SLC4A3 encodes cardiac anion exchanger 3 (AE3), a sodium-independent transporter mediating electroneutral chloride-bicarbonate exchange across the cell membrane 1. This function is critical for regulating intracellular pH and modulating cardiac action potential duration 1. Mechanistically, SLC4A3 dysfunction leads to intracellular alkalinization, which impairs L-type calcium channel current and enhances sodium-calcium exchanger activity, ultimately shortening action potential duration 2. Both loss-of-function mutations (p.Arg370Cys, p.Lys531Thr) and gain-of-function variants (p.R1016G) have been identified 23. SLC4A3 is now recognized as a major genetic cause of short QT syndrome (SQTS), accounting for approximately 15% of genotyped cases 4. Pathogenic variants are associated with abbreviated QT intervals and ventricular arrhythmias, including delayed afterdepolarizations that trigger sudden cardiac death 25. Class Ia antiarrhythmics (quinidine, sotalol) effectively prolong action potential duration and reduce arrhythmia events in SLC4A3-associated SQTS 2. Beyond cardiac function, SLC4A3 mutations cause progressive retinal atrophy in dogs, suggesting potential retinal involvement in humans 6. The gene's clinical significance justifies genome sequencing approaches in sudden cardiac death cases 7.