Identification of a novel missense mutation in non-syndromic familial multiple supernumerary teeth

Tooth development is the result of the interaction between oral epithelium and the ectopic mesenchyme of the neural crest, and the teeth finally form through a series of cell divisions and morphogenesis, which is controlled by the coordinated functions of numerous genes (Murakami et al., 2017). Multiple supernumerary teeth may occur during the onset of the proliferation phase of tooth germ development if there are developmental defects or genetic mutations. The exact gene etiology of supernumerary teeth is poorly understood, but there are emerging case reports regarding multiple supernumerary teeth with an obvious tendency of family aggregation (Kaya et al., 2011, Lei et al., 2011, Leyland et al., 2006). Supernumerary teeth with functional abnormalities refer to teeth that have either erupted or remain unerupted in addition to primary and permanent dentition (Anthonappa et al., 2013a). Moreover, it may occur singly, multiply, unilaterally, or bilaterally in the maxilla, mandible, or both jaws (Desai & Shah, 1998). According to the intraoral position of the supernumerary teeth, the classification is mesiodens; paramolar; distomolar, and parapremolar (Mason & Rule, 1995). Luten (1967) suggest, bicuspids (3%), upper central incisors (11%), mesiodens (36%), and upper lateral incisors (50%), while Shapira and Kuftinec (1989) state the order of increasing frequency as: lateral incisors and canines, premolars, molars, and upper central incisors. The prevalence of supernumerary teeth ranges from 1.5% to 3%. Besides, these figures have been redemonstrated a higher prevalence range (Anthonappa et al., 2013b). In most cases, multiple supernumerary teeth are associated with syndromes (Aggarwal et al., 2003, Bufalino et al., 2012, Jugessur et al., 2009), while non-syndromic multiple supernumerary teeth are very rare (Kaya et al., 2011).

As supernumerary teeth are more commonly found in syndromes, previous studies focused on the genetic variations of syndromes with the manifestation of supernumerary teeth, for instance, the runt-related transcription factor 2 (RUNX2; OMIM 600211) gene in cleidocranial dysplasia (CCD; OMIM 119600) (Otto et al., 2002), the adenomatous polyposis coli (APC; OMIM 611731) gene in Gardner syndrome (OMIM 175100) (Yusof, 1990), and the Nance-Horan syndrome (NHS; OMIM 300457) gene in Nance-Horan syndrome (NHS; OMIM 302350) (Burdon et al., 2003). Although multiple supernumerary teeth usually occurred in association with the abovementioned syndromes, we found two cases of familial multiple supernumerary teeth without any syndromes, which aroused our strong interest in exploring the underlying genetic mechanisms of the disease.

For supernumerary teeth cause a wide range of complications such as crowding, displacement, cyst formation, impaction, and root resorption, early genetic diagnosis is essential to avoid the potential complications. In the present study, we described the clinical features and genetic characteristics of the two patients with non-syndromic multiple supernumerary teeth in the same family and detected the genetic variations of this family through whole-genome sequencing (WGS) analysis and Sanger sequencing verification.

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