Background-Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of Ϸ30% by the age of 30 years. Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic reticulum calcium release channel (ryanodine receptor type 2 [RyR2]). Methods and Results-In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders. Conclusions-Our data illustrate that mutations of the RyR2 gene cause at least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling. Key Words: ryanodine receptor calcium release channel Ⅲ sarcoplastic reticulum Ⅲ tachycardia Ⅲ genetics I nherited cardiac disorders associated with a propensity to malignant ventricular tachyarrhythmias constitute an important cause of sudden death in both young and adult individuals. 1 The identification of defective genes that cause the clinical phenotype has the potential to allow molecular diagnostics to identify benign arrhythmias from those that should be treated. In addition, knowledge of the defective protein and its cellular function will allow the development of targeted therapies. Defective genes that cause several of these types of arrhythmic disorders have been identified to date and, thus far, they primarily code for various ion channels in the cardiomyocyte plasma membrane.Long-QT syndrome, which is characterized by a delayed repolarization phase of the cardiac action potential and a risk of life-threatening tachyarrhythmias such as torsade de pointes, was recently shown to be caused by inactivating mutations of the cardiac potassium channels KCNQ1, HERG, minK, or MiRP or activating mutations of the sodium channel SCN5A. 2,3 Activating mutations of SCN5A may cause Brugada's syndrome, a rare dominantly inherited electrophysiological disorder with right bundle branch block on ECG and a propensity to ventricular fibrillation. 4 Arrhythmogenic right ventricular dysplasia (ARVD) is characterized by fatty infiltration and fibrosis of the myocardium, resulting in electric instability and risk of fatal ventricular arrhythmias. At least 6 chromosomal loci for the autosomal-dominant form of ARVD have been mapped, 5-10 and a deletion of the p...