Novel TBX20 Variations Susceptible to Sporadic Atrial Fibrillation

Background/Objectives: Atrial fibrillation (AF), the most prevalent form of clinical cardiac arrhythmia globally, is associated with markedly increased morbidity, mortality, and socio-economic expenditure. Accumulating strong evidence highlights genetic abnormalities underpinning its etiopathogenesis. A recent investigation has demonstrated that mutations in the TBX20 gene, which codes for a T-box transcription factor essential for proper cardiovascular development and structural remodeling, contribute to familial AF. Nevertheless, the mutational prevalence and spectrum of this gene in patients with sporadic AF remain unknown. Methods: A cohort of 352 individuals suffering from sporadic AF and a group of 376 healthy subjects without AF history were recruited prospectively. Sanger sequencing examination of TBX20 was implemented in all research participants. The functional impacts of the discovered TBX20 variations were quantitatively measured by dual-reporter gene analysis. Results: Two novel heterozygous truncating TBX20 variations, NM_001077653.2: c.725C>A; p.(Ser242*) and NM_001077653.2: c.826A>T; p.(Lys276*), were detected in two of the 352 cases with sporadic AF, respectively, with a mutational prevalence of approximately 0.57%. The two TBX20 variants were absent from the 752 control chromosomes. Functional measurements revealed that both Ser242* and Lys276* variants lost transactivation on KCNH2 and NPPA, two genes responsible for AF. In addition, each of the two variations abrogated the synergistic transactivation of NPPA by TBX20 together with NKX2.5, another gene reported to cause AF. Conclusions: The current data indicate haplo-insufficient TBX20 variations as new genetic defects predisposing to sporadic AF and hence are conducive to improving the prophylaxis and treatment strategies of sporadic AF in a subset of patients.