Cardiac Sodium Channel Gene SCN5A Research Articles

Long-term prognosis of patients with an SCN5A loss-of-function variant and progressive cardiac conduction disorder or Brugada syndrome

The long-term prognosis of patients with a loss-of-function variant in the cardiac sodium channel gene SCN5A is unknown. This study aimed to evaluate the long-term arrhythmic risk in patients with an SCN5A loss-of-function variant to identify predictors of arrhythmic events. Probands and family members with (likely-)pathogenic SCN5A loss-of-function variants were retrospectively included. Clinical and ECG data at baseline and last follow-up were collected. Patients with a history of cardiac arrest, sustained ventricular tachycardia, symptomatic or documented atrial tachy- or bradyarrhythmia, or arrhythmogenic syncope, were categorized as symptomatic. Arrhythmic events at follow-up were defined as sudden death, aborted cardiac arrest, documented ventricular fibrillation and/or sustained ventricular tachycardia. We included 615 patients (349 males, 242 probands, 157 spontaneous type-1 Brugada-ECG and 111 symptomatic at baseline). During 9.5 (5.0-14.3) years follow-up, arrhythmic events occurred in 41 patients (6.7%), equating an overall event rate of 0.7%/year; 2.0%/year in symptomatic and 0.3%/year in asymptomatic patients. In the overall study population, symptoms at baseline, male sex, and QRS prolongation were identified as independent predictors of arrhythmic events. In asymptomatic patients, also male sex and QRS prolongation were identified as predictors. Asymptomatic women with QRS <100ms did not experience arrhythmic events at follow-up. Key predictors of arrhythmic risk in patients with an SCN5A loss-of-function variant, regardless of a Brugada syndrome diagnosis, are symptoms at baseline, male sex, and prolonged QRS. Our findings may enable more tailored management strategies in patients with an SCN5A loss-of-function variant based on their individual risk profiles.

Population-specific and cross-ancestry genome-wide association study identifies shared genetic architecture and 6 new risk loci including CAMK2D associated for Brugada syndrome

Abstract Introduction The Brugada syndrome (BrS) is an inherited arrhythmia characterized by coved-type ST-segment elevation in the right precordial leads and an increased risk for sudden cardiac death. Genome-wide association studies (GWAS) of BrS, mainly performed in European ancestry, have illustrated its complex genetic architecture as an polygenic disease besides a monogenic trait due to mutations in the major responsible cardiac sodium channel gene SCN5A. Clinical manifestations of BrS including the disease prevalence and the incidence of sudden death are known to be variable between Asian and European populations, however, its underlying mechanisms are largely unknown. Objectives We aimed to identify novel BrS-associated loci and to assess ancestry-dependent genetic heterogeneity that may underlie the variable clinical manifestations of BrS patients across different populations. Methods We performed a genome-wide meta-analysis of BrS in the Japanese ancestry (940 cases and 1,634 controls), followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3,760 cases and 11,635 controls) to identify novel risk loci and compared the allelic effects between two ancestries. We characterized the novel loci based on fine-mapping of potential causal variants, and expression and splicing quantitative trait associations using the Genotype-Tissue Expression (GTEx) database. Results The Japanese-specific genome-wide meta-analysis identified a novel association signal near the ZSCAN20 (lead variant, rs2336244; P=1.0E-08) besides previously reported 4 association signals at the SCN5A-SCN10A and HEY2 loci. Cross-ancestry genome-wide meta-analysis identified 17 association signals including 6 novel loci. The effect directions were consistent for 94.1% of the variants (16 of 17; P for sign test = 0.00027) and their allelic effects were highly correlated across ancestries (Pearson’s R=0.91 [P=2.9E-07]). The genetic risk score (GRS) derived from European-ancestry GWAS of BrS was significantly associated with the risk of BrS in the Japanese populations (odds ratio, 2.12 [95% confidence interval, 1.94–2.31]; P=1.2E-61), suggesting the shared genetic architecture across ancestries. The functional characterization of the 6 novel loci showed that one lead SNP on CAMK2D promotes an alternative splicing resulting in an isoform switch of calmodulin kinase II that favors up-regulation of the pro-inflammatory isoform δ9 and down-regulation of the pro-survival isoform δ3. Conclusions Our results identified 6 novel susceptible loci associated with BrS and revealed shared genetic architecture across ancestries.GWAS Manhattan plotShared genetic architecture

Patient-specific iPSC-derived cardiomyocytes reveal aberrant activation of Wnt/β-catenin signaling in SCN5A-related Brugada syndrome

BackgroundMutations in the cardiac sodium channel gene SCN5A cause Brugada syndrome (BrS), an arrhythmic disorder that is a leading cause of sudden death and lacks effective treatment. An association between SCN5A and Wnt/β-catenin signaling has been recently established. However, the role of Wnt/β-catenin signaling in BrS and underlying mechanisms remains unknown.MethodsThree healthy control subjects and one BrS patient carrying a novel frameshift mutation (T1788fs) in the SCN5A gene were recruited in this study. Control and BrS patient-specific induced pluripotent stem cells (iPSCs) were generated from skin fibroblasts using nonintegrated Sendai virus. All iPSCs were differentiated into cardiomyocytes using monolayer-based differentiation protocol. Action potentials and sodium currents were recorded from control and BrS iPSC-derived cardiomyocytes (iPSC-CMs) by single-cell patch clamp.ResultsBrS iPSC-CMs exhibited increased burden of arrhythmias and abnormal action potential profile featured by slower depolarization, decreased action potential amplitude, and increased beating interval variation. Moreover, BrS iPSC-CMs showed cardiac sodium channel (Nav1.5) loss-of-function as compared to control iPSC-CMs. Interestingly, the electrophysiological abnormalities and Nav1.5 loss-of-function observed in BrS iPSC-CMs were accompanied by aberrant activation of Wnt/β-catenin signaling. Notably, inhibition of Wnt/β-catenin significantly rescued Nav1.5 defects and arrhythmic phenotype in BrS iPSC-CMs. Mechanistically, SCN5A-encoded Nav1.5 interacts with β-catenin, and reduced expression of Nav1.5 leads to re-localization of β-catenin in BrS iPSC-CMs, which aberrantly activates Wnt/β-catenin signaling to suppress SCN5A transcription.ConclusionsOur findings suggest that aberrant activation of Wnt/β-catenin signaling contributes to the pathogenesis of SCN5A-related BrS and point to Wnt/β-catenin as a potential therapeutic target.

Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization.

Brugada syndrome (BrS) is an inherited arrhythmia syndrome caused by loss-of-function variants in the cardiac sodium channel gene SCN5A (sodium voltage-gated channel alpha subunit 5) in ≈20% of subjects. We identified a family with 4 individuals diagnosed with BrS harboring the rare G145R missense variant in the cardiac transcription factor TBX5 (T-box transcription factor 5) and no SCN5A variant. We generated induced pluripotent stem cells (iPSCs) from 2 members of a family carrying TBX5-G145R and diagnosed with Brugada syndrome. After differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), electrophysiologic characteristics were assessed by voltage- and current-clamp experiments (n=9 to 21 cells per group) and transcriptional differences by RNA sequencing (n=3 samples per group), and compared with iPSC-CMs in which G145R was corrected by CRISPR/Cas9 approaches. The role of platelet-derived growth factor (PDGF)/phosphoinositide 3-kinase (PI3K) pathway was elucidated by small molecule perturbation. The rate-corrected QT (QTc) interval association with serum PDGF was tested in the Framingham Heart Study cohort (n=1893 individuals). TBX5-G145R reduced transcriptional activity and caused multiple electrophysiologic abnormalities, including decreased peak and enhanced "late" cardiac sodium current (INa), which were entirely corrected by editing G145R to wild-type. Transcriptional profiling and functional assays in genome-unedited and -edited iPSC-CMs showed direct SCN5A down-regulation caused decreased peak INa, and that reduced PDGF receptor (PDGFRA [platelet-derived growth factor receptor α]) expression and blunted signal transduction to PI3K was implicated in enhanced late INa. Tbx5 regulation of the PDGF axis increased arrhythmia risk due to disruption of PDGF signaling and was conserved in murine model systems. PDGF receptor blockade markedly prolonged normal iPSC-CM action potentials and plasma levels of PDGF in the Framingham Heart Study were inversely correlated with the QTc interval (P<0.001). These results not only establish decreased SCN5A transcription by the TBX5 variant as a cause of BrS, but also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor-mediated PI3K signaling.

Dominant negative effects of SCN5A missense variants

PurposeUp to 30% of patients with Brugada syndrome (BrS) carry loss-of-function (LoF) variants in the cardiac sodium channel gene SCN5A encoding for the protein NaV1.5. Recent studies suggested that NaV1.5 can dimerize, and some variants exert dominant negative effects. In this study, we sought to explore the generality of missense variant NaV1.5 dominant negative effects and their clinical severity. MethodsWe identified 35 LoF variants (<10% of wild type [WT] peak current) and 15 partial LoF variants (10%-50% of WT peak current) that we assessed for dominant negative effects. SCN5A variants were studied in HEK293T cells, alone or in heterozygous coexpression with WT SCN5A using automated patch clamp. To assess the clinical risk, we compared the prevalence of dominant negative vs putative haploinsufficient (frameshift, splice, or nonsense) variants in a BrS consortium and the Genome Aggregation Database population database. ResultsIn heterozygous expression with WT, 32 of 35 LoF and 6 of 15 partial LoF variants showed reduction to <75% of WT-alone peak current, showing a dominant negative effect. Individuals with dominant negative LoF variants had an elevated disease burden compared with the individuals with putative haploinsufficient variants (2.7-fold enrichment in BrS cases, P = .019). ConclusionMost SCN5A missense LoF variants exert a dominant negative effect. This class of variant confers an especially high burden of BrS.

Abstract 9803: Most SCN5A Missense Loss-of-Function Variants Also Have a Dominant Negative Effect

Introduction: Up to 30% of patients with Brugada Syndrome (BrS) carry loss of function (LoF) variants in the cardiac sodium channel gene SCN5A . Recent studies have suggested that the protein product Na V 1.5 can form dimers, suggesting the possibility that LoF variants may have dominant negative effects. Methods: We identified 36 SCN5A missense variants previously found to have peak current &lt;10% compared to wild-type (WT). HEK293T cells were engineered to stably express one or two copies of SCN5A using AttB-AttP landing pad and Sleeping Beauty transposon systems. Cell lines were created expressing the missense LoF SCN5A variants alone or in heterozygous co-expression with WT SCN5A . Channel expression was validated by flow cytometry and peak sodium currents were measured using automated patch clamp (&gt;20 replicate cells/variant). To assess clinical risk, we compared case versus control ratios among different variant mechanisms using a published BrS case consortium and the gnomAD population database. Results: 32/36 LoF variants studied alone had peak current &lt;10% as expected. In heterozygous experiments, WT alone was normalized to 100% and WT+WT showed ~200% peak current. In heterozygous expression with WT, 29/32 LoF variants showed a reduction to less than 75% normalized peak current, demonstrating a dominant negative effect. We next tested the hypothesis that dominant negative variants carry a higher disease risk than other variant classes. We observed a 5.0-fold enrichment for BrS cases among carriers of dominant negative missense variants compared to putative haploinsufficient variants (frameshift/splice site) (p=0.003). Conclusions: Most SCN5A missense LoF variants also have a dominant negative effect. Case-control comparisons reveal that this variant class carries an outsized BrS risk compared to other classes of pathogenic variants. Figure . A) SCN5A homozygous expression. B) SCN5A heterozygous expression. C) Case-control analysis.

Cardiomyocyte-specific deletion of \u03b2-catenin protects mouse hearts from ventricular arrhythmias after myocardial infarction

Wnt/β-catenin signaling is activated in the heart after myocardial infarction (MI). This study aims to investigate if β-catenin deletion affects post-MI ion channel gene alterations and ventricular tachycardias (VT). MI was induced by permanent ligation of left anterior descending artery in wild-type (WT) and cardiomyocyte-specific β-catenin knockout (KO) mice. KO mice showed reduced susceptibility to VT (18% vs. 77% in WT) at 8 weeks after MI, associated with reduced scar size and attenuated chamber dilation. qPCR analyses of both myocardial tissues and purified cardiomyocytes demonstrated upregulation of Wnt pathway genes in border and infarct regions after MI, including Wnt ligands (such as Wnt4) and receptors (such as Fzd1 and Fzd2). At 1 week after MI, cardiac sodium channel gene (Scn5a) transcript was reduced in WT but not in KO hearts, consistent with previous studies showing Scn5a inhibition by Wnt/β-catenin signaling. At 8 weeks after MI when Wnt genes have declined, Scn5a returned to near sham levels and K+ channel gene downregulations were not different between WT and KO mice. This study demonstrated that VT susceptibility in the chronic phase after MI is reduced in mice with cardiomyocyte-specific β-catenin deletion primarily through attenuated structural remodeling, but not ion channel gene alterations.

Postoperative supraventricular tachycardia and polymorphic ventricular tachycardia due to a novel SCN5A variant: a case report of a rare comorbidity that is difficult to diagnose

BackgroundLoss-of-function mutations of human cardiac sodium channel gene SCN5A induce a wide range of arrhythmic disorders. Mutation carriers with co-existing conditions such as congenital heart diseases and histories of cardiac surgeries, could develop complex arrhythmic events that are difficult to diagnose.Case presentationA 41-year-old Japanese male with a history of a surgical closure of an ASD presented impairment of consciousness by wide QRS tachycardia. Because the patient’s baseline ECG in sinus rhythm showed similar QRS axis with right bundle brunch block morphology, we suspected supraventricular tachycardia (SVT). During hospitalization, the patient developed polymorphic ventricular tachycardia that was induced by bradycardia. In an electrophysiological study, the SVT was identified as right atrial incisional tachycardia circulating around the scar in the right atrium.The genetic analysis revealed a heterozygous SCN5A c.4037–4038 del TC, p. L1346HfsX38 variant. We diagnosed this patient as having progressive cardiac conduction disorder (PCCD) and polymorphic VT caused by the mutation. Incisional tachycardia with wide QRS morphology was a by-standing comorbidity related to the history of cardiac surgery which could miss lead the diagnosis.The patient’s SVT was eliminated by radiofrequency catheter ablation. An implantable cardioverter defibrillator (ICD) was implanted for the secondary prevention of polymorphic VT. Cardiac pace-making therapy by the ICD to avoid bradycardia effectively suppressed the patient’s arrhythmic events.ConclusionsWe treated a patient with a sodium channel gene variant. Co-existing SVT originated by a scar in the right atrium made the diagnosis extremely difficult. A multilateral diagnostic approach using an ECG analysis, an electrophysiological study, and genetic screening enabled effective combination therapy comprised of catheter ablation and an ICD.

A Bayesian method to estimate variant-induced disease penetrance.

A major challenge emerging in genomic medicine is how to assess best disease risk from rare or novel variants found in disease-related genes. The expanding volume of data generated by very large phenotyping efforts coupled to DNA sequence data presents an opportunity to reinterpret genetic liability of disease risk. Here we propose a framework to estimate the probability of disease given the presence of a genetic variant conditioned on features of that variant. We refer to this as the penetrance, the fraction of all variant heterozygotes that will present with disease. We demonstrate this methodology using a well-established disease-gene pair, the cardiac sodium channel gene SCN5A and the heart arrhythmia Brugada syndrome. From a review of 756 publications, we developed a pattern mixture algorithm, based on a Bayesian Beta-Binomial model, to generate SCN5A penetrance probabilities for the Brugada syndrome conditioned on variant-specific attributes. These probabilities are determined from variant-specific features (e.g. function, structural context, and sequence conservation) and from observations of affected and unaffected heterozygotes. Variant functional perturbation and structural context prove most predictive of Brugada syndrome penetrance.

ROLE OF SCN5A MUTATION T512I IN YOUNG PATIENT WITH RIGHT VENTRICULAR TACHYCARDIA AND CARDIOMYOPATHY

Mutations in the cardiac sodium channel gene SCN5A are associated with congenital arrhythmia syndromes, like long QT and Brugada syndromes. The role of SCN5A mutation T512I in ventricular tachycardia and right ventricular cardiomyopathy is unclear. A 26 year-old woman had ventricular tachycardia (

Experimental Models of Brugada syndrome.

Brugada syndrome is an inherited, rare cardiac arrhythmogenic disease, associated with sudden cardiac death. It accounts for up to 20% of sudden deaths in patients without structural cardiac abnormalities. The majority of mutations involve the cardiac sodium channel gene SCN5A and give rise to classical abnormal electrocardiogram with ST segment elevation in the right precordial leads V1 to V3 and a predisposition to ventricular fibrillation. The pathophysiological mechanisms of Brugada syndrome have been investigated using model systems including transgenic mice, canine heart preparations, and expression systems to study different SCN5A mutations. These models have a number of limitations. The recent development of pluripotent stem cell technology creates an opportunity to study cardiomyocytes derived from patients and healthy individuals. To date, only a few studies have been done using Brugada syndrome patient-specific iPS-CM, which have provided novel insights into the mechanisms and pathophysiology of Brugada syndrome. This review provides an evaluation of the strengths and limitations of each of these model systems and summarizes the key mechanisms that have been identified to date.

Multiple mechanisms underlie increased cardiac late sodium current

We recently reported a quantitative relationship between the degree of functional perturbation reported in the literature for 356 variants in the cardiac sodium channel gene SCN5A and the penetrance of resulting arrhythmia phenotypes. In the course of that work, we identified multiple SCN5A variants, including R1193Q, that are common in populations but are reported in human embryonic kidney (HEK) cells to generate large late sodium current (INa-L). The purpose of this study was to compare the functional properties of R1193Q with those of the well-studied type 3 long QT syndrome mutation ΔKPQ. We compared functional properties of SCN5A R1193Q with those of ΔKPQ in Chinese hamster ovary (CHO) cells at baseline and after exposure to intracellular phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which inhibits INa-L generated by decreased Phosphoinositide 3-kinase (PI3K) activity. We also used CRISPR/Cas9 editing to generate R1193Q in human-induced pluripotent stem cells differentiated to cardiomyocytes (hiPSC-CMs). Both R1193Q and ΔKPQ generated robust INa-L in CHO cells. PIP3 abrogated the late current phenotype in R1193Q cells but had no effect on ΔKPQ. Homozygous R1193Q hiPSC-CMs displayed increased INa-L and long action potentials with frequent triggered beats, which were reversed with the addition of PIP3. The consistency between the late current produced in HEK cells, CHO cells, and hiPSC-CMs suggests that the late current is a feature of the SCN5A R1193Q variant in human cardiomyocytes but that the mechanism by which the late current is produced is distinct and indirect, as compared with the more highly penetrant ΔKPQ. These data suggest that observing a late current in an invitro setting does not necessarily translate to highly pathogenic type 3 long QT syndrome phenotype but depends on the underlying mechanism.

Genotype-phenotype dilemma in a case of sudden cardiac death with the E1053K mutation and a deletion in the SCN5A gene

Mutations in the cardiac sodium channel gene SCN5A may result in various arrhythmia syndromes such as long QT syndrome type 3 (LQTS), Brugada syndrome (BrS), sick sinus syndrome (SSS), cardiac conduction diseases (CCD) and possibly dilated cardiomyopathy (DCM). In most of these inherited cardiac arrhythmia syndromes the phenotypical expression may range from asymptomatic phenotypes to sudden cardiac death (SCD).A 16-year-old female died during sleep. Autopsy did not reveal any explanation for her death and a genetic analysis was performed. A variant in the SCN5A gene (E1053K) that was previously described as disease causing was detected. Family members are carriers of the same E1053K variant, some even in a homozygous state, but surprisingly did not exhibit any pathological cardiac phenotype. Due to the lack of genotype-phenotype correlation further genetic studies were performed. A novel deletion in the promoter region of SCN5A was identified in the sudden death victim but was absent in other family members.These findings demonstrate the difficulties in interpreting the results of a family-based genetic screening and underline the phenotypic variability of SCN5A mutations.

Management of Brugada Syndrome 2016: Should All High Risk Patients Receive an ICD? All High-Risk Patients Should Receive an Implantable Cardiac Defibrillator.

Management of Brugada Syndrome 2016: Should All High Risk Patients Receive an ICD? All High-Risk Patients Should Receive an Implantable Cardiac Defibrillator.

Triggers for arrhythmogenesis in the Brugada and long QT 3 syndromes

Cardiac arrhythmias are a prevalent cause of morbidity and mortality. In many cases, inheritable mutations in the genes encoding cardiac ion channels are the underlying cause of arrhythmias. Relative to other arrhythmogenic disorders, Brugada syndrome (BrS) is recently identified and not well-understood. Although most often referred to as a disease of cardiac sodium channels, familial BrS is now associated with 9 different genes. Of these genes, 4 alter sodium currents, and the most common known genetic cause remains loss-of-function mutants in the cardiac sodium channel gene SCN5A. Long QT syndrome (LQTs) has a much longer history and is associated with at least 17 genes. LQT3, which is the third most common LQTs, is due to gain-of-function mutations in SCN5A.The first sign for BrS and LQTs patients may be sudden death. The triggers for these sudden deaths include exercise, fever, ischemia, and drug use. In this paper we review the effects of acidosis and fever on BrS and LQTs, discuss Brugada phenocopy syndrome drawing from published literature, and present our own patch-clamp data from mutant channels at low pH. We show that, at low pH, there is a preferential block of peak currents and preferential increase of persistent current in a common BrS/LQTs mutant compared to wild type sodium channels. Our data complements the existing literature on the importance of environmental triggers to arrhythmias.

Post-transcriptional regulation of cardiac sodium channel gene SCN5A expression and function by miR-192-5p

The SCN5A gene encodes cardiac sodium channel Nav1.5 and causes lethal ventricular arrhythmias/sudden death and atrial fibrillation (AF) when mutated. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, and involved in the pathogenesis of many diseases. However, little is known about the regulation of SCN5A by miRNAs. Here we reveal a novel post-transcriptional regulatory mechanism for expression and function of SCN5A/Nav1.5 via miR-192-5p. Bioinformatic analysis revealed that the 3′-UTR of human and rhesus SCN5A, but not elephant, pig, rabbit, mouse, and rat SCN5A, contained a target binding site for miR-192-5p and dual luciferase reporter assays showed that the site was critical for down-regulation of human SCN5A. With Western blot assays and electrophysiological studies, we demonstrated that miR-192-5p significantly reduced expression of SCN5A and Nav1.5 as well as peak sodium current density INa generated by Nav1.5. Notably, in situ hybridization, immunohistochemistry and real-time qPCR analyses showed that miR-192-5p was up-regulated in tissue samples from AF patients, which was associated with down-regulation of SCN5A/Nav1.5. These results demonstrate an important post-transcriptional role of miR-192-5p in post-transcriptional regulation of Nav1.5, reveal a novel role of miR-192-5p in cardiac physiology and disease, and provide a new target for novel miRNA-based antiarrhythmic therapy for diseases with reduced INa.

Use of Drugs in Long QT Syndrome Type 3 and Brugada Syndrome

This review focuses on the available evidence about safe use of drugs in long QT syndrome type 3 and Brugada syndrome. Both syndromes are associated with malignant arrhythmias and mutations in the cardiac sodium channel gene SCN5A. Both cardiovascular and noncardiovascular drugs have the ability to block (multiple) cardiac ion channels, which may make the use of these drugs extremely dangerous in these syndromes. We emphasize the importance of making patient-specific prescribing decisions that are based on up-to-date risk-stratification. In this review, we provide a knowledge base, considerations, and recommendations for these problems.

A Heterozygous Deletion Mutation in the Cardiac Sodium Channel Gene SCN5A with Loss- and Gain-of-Function Characteristics Manifests as Isolated Conduction Disease, without Signs of Brugada or Long QT Syndrome

BackgroundThe SCN5A gene encodes for the α-subunit of the cardiac sodium channel NaV1.5, which is responsible for the rapid upstroke of the cardiac action potential. Mutations in this gene may lead to multiple life-threatening disorders of cardiac rhythm or are linked to structural cardiac defects. Here, we characterized a large family with a mutation in SCN5A presenting with an atrioventricular conduction disease and absence of Brugada syndrome.Method and ResultsIn a large family with a high incidence of sudden cardiac deaths, a heterozygous SCN5A mutation (p.1493delK) with an autosomal dominant inheritance has been identified. Mutation carriers were devoid of any cardiac structural changes. Typical ECG findings were an increased P-wave duration, an AV-block I° and a prolonged QRS duration with an intraventricular conduction delay and no signs for Brugada syndrome. HEK293 cells transfected with 1493delK showed strongly (5-fold) reduced Na+ currents with altered inactivation kinetics compared to wild-type channels. Immunocytochemical staining demonstrated strongly decreased expression of SCN5A 1493delK in the sarcolemma consistent with an intracellular trafficking defect and thereby a loss-of-function. In addition, SCN5A 1493delK channels that reached cell membrane showed gain-of-function aspects (slowing of the fast inactivation, reduction in the relative fraction of channels that fast inactivate, hastening of the recovery from inactivation).ConclusionIn a large family, congregation of a heterozygous SCN5A gene mutation (p.1493delK) predisposes for conduction slowing without evidence for Brugada syndrome due to a predominantly trafficking defect that reduces Na+ current and depolarization force.

Variable phenotype expression with a frameshift mutation of the cardiac sodium channel gene SCN5A

Loss-of-function mutations in the cardiac sodium channel α-subunit gene SCN5A result in multiple inherited arrhythmic syndromes. This case report describes 2 unrelated probands carrying an identical SCN5A frameshift mutation, V1764fsX1786, who exhibited distinct clinical manifestations: progressive cardiac conduction defect (PCCD)/Brugada syndrome (patient #1) and idiopathic ventricular fibrillation (IVF) (patient #2). Using a whole-cell patch clamp technique, cells expressing V1764fsX1786 showed no observable Na+ current. Therefore, a significant phenotypic overlap was found between IVF and PCCD/Brugada syndrome in the 2 probands with the V1764fsX1786, loss-of-function frameshift mutation of the cardiac sodium channel gene SCN5A.

CONCOMITANT BRUGADA-LIKE AND SHORT QT ELECTROCARDIOGRAM LINKED TO SCN5A MUTATION

ObjectivesMutations in the α-subunit of cardiac sodium channel gene SCN5A can lead to the overlapping phenotypes of both the Brugada and type 3 long QT syndromes. However, the combination of...