The graphical abstract represents three possible functional conditions. On the left is a cell with no disease-causing variant in the potassium voltage-gated channel subfamily H member 2 ( KCNH2) gene, and therefore, potassium channels are composed by four wild-type (WT) subunits (blue small circles). In the middle panel is a cell with haploinsufficiency (HI): there are less potassium channels available, but all with WT subunits. On the right panel is a cell with a mutation causing a dominant-negative (DN) effect: channels are composed by a random mix of WT and mutant subunits (red small circles). The amount of rapid component of the delayed rectifier potassium current (IKr) is progressively decreasing going from WT to HI to DN with an opposite increase in QT interval corrected for heart rate (QTc) and arrhythmic risk.