The First Report of a Missense Variant in RFX2 Causing Non-Syndromic Tooth Agenesis in a Consanguineous Pakistani Family

Sher Alam Khan; Saadullah Khan; Noor Muhammad; Zia Ur Rehman; Muhammad Adnan Khan; Abdul Nasir; Umm-E- Kalsoom; Anwar Kamal Khan; Hassan Khan; Naveed Wasif

doi:10.3389/fgene.2021.782653

The First Report of a Missense Variant in RFX2 Causing Non-Syndromic Tooth Agenesis in a Consanguineous Pakistani Family

Front Genet. 2022 Jan 25:12:782653. doi: 10.3389/fgene.2021.782653. eCollection 2021.

Authors

Affiliations

¹ Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Pakistan.
² Dental Material, Institute of Basic Medical Sciences, Khyber Medical University Peshawar, Peshawar, Pakistan.
³ Department of Molecular Science and Technology, Ajou University, Suwon, South Korea.
⁴ Department of Biochemistry, Hazara University, Mansehra, Pakistan.
⁵ Institute of Human Genetics, University of Ulm, Ulm, Germany.
⁶ Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

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.

Keywords: RFX2; hedgehog and fibroblast growth factor signaling pathways; missense variant; non-syndromic; tooth agenesis.