A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene.

Short QT syndrome (SQTS) leads to an abbreviated QTc interval and predisposes patients to life-threatening arrhythmias. To date, two forms of the disease have been identified: SQT1, caused by a gain of function substitution in the HERG (I(Kr)) channel, and SQT2, caused by a gain of function substitution in the KvLQT1 (I(Ks)) channel. Here we identify a new variant, "SQT3", which has a unique ECG phenotype characterized by asymmetrical T waves, and a defect in the gene coding for the inwardly rectifying Kir2.1 (I(K1)) channel. The affected members of a single family had a G514A substitution in the KCNJ2 gene that resulted in a change from aspartic acid to asparagine at position 172 (D172N). Whole-cell patch-clamp studies of the heterologously expressed human D172N channel demonstrated a larger outward I(K1) than the wild-type (P<0.05) at potentials between -75 mV and -45 mV, with the peak current being shifted in the former with respect to the latter (WT, -75 mV; D172N, -65 mV). Coexpression of WT and mutant channels to mimic the heterozygous condition of the proband yielded an outward current that was intermediate between WT and D172N. In computer simulations using a human ventricular myocyte model the increased outward I(K1) greatly accelerated the final phase of repolarization, and shortened the action potential duration. Hence, unlike the known mutations in the two other SQTS forms (N588K in HERG and V307L in KvLQT1), simulations using the D172N and WT/D172N mutations fully accounted for the ECG phenotype of tall and asymmetrically shaped T waves. Although we were unable to test for inducibility of arrhythmia susceptibility due to lack of patients' consent, our computer simulations predict a steeper steady-state restitution curve for the D172N and WT/D172N mutation, compared with WT or to HERG or KvLQT1 mutations, which may predispose SQT3 patients to a greater risk of reentrant arrhythmias.

Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice.

CONTEXT: In long QT syndrome (LQTS), disease severity and response to therapy vary according to the genetic loci. There exists a critical need to devise strategies to expedite genetic analysis. OBJECTIVE: To perform genetic screening in patients with LQTS to determine the yield of genetic testing, as well as the type and the prevalence of mutations. DESIGN, PATIENTS, AND SETTING: We investigated whether the detection of a set of frequently mutated codons in the KCNQ1, KCNH2, and SCN5A genes may translate in a novel strategy for rapid efficient genetic testing of 430 consecutive patients referred to our center between June 1996 and June 2004. The entire coding regions of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 were screened by denaturing high-performance liquid chromatography and DNA sequencing. The frequency and the type of mutations were defined to identify a set of recurring mutations. A separate cohort of 75 consecutive probands was used as a validation group to quantify prospectively the prevalence of the recurring mutations identified in the primary LQTS population. MAIN OUTCOME MEASURES: Development of a novel approach to LQTS genotyping. RESULTS: We identified 235 different mutations, 138 of which were novel, in 310 (72%) of 430 probands (49% KCNQ1, 39% KCNH2, 10% SCN5A, 1.7% KCNE1, and 0.7% KCNE2). Fifty-eight percent of probands carried nonprivate mutations in 64 codons of KCNQ1, KCNH2, and SCN5A genes. A similar occurrence of mutations at these codons (52%) was confirmed in the prospective cohort of 75 probands and in previously published LQTS cohorts. CONCLUSIONS: We have developed an approach to improve the efficiency of genetic screening for LQTS. This novel method may facilitate wider access to genotyping resulting in better risk stratification and treatment of LQTS patients.

Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers.

CONTEXT: Data on the efficacy of beta-blockers in the 3 most common genetic long QT syndrome (LQTS) loci are limited. OBJECTIVE: To describe and assess outcome in a large systematically genotyped population of beta-blocker-treated LQTS patients. DESIGN, SETTING, AND PATIENTS: Consecutive LQTS-genotyped patients (n = 335) in Italy treated with beta-blockers for an average of 5 years. MAIN OUTCOME MEASURES: Cardiac events (syncope, ventricular tachycardia/torsades de pointes, cardiac arrest, and sudden cardiac death) while patients received beta-blocker therapy according to genotype. RESULTS: Cardiac events among patients receiving beta-blocker therapy occurred in 19 of 187 (10%) LQT1 patients, 27 of 120 (23%) LQT2 patients, and 9 of 28 (32%) LQT3 patients (P<.001). The risk of cardiac events was higher among LQT2 (adjusted relative risk, 2.81; 95% confidence interval [CI], 1.50-5.27; P =.001) and LQT3 (adjusted relative risk, 4.00; 95% CI, 2.45-8.03; P<.001) patients than among LQT1 patients, suggesting inadequate protection from beta-blocker therapy. Other important predictors of risk were a QT interval corrected for heart rate that was more than 500 ms in patients receiving therapy (adjusted relative risk, 2.01; 95% CI, 1.16-3.51; P =.01) and occurrence of a first cardiac event before the age of 7 years (adjusted RR, 4.34; 95% CI, 2.35-8.03; P<.001). CONCLUSION: Among patients with genetic LQTS treated with beta-blockers, there is a high rate of cardiac events, particularly among patients with LQT2 and LQT3 genotypes.

Risk stratification in the long-QT syndrome.

BACKGROUND: Mutations in potassium-channel genes KCNQ1 (LQT1 locus) and KCNH2 (LQT2 locus) and the sodium-channel gene SCN5A (LQT3 locus) are the most common causes of the long-QT syndrome. We stratified risk according to the genotype, in conjunction with other clinical variables such as sex and the length of the QT interval. METHODS: We evaluated 647 patients (386 with a mutation at the LQT1 locus, 206 with a mutation at the LQT2 locus, and 55 with a mutation at the LQT3 locus) from 193 consecutively genotyped families with the long-QT syndrome. The cumulative probability of a first cardiac event, defined as the occurrence of syncope, cardiac arrest, or sudden death before the age of 40 years and before the initiation of therapy, was determined according to genotype, sex, and the QT interval corrected for heart rate (QTc). Within each genotype we also assessed risk in the four categories derived from the combination of sex and QTc (<500 msec or > or =500 msec). RESULTS: The incidence of a first cardiac event before the age of 40 years and before the initiation of therapy was lower among patients with a mutation at the LQT1 locus (30 percent) than among those with a mutation at the LQT2 locus (46 percent) or those with a mutation at the LQT3 locus (42 percent) (P<0.001 by Fisher's exact test). Multivariate analysis showed that the genetic locus and the QTc, but not sex, were independent predictors of risk. The QTc was an independent predictor of risk among patients with a mutation at the LQT1 locus and those with a mutation at the LQT2 locus but not among those with a mutation at the LQT3 locus, whereas sex was an independent predictor of events only among those with a mutation at the LQT3 locus. CONCLUSIONS: The locus of the causative mutation affects the clinical course of the long-QT syndrome and modulates the effects of the QTc and sex on clinical manifestations. We propose an approach to risk stratification based on these variables.

Natural history of Brugada syndrome: insights for risk stratification and management.

BACKGROUND: Treatment of patients with Brugada syndrome is complicated by the incomplete information on the natural history of the disease related to the small number of cases reported. Furthermore, the value of programmed electrical stimulation (PES) for risk stratification is highly debated. The objective of this study was to search for novel parameters to identify patients at risk of sudden death. METHODS AND RESULTS: Clinical data were collected for 200 patients (152 men, 48 women; age, 41+/-18 years) and stored in a dedicated database. Genetic analysis was performed, and mutations on the SCN5A gene were identified in 28 of 130 probands and in 56 of 121 family members. The life-table method of Kaplan-Meier used to define the cardiac arrest-free interval in patients undergoing PES failed to demonstrate an association between PES inducibility and spontaneous occurrence of ventricular fibrillation. Multivariate Cox regression analysis showed that after adjusting for sex, family history of sudden death, and SCN5A mutations, the combined presence of a spontaneous ST-segment elevation in leads V1 through V3 and the history of syncope identifies subjects at risk of cardiac arrest (HR, 6.4; 95% CI, 1.9 to 21; P<0.002). CONCLUSIONS: The information on the natural history of patients obtained in this study allowed elaboration of a risk-stratification scheme to quantify the risk for sudden cardiac death and to target the use of the implantable cardioverter-defibrillator.