Discovery of SOX5 as a New Causative Gene for Atrial Fibrillation

<b>Background/Objectives:</b> Atrial fibrillation (AF), characteristic of chaotic atrial electrical activity along with ineffective atrial systole, remains the most frequent sustained cardiac dysrhythmia, with an overall lifetime risk for AF being approximately 15% to 40% in the global population. AF is associated with substantially enhanced risks for multiple adverse clinical outcomes, including thromboembolic cerebral stroke, dementia, chronic kidney disease, myocardial infarction, cardiac failure, and even premature cardiac demise. Although remarkable advances have been achieved toward unravelling the complex hereditary etiopathogenesis underpinning AF, it has become increasingly clear that inherited determinants predisposing to AF in a vast majority of individuals are still uncertain. <b>Methods:</b> A Chinese pedigree with idiopathic AF and another group of 236 cases suffering idiopathic AF along with 312 unrelated healthy volunteers were prospectively recruited. Exome-wide sequencing and Sanger sequencing assays were implemented in research participants. The functional effects of the discovered variations in the <i>SOX5</i> gene were explored through dual-luciferase reporter analysis. <b>Results:</b> Two novel <i>SOX5</i> mutants, NM_006940.6: c.355C>T; p.(Gln119*) and NM_006940.6: c.640G>T; p.(Glu214*), were identified in the AF pedigree and one of the 236 unrelated patients affected with AF, respectively. These two heterozygous truncating SOX5 variations were absent from the 624 control chromosomes. Quantitative luciferase reporter assays unraveled that both Gln119*- and Glu214*-mutant SOX5 lost the ability to transactivate <i>GJA1</i>. Additionally, the two variations abolished the synergistic transactivation of <i>SCN5A</i> by SOX5 and SHOX2. <b>Conclusions:</b> The current findings indicate <i>SOX5</i> as a novel gene contributing to AF, which adds more insight to the molecular pathogenesis of AF, and provides a potential target for personalized precision medicine.