Abstract-Mutations in SCN5A, the gene encoding the cardiac Na ϩ channel, have been identified in 2 distinct diseases associated with sudden death: one form of the long-QT syndrome (LQT 3 ) and the Brugada syndrome. We have screened SCN5A in a large 8-generation kindred characterized by a high incidence of nocturnal sudden death, and QT-interval prolongation and the "Brugada ECG" occurring in the same subjects. An insertion of 3 nucleotides (TGA) at position 5537, predicted to cause an insertion of aspartic acid (1795insD) in the C-terminal domain of the protein, was linked to the phenotype and was identified in all electrocardiographically affected family members. ECGs were obtained from 79 adults with a defined genetic status (carriers, nϭ43; noncarriers, nϭ36). In affected individuals, PR and QRS durations and QT intervals are prolonged (PϽ0.0001 for all parameters). ST segment elevation in the right precordial leads is present as well (PϽ0.0001). Twenty-five family members died suddenly, 16 of them during the night. Expression of wild-type and mutant Na ϩ channels in Xenopus oocytes revealed that the 1795insD mutation gives rise to a 7.3-mV negative shift of the steady-state inactivation curve and an 8.1-mV positive shift of the steady-state activation curve. The functional consequence of both shifts is likely to be a reduced Na ϩ current during the upstroke of the action potential. LQT 3 and Brugada syndrome are allelic disorders but may also share a common genotype. Key Words: long-QT syndrome Ⅲ Brugada syndrome Ⅲ SCN5A Ⅲ arrhythmia Ⅲ Na ϩ channel S CN5A, the gene that encodes the human cardiac Na ϩ channel ␣ subunit, 1 is mutated in one form of the long-QT syndrome (LQT 3 ) and in Brugada syndrome. 2,3 There are characteristic and readily distinguishable ECG patterns in these 2 syndromes. In LQT 3 patients, a long isoelectric ST segment precedes a peaked T wave. 4 Brugada syndrome is diagnosed on the basis of characteristic ECG features in the absence of structural heart disease; these features include right precordial ST-segment elevation, which may be intermittent, and which is exacerbated by Na ϩ channel block and ameliorated by isoproterenol. 5,6 QT intervals have been reported to be normal in patients with Brugada syndrome. 5 Clinically, there appears to be some overlap between the 2 syndromes, as both exhibit a relatively high incidence of nocturnal sudden cardiac death without prior symptoms. 6 -8 The prolonged QT interval in LQT 3 results from persistent inward Na ϩ current during the plateau phase of the action potential, secondary to incomplete inactivation of mutated channels. 9 Changes in the ␣ and ␤ 1 subunit interaction have also been implicated. 10 Although functional abnormalities have been described for Brugada syndrome-related SCN5A mutant channels, 3,11 the mechanism(s) whereby these explain the Brugada phenotype are less clear.In this study we present clinical and genetic data of a single large SCN5A-linked family, phenotypically characterized by nocturnal death and electrocardiograph...

Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases1–3. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10−68; rs9388451, P = 5.1 × 10−17) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10−14). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10−81). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction4–7 can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development8. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

Background-The electrocardiographic short QT-interval syndrome forms a distinct clinical entity presenting with a high rate of sudden death and exceptionally short QT intervals. The disorder has recently been linked to gain-of-function mutation in KCNH2. The present study demonstrates that this disorder is genetically heterogeneous and can also be caused by mutation in the KCNQ1 gene. Methods and Results-A 70-year man presented with idiopathic ventricular fibrillation. Both immediately after the episode and much later, his QT interval was abnormally short without any other physical or electrophysiological anomalies. Analysis of candidate genes identified a g919c substitution in KCNQ1 encoding the K ϩ channel KvLQT1. Functional studies of the KvLQT1 V307L mutant (alone or coexpressed with the wild-type channel, in the presence of IsK) revealed a pronounced shift of the half-activation potential and an acceleration of the activation kinetics leading to a gain of function in I Ks . When introduced in a human action potential computer model, the modified biophysical parameters predicted repolarization shortening. Conclusions-We present an alternative molecular mechanism for the short QT-interval syndrome. Functional and computational studies of the KCNQ1 V307L mutation identified in a patient with this disorder favor the association of short QT with mutation in KCNQ1. Key Words: death, sudden Ⅲ genetics Ⅲ arrhythmia Ⅲ ion channels Ⅲ fibrillation, ventricular I n recent years, extensive progress has been made in unraveling the pathophysiology of the monogenic arrhythmia syndromes among which are long-QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. 1 The latest addition to this class of disorders is the description of families with a high rate of sudden death and exceptionally short QT intervals, 2 recently attributed to gain-of-function mutation in KCNH2. 3 In this study, we demonstrate that this disorder is genetically heterogeneous and can also be caused by mutation in the KCNQ1 gene that encodes the KvLQT1 K ϩ channel, which, in association with the ␤-subunit IsK, forms the slow component of the cardiac delayed rectifier K ϩ current (I Ks ). 4 Methods Patient CharacteristicsA 70-year-old man was successfully resuscitated after a ventricular fibrillation episode. He had been without complaints up until then, and his family history was unremarkable. Physical examination revealed no abnormalities. His ECG is presented in Figure 1. Sinus rhythm was present with normal conduction intervals and a QT interval of 290 ms (QTc, 302 ms). Similarly short QT intervals were observed on every ECG up to 3 years of follow-up. Biochemical analysis at the time of admission, including echocardiography, exercise testing, coronary angiography, left (LV) and right ventricular (RV) angiography, scintigraphy, and ergonovine coronary spasm test, revealed no abnormalities. Nuclear LV ejection fraction was 49%. During electrophysiological study, no arrhythmias could be induced. The electrophysiology ...

Background-The mechanism of ECG changes and arrhythmogenesis in Brugada syndrome (BS) patients is unknown. Methods and Results-A BS patient without clinically detected cardiac structural abnormalities underwent cardiac transplantation for intolerable numbers of implantable cardioverter/defibrillator discharges. The patient's explanted heart was studied electrophysiologically and histopathologically. Whole-cell currents were measured in HEK293 cells expressing wild-type or mutated sodium channels from the patient. The right ventricular outflow tract (RVOT) endocardium showed activation slowing and was the origin of ventricular fibrillation without a transmural repolarization gradient. Conduction restitution was abnormal in the RVOT but normal in the left ventricle. Right ventricular hypertrophy and fibrosis with epicardial fatty infiltration were present. HEK293 cells expressing a G1935S mutation in the gene encoding the cardiac sodium channel exhibited enhanced slow inactivation compared with wild-type channels.Computer simulations demonstrated that conduction slowing in the RVOT might have been the cause of the ECG changes. Conclusions-In this patient with BS, conduction slowing based on interstitial fibrosis, but not transmural repolarization differences, caused the ECG signs and was the origin of ventricular fibrillation.

Brugada syndrome is a genetic disease associated with sudden cardiac death that is characterized by ventricular fibrillation and right precordial ST segment elevation on ECG. Loss-of-function mutations in SCN5A, which encodes the predominant cardiac sodium channel α subunit Na V 1.5, can cause Brugada syndrome and cardiac conduction disease. However, SCN5A mutations are not detected in the majority of patients with these syndromes, suggesting that other genes can cause or modify presentation of these disorders. Here, we investigated SCN1B, which encodes the function-modifying sodium channel β1 subunit, in 282 probands with Brugada syndrome and in 44 patients with conduction disease, none of whom had SCN5A mutations. We identified 3 mutations segregating with arrhythmia in 3 kindreds. Two of these mutations were located in a newly described alternately processed transcript, β1B. Both the canonical and alternately processed transcripts were expressed in the human heart and were expressed to a greater degree in Purkinje fibers than in heart muscle, consistent with the clinical presentation of conduction disease. Sodium current was lower when Na V 1.5 was coexpressed with mutant β1 or β1B subunits than when it was coexpressed with WT subunits. These findings implicate SCN1B as a disease gene for human arrhythmia susceptibility.