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...

A distinct cardiac disorder linked to chromosome 1q42-q43 causes exercise-induced polymorphic ventricular tachycardia in structurally normal hearts and is highly malignant. Delayed clinical manifestation necessitates repeated exercise electrocardiography to assure diagnosis in young individuals of the families.

The constant a priori risk for common pathogenic cryptic imbalances detected by this technology is estimated to be ~0.3%. A prevalence higher than that previously estimated was found for the 22q11.2 microdeletion. Their frequencies were independent of maternal age. These data have implications for cell-free DNA screening tests design and justify prenatal screening for 22q11 deletion, as early recognition of DGS improves its prognosis.

LQT1 is associated with diminished chronotropic response and exaggerated prolongation of QT interval after exercise. LQT2 patients differ from LQT1 patients by having marked QT interval shortening and normal heart rate response to exercise. Observing QT duration during recovery enhances the clinical diagnosis of these LQTS types.

Background-␤-Blocker efficacy in long-QT syndrome type 1 is good but variably reported, and the causes of cardiac events despite ␤-blocker therapy have not been ascertained. Methods and Results-This was a retrospective study of the details surrounding cardiac events in 216 genotyped long-QT syndrome type 1 patients treated with ␤-blocker and followed up for a median time of 10 years. Before ␤-blocker, cardiac events occurred in 157 patients (73%) at a median age of 9 years, with cardiac arrest (CA) in 26 (12%). QT-prolonging drugs were used by 17 patients; 9 of 17 (53%) had CA compared with 17 of 199 nonusers (8.5%; odds ratio, 12.0; 95% confidence interval, 4.1 to 35.3; PϽ0.001). After ␤-blocker, 75% were asymptomatic, and cardiac events were significantly reduced (PϽ0.001), with a median event count (quartile 1 to 3) per person of 0 (0 to 1). Twelve patients (5.5%) suffered CA/sudden death, but 11 of 12 (92%) were noncompliant (nϭ8), were on a QT-prolonging drug (nϭ2), or both (nϭ1) at the time of the event. The risk for CA/sudden death in compliant patients not taking QT-prolonging drugs was dramatically less compared with noncompliant patients on QT-prolonging drugs (odds ratio, 0.03; 95% confidence interval, 0.003 to 0.22; Pϭ0.001). None of the 26 patients with CA before ␤-blocker had CA/sudden death on ␤-blockers. Conclusions-␤-Blockers

The extent of genetic homogeneity underlying LOTS in Finland is unique in the whole world, providing a major advantage for screening and presymptomatic diagnosis of LOTS, and constituting an excellent basis to study the role of genetic and non-genetic factors influencing phenotypic variability in this disease.

The K897T variation has an effect on channel function and clinical phenotype. Our data warrant further investigations into the significance of this polymorphism in drug-induced and inherited LQTS.

Analysis of the entire coding region of the HERG gene of 39 Finnish LQTS patients revealed eight mutations, six of which are hitherto unreported. All these mutations are located in the evolutionarily conserved regions of HERG, including the transmembrane domains (P451L, Y569H, 1631delAG, G584S, G601S, T613M) and the cytoplasmic N‐terminus (453delC, R176W) of the channel. Our present and earlier results suggest that the LQT2 subtype accounts for approximately 20‐30% of LQTS cases in Finland. We also report the first common amino acid polymorphism (K897T) of the HERG channel, with allele frequencies of 0.84 and 0.16. Investigation of 170 genetically homogenous LQT1 patients suggests that this polymorphism may influence QT interval in female individuals. Hum Mutat 15:580–581, 2000. © 2000 Wiley‐Liss, Inc.