Subphenotypes in Non-Syndromic Orofacial Cleft Patients Based on the Tooth Agenesis Code (TAC)

Abstract

Background: It was the aim of this study to investigate tooth agenesis patterns, which are expressed to different subphenotypes according to the TAC method in a spectrum of non-syndromic orofacial cleft patients. Methods: A total of 183 orofacial cleft patient records were assessed for tooth agenesis and TAC patterns. The association between TAC and sex, and cleft type was examined, and logistic regression models were additionally applied. Additionally, the distribution of missing teeth by cleft type and the tooth agenesis inter-quadrant association were examined. Results: The most frequent cleft type was CLPL (n = 72; 39.3%), while the maxillary left lateral incisor was the most frequently missing tooth that was strongly dependent on the cleft type (29.5%, p < 0.001). Of the 31 TAC patterns identified, four were the most prevalent and occurred in 80.8% of the sample, while 20 TAC patterns were unique. Cleft type contrary to sex (p = 0.405) was found to play a significant role in TAC distribution (p = 0.001). The logistic regression’s results suggested that overall, neither sex nor cleft type were associated with tooth agenesis. Prevalence of tooth agenesis in each quadrant clearly depended on cleft type; and there was a strong association found between tooth agenesis in different quadrants. Conclusions: Thirty-one different subphenotypes were identified in TAC patterns. The first four TAC patterns accounted for the 80.8% of the sample’s variability while twenty of the patterns were unique. A strong association was present between TAC pattern and cleft type. No association was found between the sex of the patient, tooth agenesis and TAC patterns. Tooth agenesis depended strongly on the cleft type, and the most frequently missing tooth was the maxillary left lateral incisor. The interquadrant association for tooth agenesis found suggests a genetic link in the etiology of clefts.

Tooth Agenesis Patterns in Orofacial Clefting Using Tooth Agenesis Code: A Meta-Analysis

“…Hermus and Lopez-Gimenez found the TAC pattern 0.2.0.0 to be the most common, with 15.7% and 19.1%, respectively, with Bartzela finding it to be the third most common TAC pattern at a rate of 5.8%. These findings are consistent with the OFC1 dataset (11%) and the recent work by Konstantonis et al, 2022 [ 27 ]. These findings confirm that the maxillary lateral incisor is the most common tooth to have agenesis (excluding third molars) in subjects with OFC, with the definitive patterns revealing agenesis of no other tooth besides the maxillary lateral incisor alone (0.2.0.0 or 2.0.0.0) or together (2.2.0.0).…”

“…The results from the meta-analysis are further supported by looking only at the OFC1 dataset, as it is the only dataset in this analysis that has cases and controls in the same study, and also a recent publication that although not included in our analyses due to its recent appearance, we discussed here [27]. We found similar TAC patterns as compared to all studies included in the meta-analysis, with 0.2.0.0, 2.0.0.0, and 2.2.0.0 being significant when comparing cases vs. controls.…”

“…Although, this result should be interpreted with caution because only two studies included in our meta-analyses (Hermus et al 2013 and OFC1) had sex data for each pattern, and this is a limitation of this study. The most recent study by Konstantinos et al also found no relation between gender and TAC patterns [ 27 ]. Another limitation of the meta-analysis is the lack of TAC studies with both case and control groups.…”

Novel Candidate Genes for Non-Syndromic Tooth Agenesis Identified Using Targeted Next-Generation Sequencing

“…The patient inherited this novel p.Arg339Gly missense substitution from her father with cleft palate only (results not shown). This result may support the hypothesis of a common genetic link between the congenital lack of teeth and orofacial clefts, which are frequently co-occurring craniofacial defects [ 19 , 57 , 58 , 59 ]. In addition, it may confirm the assumption that dental anomalies are subclinical phenotypes of the OFC spectrum.…”

Characterization of SHH, SOX3, WNT3A and WNT9B Proteins in Human Non-Syndromic Cleft Lip and Palate Tissue

“…Different classification systems have been previously devised to categorize the variations of orofacial clefts based on their anatomical location, phenotypical variations and patterns, clinical characteristics, and other specifics [ 11 , 12 , 13 ]. Clefts of the orofacial region can be categorized by different types based on the location, including unilateral cleft lip, bilateral cleft lip, cleft lip with or without cleft palate, isolated cleft palate, cleft of the alveolus, clefts of the primary palate, clefts of the secondary palate [ 11 , 12 ].…”