Abstract
Background: The syndromic and non-syndromic congenital missing teeth phenotype is termed tooth agenesis. Since tooth agenesis is a heterogeneous disorder hence, the patients show diverse absent teeth phenotypes. Thus identifying novel genes involved in the morphogenesis of ectodermal appendages, including teeth, paves the way for establishing signaling pathways. Methods and Results: We have recruited an autosomal recessive non-syndromic tooth agenesis family with two affected members. The exome sequencing technology identified a novel missense sequence variant c.1421T > C; p.(Ile474Thr) in a regulatory factor X (RFX) family member (RFX2, OMIM: 142,765). During the data analysis eight rare variants on various chromosomal locations were identified, but the co-segregation analysis using Sanger sequencing confirmed the segregation of only two variants RFX2: c.1421T > C; p.(Ile474Thr), DOHH: c.109C > G; p.(Pro37Ala) lying in a common 7.1 MB region of homozygosity on chromosome 19p13.3. Furthermore, the online protein prediction algorithms and protein modeling analysis verified the RFX2 variant as a damaging genetic alteration and ACMG pathogenicity criteria classified it as likely pathogenic. On the other hand, the DOHH variant showed benign outcomes. Conclusion: RFX2 regulates the Hedgehog and fibroblast growth factor signaling pathways, which are involved in the epithelial and mesenchymal interactions during tooth development. Prior animal model studies have confirmed the expression of rfx2 at a developmental stage governing mouth formation. Moreover, its regulatory role and close association with ciliary and non-ciliary genes causing various dental malformations makes it a potential candidate gene for tooth agenesis phenotype. Further studies will contribute to exploring the direct role of RFX2 in human tooth development.
Highlights
Tooth agenesis (TA) is a craniofacial malformation characterized by the absence of one or more teeth due to failure in the early stages of odontogenesis (Letra et al, 1993)
The affected individuals (IV-4, 29-years, and IV-5, 24-years) showing variable missing teeth conditions were recruited at the dentistry department, Khyber Medical University, Peshawar, Khyber Pakhtunkhwa (KP), Pakistan
A dental specialist performed a clinical evaluation of the patients
Summary
Tooth agenesis (TA) is a craniofacial malformation characterized by the absence of one or more teeth due to failure in the early stages of odontogenesis (Letra et al, 1993). Populationbased studies have shown that the incidence of third molar agenesis (20%) is the most commonly known missing teeth phenotype. Based on the number of missing teeth, TA can be classified into three categories: hypodontia (six missing teeth), and anodontia (congenital absence of all primary and permanent teeth) (Stockton et al, 2000; De Coster et al, 2009). The monogenic inheritance was considered for TA in the previous studies, but recently several studies have proposed oligogenic patterns (Dinckan et al, 2018; Du et al, 2018), supporting the concept of mutational load in human genetic disorders (Posey et al, 2017). The syndromic and non-syndromic congenital missing teeth phenotype is termed tooth agenesis. Identifying novel genes involved in the morphogenesis of ectodermal appendages, including teeth, paves the way for establishing signaling pathways
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