Congenital heart disease (CHD) is the most common birth defect. Tetralogy of Fallot (TOF) is a severe form of CHD. While genetic changes in protein-coding regions are known to cause some cases, the role of non-coding regulatory regions remains unclear. Our study focused on the MEF2C promoter, which acts like a switch that controls gene activity. We identified five rare variants in TOF patients that changed gene function in heart cells. These variants also disrupted binding sites for key regulatory proteins. This work reveals how non-coding DNA variants can contribute to TOF, opening new avenues for understanding the mechanism and helping the diagnosis of CHD. (https://jmg.bmj.com/content/early/2026/06/29/jmg-2026-111657)