# Comprehensive Genetic Exploration of Fused Teeth by Whole Exome Sequencing
## 4 Discussion  
This study aimed to investigate the genetic background of fused teeth, which are frequently observed in Asian populations. We used WES analysis to evaluate 15 Japanese and Korean individuals from six families. We succeeded in extracting candidate variants that may be involved in the incidence of fused teeth using exome analysis; this is the first \begin{table}
\begin{tabular}{c c c c c c} \hline \hline \multirow{2}{*}{**Gene**} & \multicolumn{4}{c}{**Subject ***} \\ \cline{2-6}  & **A-1** & **B-1** & **C-1** & **F-1** & **F-2** \\ \hline _ERCC6_ & & & & c.2204G>T & c.2204G>T \\ _OBSCN_ & & & & c.5867C>G & c.5867C>G \\ _SLC27A3_ & c.1036C>T & & & c.2086G>A & & \\ _KIF25_ & & & c.2086G>A & & \\ \hline \hline \end{tabular}  
* Subjects are identified by family, for example, A-1 refers to patient 1 from Family A, etc.  
\end{table} 
Table 2: Candidate gene variants found in variant-positive patients. \begin{table}
\begin{tabular}{c c c c c c c c c c} \hline \hline \multirow{2}{*}{**Gene**} & \multicolumn{2}{c}{**GenBank**} & \multirow{2}{*}{**Nucleotide**} & \multicolumn{2}{c}{**Amino**} & \multicolumn{4}{c}{**MAF**} & \multirow{2}{*}{**CADD**} \\  & & **Accession** & & & & & & & & \\  & **Number** & **Substitution** & & & **gonAD** & **1000** & **EAS** & **Genomes** & **ExAC** & **(scaled)** \\ \hline _ERCC6_ & NM\_000124 & c.2204G>T & p.Arg735 Leu & rs75037497 & 0 & 0.0014 & 0 & 0.00009885 & 35 & Damaging \\ _OBSCN_ & NM\_001098623 & c.5867C>G & p.Thr1956 Ser & rs559944127 & 0 & 0 & 0.0002 & 0.0004997 & 23 & Damaging \\ _SLC27A3_ & NM\_024330 & c.1385G>A & p.Arg462 His & rs143908472 & 0.0001 & 0.0025 & 0.0002 & 0.0002 & 34 & Damaging \\ _SLC27A3_ & NM\_024330 & c.1036C>T & p.Arg467 Hrp & rs150357360 & 0.0002 & 0.002 & 0.0002 & 0.0002 & 25.7 & Damaging \\ _KIF25_ & NM\_005355 & c.208G>A & p.Gly70 Arag & rs46548637 & 0 & 0 & 0.000008241 & 26.8 & Damaging \\ \hline \hline \end{tabular}  
* Abbreviations: MAF name allele frequency; gnomAD, Genome Aggregation Database; ExAC, Exome Aggregation Consortium; gnomAD EAS, Genome Aggregation Database East Asian; CADD, Combined Annotation Dependent Depletion; PolyPhen2, Polymorphism Phenotyping v2.  
\end{table} 
Table 3: Identified variants and their pathogenicity scores. report of such variants, as far as we are aware. These variants occur in the _ERCC6_, _OBSCN_, _SLC27A3_, and _KIF25_ genes. In this study, when rare variants in individuals without fused teeth were excluded, no genotype-phenotype-matched variants were found in all families. This may indicate that the variants identified are only partially responsible for cases of fused teeth. The causative variants of tooth agenesis show incomplete penetrance [21,22]. [PERSON] et al. [23] reported that _WNT10A_ shows incomplete penetrance in the incidence of tooth agenesis in the Thai population. From our results alone, it is not possible to clarify whether the penetrance of the variants potentially causing the fused teeth is complete or incomplete. Additional studies on penetrance, such as WES analysis of larger families, are necessary. _ERCC6_ is associated with transcription-coupled nucleotide excision repair and RNA polymerase I promoter escape. It is also one of the genes responsible for the incidence of Cockayne syndrome B (OMIM # 133540 COCKAYNE SYNDROME B; CSB), an autosomal recessive disorder classified into types I, II, and III. _ERCC6_ mutations are found in 65% of Cockayne syndrome (CS) cases [24,25]. More than 10% of people with CS type I have missing or hypoplastic teeth, delayed eruption of primary teeth, occlusal disharmony, or severe dental caries [26]. A CS case report noted that intraoral findings included dental caries and anomalies in tooth size and shape [27]. Another case report presented intraoral findings of hypoplastic teeth [28]. _ERCC6_ is associated with tooth absence and dysplasia, and it may be possible to propose a similar and possibly related mechanism for the development of fused teeth.