BackgroundShort QT syndrome (SQTS) is a rare inheritable arrhythmia, associated with atrial and ventricular fibrillations, caused by mutations in six cardiac ion channel genes with high penetrance. However, genotype-specific clinical differences between SQTS patients remain to be elucidated. Methods and resultsWe screened five unrelated Japanese SQTS families, and identified three mutations in KCNH2 and KCNQ1. A novel mutation KCNH2-I560T, when expressed in COS-7 cells, showed a 2.5-fold increase in peak current density, and a positive shift (+14mV) of the inactivation curve compared with wild type. Computer simulations recapitulated the action potential shortening and created an arrhythmogenic substrate for ventricular fibrillation. In another family carrying the mutation KCNQ1-V141M, affected members showed earlier onset of manifestation and frequent complications of bradyarrhythmia. To determine genotype-specific phenotypes in SQT1 (KCNH2), SQT2 (KCNQ1), and other subtypes SQT3–6, we analyzed clinical variables in 65 mutation-positive patients among all the 132 SQTS cases previously reported. The age of manifestation was significantly later in SQT1 (SQT1: 35±19years, n=30; SQT2: 17±25years, n=8, SQT3–6: 19±15years, n=15; p=0.011). SQT2 exhibited a higher prevalence of bradyarrhythmia (SQT2: 6/8, 75%; non-SQT2: 5/57, 9%; p<0.001) and atrial fibrillation (SQT2: 5/8, 63%; non-SQT2: 12/57, 21%; p=0.012). Of 51 mutation-positive individuals from 16 SQTS families, nine did not manifest short QT, but exhibited other ECG abnormalities such as atrial fibrillation. The resulting penetrance, 82%, was lower than previously recognized. ConclusionWe propose that SQTS patients may exhibit different clinical manifestations depending upon their genotype.