The early repolarisation syndrome (ERS), a particular electrocardiographic aspect defined as a J-point elevation, notching or slurring of the terminal portion of the R wave (J wave), and tall/symmetric T wave, had been interpreted by electrophysiologists as benign until very recently. Indeed, there are now studies concluding that individuals with ERS in infero-lateral leads are at higher risk of developing ventricular arrhythmia and sudden cardiac death. Therefore, ERS potential malignant nature cannot be neglected anymore (Haïssaguerre et al. 2008). ERS phenotype has been correlated to mutations of KCNJ8, encoding the predominant cardiac KATP channel pore-forming subunit, Kir6.1, or of genes coding for the Ca2+ channels generating the L-type Ca2+ current, or the Na+ channel Nav1.5 (Haïssaguerre et al. 2008; Medeiros-Domingo A et al., 2010; Burashnikov E et al., 2010; Watanabe Het al., 2011). The cardiac KATP channel is an octameric complex of four pore-forming Kir6.1 or Kir6.2 subunits and four regulatory subunits SUR2A (encoded by ABCC9). Little is known about the extent to which KATP mutations contribute to ERS associated with sudden cardiac death. The purpose of this study was to further explore ABCC9 as a novel susceptibility gene for ERS. Direct DNA sequencing of ABCC9 was performed among 94 probands diagnosed with ERS or idiopathic ventricular fibrillation (VF). Three rare mutations were identified in ABCC9 (leading to p.A665T, p.V1137I, and pV1319I) and functionally characterized. Mutant SUR2A cDNA-containing plasmids were co-transfected with Kir6.x subunits cDNA-containing plasmids in COS-7 cells. Wild type (WT) and mutants K+ currents were recorded using the whole-cell configuration of the patch clamp technique at room temperature. We observed no effect of SUR2A V1137I variant on the K+ current when compared to WT SUR2A, whatever the co-expressed Kir6.x subunit. However, KATP current of Kir6.1-SUR2A-A665T was significantly increased only in the presence of 100 µM pinacidil, a KATP channel activator, compared to Kir6.1-SUR2A WT current (22.7 ± 3.3 pA/pF, n = 29 vs. 63.8 ± 17.3 pA/pF, n = 17, for WT and A665T, respectively; p < 0.05, Mann-Whitney rank sum test), but when expressed with Kir6.2, no difference could be detected (71.7 ± 16.8 pA/pF, n = 34 vs. 83.8 ± 26.1 pA/pF, n = 37, for WT and A665T, respectively; p = 0.46, M-W). Inside-out patch clamp recording showed that the ATP sensibility was unchanged for Kir6.2-SUR2A-A665T compared to Kir6.2-SUR2A WT channels. Function of Kir6.x-SUR2A-V1319I, and expression level and localization of Kir6.1 protein when co-expressed with SUR2A-A665T are currently under investigation. In this study, we identified ABCC9 as a novel ERS susceptibility gene and a mutation leading to a marked gain-of-function of the cardiac KATP Kir 6.1-SUR2A channel complex.