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Ectopic Maxillary Canines: Segregation Analysis and a Twin Study
1 Department of Orthodontics and Correspondence: * corresponding author, simon.camilleri{at}kcl.ac.uk, simon.camilleri{at}um.edu.mt
The etiology of ectopic canines is controversial, with opinion divided as to a genetic or environmental mechanism. This study addressed the hypothesis that genetic factors play a role in the etiology of ectopic maxillary canines. Sixty-three probands were identified, and information on the dental status of 395 relatives was determined. Pedigrees were constructed and the Relative Risk calculated. Complex segregation analysis was carried out by means of the Pedigree Analysis Package. The best mathematical model obtained was a single dominant gene with autosomal transmission, incomplete penetrance, and highly variable expression. Only two of seven pairs of monozygotic twins were concordant for ectopic canines. This is consistent with environmental or epigenetic variables affecting the phenotype. The low concordance rate is consistent with the low penetrance determined by the segregation analysis and further supports the existence of environmental factors.
Key Words: tooth eruption • ectopic • cuspid • segregation analysis • Maltese
The ectopic canine is the second most frequently impacted tooth after the third molar, appearing in 3% of the Western population (Ericson and Kurol, 1986). The etiology is controversial. A genetic basis has been suggested (Bjerklin et al., 1992; Peck et al., 1994). Several studies have shown the etiology of ectopic canines to be genetic and associated with other genetically interrelated dental anomalies (Svinhufvud et al., 1988; Bjerklin et al., 1992; Pirinen et al., 1996; Baccetti, 1998). The sex ratio shows a bias toward females (Becker et al., 1981; Ericson and Kurol, 1988), similar to other dental anomalies of genetic origin (Rose, 1966; Davis, 1987). The racial variation, female preponderance, familial occurrence, and association with other dental anomalies imply a polygenic etiology (Kotsomitis and Freer, 1997). Environmental factors have also been identified. Palatal displacement of the canine may be due to local environmental factors, such as anatomically anomalous or late-developing lateral incisor roots (Becker et al., 1981; Chaushu et al., 2002, 2003). Excess space in the dental arch has been implicated (Paschos et al., 2005). There is evidence that both genetic and environmental factors may be involved. (Ely et al., 2006). Alteration of the local environment by extraction of the deciduous canines will ameliorate the condition (Ericson and Kurol, 1988; Power and Short, 1993). The prevalence of ectopic canines in Maltese schoolchildren is 4–5.5% (Camilleri, 1995; Camilleri et al., unpublished observations). This is higher than previously published figures (Ericson and Kurol, 1986), possibly due to the ‘founder effect’, since the Maltese population has grown dramatically, from 17,000 in 1535 to over 300,000 today (Blouet, 2004). This relative abundance and familial clustering of cases prompted a study to test the hypothesis that ectopic canines have a genetic etiology.
Ethical approval was obtained from the University of Malta Medical School Ethics Committee. Informed consent was obtained from all participants prior to inclusion in the study. Thirty-seven consecutive probands with ectopic maxillary canines were identified during routine clinical examination at the private practice of SC and at the School Dental Clinic, Floriana. The inclusion criteria were Maltese Citizenship and a positive history of ectopic (buccally or palatally displaced) canines or failure of eruption of the canine tooth by the age of 16. Individuals affected by a genetic syndrome likely to have an adverse influence on tooth eruption were excluded. A further set of 26 consecutive families was selected on the strength of two probands, to identify families with a stronger predisposition. Families with an affected twin were investigated even if the other twin was unaffected. Ectopic or missing teeth were identified by clinical examination, from existing records, or family history, and radiographic investigation was undertaken only where clinically necessary. We analyzed the pedigree data to assess the familial risk of ectopic canines and other related phenotypes, using the computed familial relative risk. We used the segregation analysis program Pedigree Analysis Program (PAP) (Hasstedt, 2005) to model the inheritance of ectopic canines throughout the 63 pedigrees. Pedigree members were defined as affected or unaffected with ectopic canines (with no further clinical information used). Genetic models assumed a single locus model with penetrances and mutation frequency maximized for each model. Nested models were compared by the likelihood ratio test, where the difference in -2 ln (likelihood) has a chi-square distribution, with the degrees of freedom equal to the difference in the number of additional parameters fitted in the most general model. Sporadic (no genetic effect), recessive, and dominant models were compared with a co-dominant model. A polygenic model was also tested and compared with the dominant model. An ascertainment correction for the probands in each family was applied. Five sets of monozygotic and six sets of dizygotic twins were included in the sample. A further two sets of monozygotic twins and one set of triplets were subsequently referred by a colleague. These were not included in the pedigree or segregation analyses; however, they were used in assessments of pairwise concordance.
The number of individuals of known dental status was 524. One hundred and thirty-nine individuals had ectopic canines. The percentage of dental anomalies in the sample for first-degree relatives was noted, and differences against published population prevalences were investigated. The prevalence of ectopic canines was significantly higher in first-degree relatives (15%, p < 0.001) compared with 4.4–5.5% for the Maltese population (Camilleri, 1995; Camilleri et al., unpublished observations). Lateral incisor agenesis was also higher (7.88%, p = 0.01, as opposed to 3.21% for the general population) (Camilleri and Mulligan, 2007). There were eight cases of maxillary canine transposition in the whole sample. Three were probands, five were first-degree relatives; one was a second-degree relative. Seven were in the upper jaw, giving a prevalence of 1.4%. This is significantly higher (p < 0.001) than the prevalence of 0.27% estimated in a Caucasian population (Yilmaz et al., 2005). Two cases of mandibular canine-lateral incisor transposition were also recorded.
The percentages of first-, second-, and third-degree relatives with ectopic maxillary canines were used to calculate the relative risk (
There was no difference in ectopic canine risk between families ascertained from one or two probands for first-, second-, or third-degree relatives (p = 0.49, p = 0.52, p = 0.65). Nor was there a difference in the numbers of sib-sib and parent-offspring affected pairs for each type of family ascertainment (p = 0.89). There was an appreciable sex bias, with the affected Female-to-Male Ratio for first-, second-, and third-degree relatives being 1.78. The sex ratio for the probands was 1.64, and elimination of the probands from the calculation gave a ratio of 1.89. However, there was no appreciable risk difference between relatives of male or female probands (p = 0.77). The proportion of male first-degree relatives affected vs. the proportion of female first-degree relatives was not significant (p = 0.12).
Although there was no evidence of sex-linked transmission, 85% of the three-generation families showed instances where an obligate carrier showed a normal phenotype, although the condition was transmitted to their children (Fig. 2
We used the segregation analysis program PAP to fit different genetic models to the pedigrees, estimating parameters such as penetrance and mutation frequency. We applied a likelihood ratio test to determine any significant difference in the fit of the various models (Table 2  ). All the genetic models fitted provided a significantly better fit than the sporadic model, confirming that ectopic canines have a genetic basis. The -2log likelihood of the co-dominant model was very similar to the dominant model, but had more parameters. Therefore, the dominant model provided the more parsimonious model, with the -2log (likelihood) for the recessive model being substantially higher. A mixed-dominant model did not provide a sufficiently improved fit, implying that there is no evidence for a polygenic component in addition to the Mendelian locus. These results show that a single dominant gene best accounts for the inheritance of ectopic canines in these pedigrees, with a mutation frequency of 11% and penetrances of 36% in mutation carriers.
From the dominant model fitted in the segregation analysis, the risk to the sibling of an ectopic canine case was calculated to be 0.18. This is similar to the estimate of 0.15 obtained from the pedigree analysis (RR 2.78 x population prevalence 5.5%). The population prevalence predicted by the dominant model was determined according to the formula: q2 * p1 + 2 q (1 – q) p2 + (1 – q)2 p3, where q is the allele frequency, and p1, p2, and p3 are the penetrances for the three genotypes. The calculated prevalence was 7%, which also compared well with the estimated population prevalence of 5.5%. This supports the dominant model as being the most likely.
Seven pairs of monozygotic twins were found. Of these, five were completely discordant, in that one twin was unaffected (Fig. 2
Dental Anomalies There was a significantly higher prevalence of ectopic canines in first-degree relatives of ectopic canine probands (15%, p < 0.001) as compared with figures for the Maltese population (Camilleri, 1995; Camilleri et al., unpublished observations). Familial clustering is a common feature of the trait; however, this could be due to environmental as well as genetic factors. The prevalence of canine transposition in the sample was far higher than the 0.27% prevalence estimated in a Caucasian population (Yilmaz et al., 2005). The highly significant difference is indicative of canine transposition being an extreme variant of ectopic canine, and is consistent with the highly variable expression exhibited. The prevalence of lateral incisor agenesis in the Maltese population is 3.21% (Camilleri and Mulligan, 2007). The high figure found in association with ectopic canines suggests that both traits are related, in keeping with previous evidence (Becker et al., 1981; Svinhufvud et al., 1988; Peck et al., 1994; Pirinen et al., 1996; Baccetti, 1998).
Pedigree Analysis
Considering the high population prevalence, the figure for There was a considerable sex bias toward females, and, surprisingly, elimination of the probands from the calculation produced an increase in the Female-to-Male ratio of the sample. There is no plausible explanation to date for this bias. However, there was no significant difference between the risks to relatives of male or female probands, as expected for an autosomal major gene. Were the trait to be multifactorial, the risk would be higher for the relatives of the less susceptible sex (Farrer and Cupples, 1998).
Segregation Analysis
Twins Monozygotic twins share identical DNA sequences; however, they are often discordant for certain phenotypes. Hypodontia, a genetic disorder associated with ectopic canines, is more prevalent in twins. These twins exhibit a high degree of discordance (Keene, 1971; Lapter et al., 1998; Townsend et al., 2005). It is possible that epigenetic events may be responsible for discordant expression in genetically identical individuals. Indeed, certain imprinting-associated diseases, such as Beckwith-Wiedemann Syndrome, are associated with multiple births and discordance in monozygotic twins (Elliott and Maher, 1994). In contrast, ectopic movement of the maxillary canine has been detected in children as young as 5 years of age (McSherry and Richardson, 1999), and the rapidly growing child is susceptible to a multitude of factors that potentially affect intrabony movement of the canine. Evidence for environmental influence on epigenetic mechanisms further clouds the issue (Bird, 2007). In conclusion, the evidence gathered from analysis of the pedigrees supports the hypothesis of a genetic etiology for ectopic canines, with a single locus being involved, although genetic heterogeneity across pedigrees cannot be ruled out in a modeling study. The most likely mode of transmission is autosomal-dominant. The incomplete penetrance of the dominant locus allows for an environmental component. Further investigation into the molecular etiology of ectopic canines is therefore justified, although the number of monozygotic twins in the sample, plus the discordance of these twins, raises the possibility of gene silencing.
This research was funded jointly by the Faculty of Dental Surgery of the University of Malta (SC) and by the Dental Institute, King’s College London (FM), with additional support from the Wellcome Trust (GR076024, to CML).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License http://creativecommons.org/licenses/by-nc-nd/3.0/us/, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Received for publication March 28, 2007. Revision received January 29, 2008. Accepted for publication February 8, 2008.
Journal of Dental Research, Vol. 87, No. 6,
580-583 (2008)
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ABSTRACT
INTRODUCTION
R) to the first-, second-, and third-degree relatives. This is calculated as (
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