TBX5 is a T-box transcription factor essential for cardiac and forelimb development, functioning primarily as a transcriptional activator 1. During early cardiogenesis, TBX5 activates genes associated with cardiomyocyte maturation and septation signaling, while later in development it patterns the cardiac conduction system and maintains mature cardiomyocyte function 1. TBX5 maintains atrial identity by binding to an atrial-specific enhancer network and regulating chr12 architecture in post-natal cardiomyocytes 2. The protein interacts with other cardiac transcription factors in developmental networks 34, and cooperates with factors like MEF2C and PHF7 in fibroblast reprogramming toward cardiomyocytes 5. Dominant mutations in TBX5 cause Holt-Oram syndrome, characterized by congenital heart defects (septal defects, arrhythmias) and forelimb abnormalities 67. A systematic review identified 108 TBX5 variants in 277 patients, revealing a genotype-phenotype relationship: missense variants cluster in the T-box domain and associate with increased arrhythmia risk (48% vs 30%), while protein-truncating variants more frequently cause limb abnormalities (85% vs 64%) 6. These findings underscore TBX5's critical role in maintaining both cardiac structure and conduction system function.