range 10 38) Gender Female: 44, male: 27 Number of missing tooth 1: 13 2: : : : 10 NA: 2 Number of affected parents 0: 114 1: 26 NA: 2 Number of affected siblings Number of siblings IQR, interquartile range; NA, not available. Written informed consent was obtained from all participants in the family sample and validation subsample. Written informed consent was obtained from the next of kin in the case of those aged below 20 years. On the other hand, informed consent was not obtained for all patients in the population-based sample except for the validation subsample as the entire data were anonymized prior to the data being shared with the study authors. This applies according to the ethical guidelines for epidemiology research in Japan (5). This study was approved by the Ethics Committee of Aichi-Gakuin University and Toyota Memorial Hospital. The pattern of tooth agenesis We assumed that the number of tooth agenesis of the i-th tooth among all students has a binomial distribution, Bin(n, p i ), where n and p i represent the sample size and a risk of exhibiting agenesis at the i-th tooth, respectively. Here, we used the Fédération Dentaire Internationale (FDI) tooth numbering system to represent tooth number, i (6). On the basis of the assumption that the incidence of agenesis of the i-th tooth is independent of that of the i -th tooth, the likelihood function is given by Π i Bin(n, p i ). Model parameters and indices that characterized the fit of the model were calculated, and the model was compared with nested submodels created by constraining parameters in a stepwise fashion. Akaike s information criterion (AIC), Bayesian information criterion (BIC), the log-likelihood ratio, and the log-likelihood ratio chi-square statistic (χ 2 ) were used to compare nested models. All analyses were performed in the r statistical environment (version ) (7). Results Prevalence Of the 3875 subjects, there were 269 with congenitally absent permanent teeth, excluding third molars. Of 168

3 Genetic epidemiology of tooth agenesis in Japan Table 2. by the number of missing teeth in probands Number of missing teeth (95% confidence interval) % ( %) % ( %) % ( %) 6 or more 43.8% ( %) these, only five students (1.9%) were found to have more than six missing teeth (Table S1, Supporting information). Consequently, the prevalences of hypodontia and oligodontia were 6.8% (95% CI: %) and 0.1% (95% CI: %), respectively. In total, the prevalence of permanent tooth agenesis was 7.0% (95% CI: %). The prevalence of tooth agenesis for females (7.2%, 95% CI: %) was higher than for males (6.7%, 95% CI: %), although the difference was not statistically significant. Among a total of 460 missing teeth (Table S2), 160 (34.8%) were lower second premolars, 141 (30.7%) were upper second premolars, and 39 (8.5%) were lower lateral incisors. Compared with the proportions of missing teeth between hypodontia and oligodontia, canines, first and second premolars were more likely to be missing in oligodontia than in hypodontia, although some of these teeth were not statistically different possibly due to low statistical power (Table S3). Many family members had considerably more missing teeth than individuals in the population-based sample (Table 1). Altogether, sibling recurrence risk of tooth agenesis was 32.6% (95% CI: %). With the increasing number of missing teeth in a proband, sibling recurrence risk eventually resulted in around 25.0% at the number of missing teeth below five but increased sharply to 43.8% at the number of six or more (Table 2). The pattern of tooth agenesis The results of our model-fitting procedure for the population-based sample are shown in Table 3. The full model (Model 1) did not constrain the probability of tooth agenesis incidence, p i, for all teeth, where i refers to tooth number according to the FDI system. Adding constraints to equate p i and p j (i j) in each quadrant resulted in a significantly poorer fit and higher AIC and BIC compared with Model 1. In Model 2, p i was constrained to reflect bilateral symmetry. This model resulted in a non-significant deterioration in fit and more negative AIC and BIC and was thus considered preferable. In Model 3, we constrained p i to be equal in bilateral and bimaxillary symmetry, which resulted in a significantly poorer fit compared with the full model. Therefore, we made various minor amendments to Model 2. First, we added constraints to Model 2 to equate p i and p j (i j) in each quadrant, which resulted in a significantly poorer fit compared with Model 1 and higher AIC and BIC, and were not supported. Next, we loosened the constraints of Model 2 by allowing p i to have bilateral asymmetry. These models were essentially identical in goodness of fit, but had a slightly higher AIC and BIC. These results suggest that Model 2 was the best supported. The p i estimates based on Model 2 are shown in Table S4. Given that the bilateral symmetry model was best supported, then we compared the frequencies between unilateral and bilateral occurrence of tooth agenesis. The estimated proportions of unilateral and bilateral agenesis are shown in Table S5. Unilateral agenesis of upper canines and second premolars occurred more often than bilateral agenesis, as evidenced by non-overlap of 95% confidence intervals. For the other teeth both types of agenesis were not significantly different in frequency. Discussion Many of previous studies regarding the prevalence of non-syndromic tooth agenesis have concerns about the methodological problems. To identify only studies using sound methodology, the following criteria were used; first, a sample was considered representative of the general population. Second, the diagnosis of dental agenesis was made after the age of seven because the radiographic diagnosis of dental agenesis of a mandibular second premolar before the age of seven is probably not conclusive (2). Third, panoramic radiography was used to diagnose the number of teeth. If all subjects were not diagnosed by panoramic radiograph, the diagnosing method was validated using panoramic radiography as the gold standard. On the other hand, conventional radiography, such as the lateral oblique method are frequently plagued by distorted images and superimposition of anatomic structures (8). Of the many previous articles regarding the prevalence of tooth agenesis, only five satisfied these criteria (Table S6). The prevalence reported in these studies ranged from 6.5 to 7.4% (9 13), a range that includes the prevalence estimated in our study. In all five studies, as well as in ours, the prevalence of tooth agenesis was higher in females than in males, but the differences were statistically significant in only one study (9). Our study revealed that the lower second premolars were the most commonly missing tooth, followed by the upper second premolar and lateral incisor. This finding in the Japanese population is in close accord with findings in other populations (2, 9, 10). On the other hand, this study has findings that contradict previous studies such as higher prevalence of upper canines (8.6%) and lower prevalence of upper lateral incisors (3.0%) in affected subjects than those reported (9 13). The reason can be considered that the allelic frequency spectra of agenesis susceptibility differ between populations. Also, the possibility of measurement error cannot be completely ruled out because contradicted findings on upper canines and lateral incisors are found in the study of the Chinese population (9). To our knowledge, this is the first study to estimate sibling recurrence risk of tooth agenesis formally. In our 169

4 Machida et al. Table 3. Model fitting of tooth agenesis for population-based sample a logl AIC BIC χ 2 Δdf p-value Model 1: saturated model Model 1 + p i2 = p i Model 1 + p i3 = p i <0.001 Model 1 + p i3 = p i <0.001 Model 1 + p i1 = p i <0.001 Model 2: bilateral symmetry model Model 2 + p 15 p Model 2 + p 12 p Model 2 + p 35 p Model 2 + p 32 p Model 2 + p i2 = p i Model 2 + p i3 = p i <0.001 Model 2 + p i3 = p i <0.001 Model 2 + p i1 = p i Model 3: bilateral and bimaxiral symmetry model <0.001 logl, log-likelihood; AIC, Akaike s Information Criteria based on the full model; BIC, Bayesian information criterion; Δdf, degrees of freedom obtained by subtracting the df of the saturated model from the df of each model. a p i for all teeth, where i refers to a given tooth numbered according to the FDI system, for example, 1 = first incisor, 2 = lateral incisor, 3 = canine, 4 = first premolar, 5 = lateral premolar, 6 = first molar, 7 = second molar). The row given in bold shows the best supported model. study, we found that sibling recurrence risk of hypodontia and oligodontia were 24.5% (95% CI: %) and 43.8% (95% CI: %), respectively. This finding validated the differentiation between oligodontia and hypodontia with a cutoff value of six missing teeth. This result indicated that the severe oligodontia phenotype might be transmitted following a primarily dominant pattern, whereas the mild hypodontia phenotype might not be. In fact, many genes associated with familial oligodontia, such as MSX1, AXIN, PAX9, EDA, and EDARADD were identified in apparently non-familial cases (14). We employed a simple binomial model to describe patterns of tooth agenesis. The results of the model-fitting procedure revealed that a model with symmetry of tooth agenesis between the right and left sides, both in the maxilla and mandible, might be the most parsimonious and best fitting. Furthermore, comparing bilateral and unilateral agenesis, unilateral agenesis of upper canines and second premolars occurred significantly more often than bilateral agenesis of these, but for the other teeth both types of agenesis were not significantly different in frequency (Table S5). This finding partly contradicts previous studies (2, 10) though they might suffer from selection bias. These findings can be interpreted in the context of odontogenesis. Organs originating from the branchial arch occur symmetrically and the time and order of tooth eruption are symmetric in each jaw (15). Our finding supports this symmetric process of odontogenesis. In conclusion, we confirmed the prevalence of tooth agenesis to be 7.0%, which is consistent with previous evidence(9 13). We also estimated sibling recurrence risk, which validated the differentiation between oligodontia and hypodontia. The sibling recurrence risk of oligodontia similar to a dominant segregation ratio implies that a substantial portion of patients with oligodontia might be transmitted in a dominant fashion. As for the pattern of tooth agenesis, the likelihood of tooth agenesis proved to be left right symmetric. Supporting Information Additional supporting information may be found in the online version of this article at the publisher s web-site. Acknowledgements We thank all of the family members and dentists, especially E. Kondo, M. Osawa, and R. Osawa, who participated in this study. We also thank the members of the board of education, Toyota City. References 1. Nieminen P. Genetic basis of tooth agenesis. J Exp Zool B Mol Dev Evol 2009: 312B: Polder BJ, Van t Hof MA, Van der Linden FPGM, Kuijpers-Jagtman AM. A meta-analysis of the prevalence of dental agenesis of permanent teeth. Community Dent Oral Epidemiol 2004: 32: Fleiss J. Statistical methods for rates and proportions. New York, NY: John Wiley, Sham P. Statistics in human genetics. London: Arnold Publications, Japanese Ministry of Education, Culture, Sports, Science and Technology, Ministry of Health, Labor and Welfare. Ethical guidelines for epidemiological research[in Japanese]. Japanese Ministry of Education, Culture, Sports, Science and Technology, Peck S, Peck L. Tooth numbering progress. Angle Orthod 1996: 66: R Development CoreTeam. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing, Langland OE, Langlais RP, Charles RM. Panoramic radiology. Philadelphia, PA: Lea and Febiger, Davis PJ. Hypodontia and hyperdontia of permanent teeth in Hong Kong schoolchildren. Community Dent Oral Epidemiol 1987: 15: Rølling S, Poulsen S. Agenesis of permanent teeth in 8138 Danish schoolchildren: prevalence and intra-oral distribution according to gender. Int J Paediatr Dent 2009: 19:

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