Case report: A novel de novo loss of function variant in the DNA-binding domain of TBX2 causes severe osteochondrodysplasia

Misbahuddin M Rafeeq; Hussam Aly Sayed Murad; Najumuddin; Samee Ullah; Zaheer Ahmed; Qamre Alam; Muhammad Bilal; Alaa Hamed Habib; Ziaullah M Sain; Muhammad Jawad Khan; Muhammad Umair

doi:10.3389/fgene.2022.1117500

Case report: A novel de novo loss of function variant in the DNA-binding domain of TBX2 causes severe osteochondrodysplasia

Front Genet. 2023 Jan 17:13:1117500. doi: 10.3389/fgene.2022.1117500. eCollection 2022.

Authors

Affiliations

¹ Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia.
² National Center for Bioinformatics (NCB), Quaid-i-Azam University, Islamabad, Pakistan.
³ National Center for Bioinformatics (NCB), Islamabad, Pakistan.
⁴ Department of Biosciences, COMSATS University, Islamabad, Pakistan.
⁵ Molecular Genomics and Precision Medicine, ExpressMed Laboratories, Zinj, Bahrain.
⁶ Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan.
⁷ Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
⁸ Department of Microbiology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia.
⁹ Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan.
¹⁰ Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGH), Riyadh, Saudi Arabia.

Abstract

Background: T-box family members are transcription factors characterized by highly conserved residues corresponding to the DNA-binding domain known as the T-box. TBX2 has been implicated in several developmental processes, such as coordinating cell fate, patterning, and morphogenesis of a wide range of tissues and organs, including lungs, limbs, heart, kidneys, craniofacial structures, and mammary glands. Methods: In the present study, we have clinically and genetically characterized a proband showing a severe form of chondrodysplasia with developmental delay. Whole-exome sequencing (WES), Sanger sequencing, and 3D protein modeling were performed in the present investigation. Results: Whole-exome sequencing revealed a novel nonsense variant (c.529A>T; p.Lys177*; NM_005994.4) in TBX2. 3D-TBX2 protein modeling revealed a substantial reduction of the mutated protein, which might lead to a loss of function (LOF) or nonsense-mediated decay (NMD). Conclusion: This study has not only expanded the mutation spectrum in the gene TBX2 but also facilitated the diagnosis and genetic counseling of related features in affected families.

Keywords: TBX2; WES; chondrodysplasia; nonsense mutation; novel variant.

Publication types

Case Reports

Grants and funding

This research work was funded by Institutional Fund Projects under grant no. (IFPIP:113-828-1443). The authors gratefully acknowledge technical and financial support provided by the Ministry of Education and King Abdulaziz University, DSR, Jeddah, Saudi Arabia.