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SCN5A gene variants are associated with both Brugada syndrome and conduction disturbances, sometimes expressing an overlapping phenotype. Functional consequences of SCN5A variants assessed by patch‐clamp electrophysiology are particularly beneficial for correct pathogenic classification and are related to disease penetrance and severity. Here, we identify a novel SCN5A loss of function variant, p.1449Y>H, which presented with high penetrance and complete left bundle branch block, totally masking the typical findings on the electrocardiogram. We highlight the possibility of this overlap combination that makes impossible an electrocardiographic diagnosis and, through a functional analysis, associate the p.1449Y>H variant to SCN5A pathogenicity. [ABSTRACT FROM AUTHOR]

Background: The epinephrine infusion test (EIT) typically induces marked QT prolongation in LQT1, but not LQT3, while the efficacy of β‐blocker therapy is established in LQT1, but not LQT3. We encountered an LQT3 family, with an SCN5A V1667I mutation, that exhibited epinephrine‐induced marked QT prolongation. Methods: Wild‐type (WT) or V1667I‐SCN5A was transiently expressed into tsA‐201 cells, and whole‐cell sodium currents (INa) were recorded using patch‐clamp techniques. To mimic the effects of epinephrine, INa was recorded after the application of protein kinase A (PKA) activator, 8‐CPT‐cAMP (200 μM), for 10 minutes. Results: The peak density of V1667I‐INa was significantly larger than WT‐INa (WT: 469 ± 48 pA/pF, n = 20; V1667I: 690 ± 62 pA/pF, n = 19, P <.01). The steady‐state activation (SSA) and fast inactivation rate of V1667I‐INa were comparable to WT‐INa. V1667I‐INa displayed a significant depolarizing shift in steady‐state inactivation (SSI) in comparison to WT‐INa (V1/2‐WT: −88.1 ± 0.8 mV, n = 17; V1667I: −82.5 ± 1.1 mV, n = 17, P <.01), which increases window currents. Tetrodotoxin (30 μM)‐sensitive persistent V1667I‐INa was comparable to WT‐INa. However, the ramp pulse protocol (RPP) displayed an increased hump in V1667I‐INa in comparison to WT‐INa. Although 8‐CPT‐cAMP shifted SSA to hyperpolarizing potentials in WT‐INa and V1667I‐INa to the same extent, it shifted SSI to hyperpolarizing potentials much less in V1667I‐INa than in WT‐INa (V1/2‐WT: −92.7 ± 1.3 mV, n = 6; V1667I: −85.3 ± 1.6 mV, n = 6, P <.01). Concordantly, the RPP displayed an increased hump in V1667I‐INa, but not in WT‐INa. Conclusions: We demonstrated an increase of V1667I‐INa by PKA activation, which may provide a rationale for the efficacy of β‐blocker therapy in some cases of LQT3. [ABSTRACT FROM AUTHOR]

Background: A large number of SCN5A variants have been reported to underlie Brugada syndrome (BrS). However, the evidence supporting individual variants is highly heterogeneous. Objective: We systematically re‐evaluated all SCN5A variants reported in BrS using the 2015 American college of medical genetics and genomics and the association for molecular pathology (ACMG‐AMP) guidelines. Methods: A PubMed/Embase search was performed to identify all reported SCN5A variants in BrS. Standardized bioinformatic re‐analysis (SIFT, PolyPhen, Mutation Taster, Mutation assessor, FATHMM, GERP, PhyloP, and SiPhy) and re‐evaluation of frequency in the gnomAD database were performed. Fourteen ACMG‐AMP rules were deemed applicable for SCN5A variant analysis. Results: Four hundred and eighty unique SCN5A variants were identified, the majority of which 425 (88%) were coding variants. One hundred and fifty‐six of 425 (37%) variants were classified as pathogenic/likely pathogenic. Two hundred and fifty‐eight (60%) were classified as variants of uncertain significance, while a further 11 (3%) were classified as benign/likely benign. When considering the subset of variants that were considered "null" variants separately, 95% fulfilled criteria for pathogenicity/likely pathogenicity. In contrast, only 17% of missense variants fulfilled criteria for pathogenicity/likely pathogenicity. Importantly, however, only 25% of missense variants had available functional data, which was a major score driver for pathogenic classification. Conclusion: Based on contemporary ACMG‐AMP guidelines, only a minority of SCN5A variants implicated in BrS fulfill the criteria for pathogenicity or likely pathogenicity. [ABSTRACT FROM AUTHOR]

A Tricky Case of Pediatric Overlap Syndrome We describe the case of 2-year-old baby with compound heterozygosity for paternal and maternal alleles mutation of α-subunit of the cardiac sodium channel (SCN5A), sinus node dysfunction, atrial flutter recurrences, and drug induced long-QT syndrome. In this setting, we chose at first to perform linear ablation of cavotricuspid isthmus resulting in a bidirectional isthmus block. As a second step, we decided to implant a miniaturized loop recorder that, with a minimally invasive procedure, permits us to follow the development of the disease in order to define the future strategy. After 8 months follow-up, automatic daily loop-recorder transmissions disclose the complete absence of any arrhythmia along with asymptomatic ventricular pauses due to sinus node dysfunction. Echocardiography shows normal findings, in particular no left ventricular dysfunction. [ABSTRACT FROM AUTHOR]

p.Y1449C SCN5A Mutation in a Family with Overlap Disorder Mutations in the SCN5A gene, which encodes the cardiac sodium channel, have been associated with cardiac arrhythmia syndromes and conduction disease. Specific SCN5A mutations had initially been considered to cause specific phenotypes. More recently, some SCN5A mutations have been associated with overlap syndromes, characterized by phenotypic heterogeneity within and between mutation carriers. Here we report and associate the presence of the p.Y1449C SCN5A mutation in a single family with a spectrum of cardiac phenotypes including conduction disease, Brugada syndrome and atrial arrhythmias, for the first time to our knowledge. [ABSTRACT FROM AUTHOR]

Channelopathies in Infantile Arrhythmias Background Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades, and postmortem analyses in SIDS victims have provided evidence of this association. However, the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear. Methods and Results Seven infants with potentially lethal arrhythmias at age < 1 year (5 males, age of onset 44.1 ± 72.1 days) were genetically analyzed for KCNQ1, KCNH2, KCNE1-5, KCNJ2, SCN5A, GJA5, and CALM1 by using denaturing high-performance liquid chromatography and direct sequencing. Whole-cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with SCN5A and KCNH2 cDNA. In 5 of 7 patients, we identified 4 mutations (p.N1774D, p.T290fsX53, p.F1486del and p.N406K) in SCN5A, and 1 mutation (p.G628D) in KCNH2. N1774D, F1486del, and N406K in SCN5A displayed tetrodotoxin-sensitive persistent late Na+ currents. By contrast, SCN5A-T290fsX53 was nonfunctional. KCNH2-G628D exhibited loss of channel function. Conclusion Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies. Functional assays revealed both gain and loss of channel function in SCN5A mutations, as well as loss of function associated with the KCNH2 mutation. [ABSTRACT FROM AUTHOR]

SCN5A deletion only detected by MLPA. A 14-year-old boy presented with atrial flutter. His ECG showed Brugada changes, first-degree AV block and major sinus pauses. Polymorphic VT was inducible at electrophysiology study. A pacemaker defibrillator was placed. Classic sequencing for SCN5A was normal. Multiplex ligation-dependent probe amplification, however, detected a major deletion in SCN5A. It is predicted that this deletion would result in haploinsufficiency. The report is the first description of a large-scale rearrangement of the SCN5A gene and supports the association between the molecular pathology and the phenotypic expression. (J Cardiovasc Electrophysiol, Vol. 22, pp. 1073-1076, September 2011) [ABSTRACT FROM AUTHOR]

Effects of H558R on SSS-Related Mutant Channels. Introduction: Mutations in SCN5A, the gene encoding α subunit of cardiac type sodium channel, Nav1.5, lead to familial sick sinus syndrome (SSS). Although several molecular mechanisms for this genetic condition have been explored, the underlying mechanisms for the variable genotype–phenotype relationships have not been well addressed. One of the important contributors to such relationships is the genetic background such as single-nucleotide polymorphisms. Methods and Results: To clarify the effects of a common polymorphism in SCN5A gene, H558R, on SCN5A-related SSS phenotype, we investigated the electrophysiological properties of all of the 13 known SSS-related hNav1.5 mutant channels on both H558 and R558 background. Electrophysiological properties of hNav1.5 mutant channels were investigated by the whole-cell patch clamp technique in HEK293 cells. When peak currents were affected by the mutation, cell surface biotinylation was performed to quantify the fraction of correctly cell membrane-targeted mutant channels. Loss-of-function defect of D1275N in SCN5A was rescued by R558 through enhancing cell surface targeting and improving steady-state activation of the mutant channels. In contrast, the defects of mutants E161K, P1298L, and R1632H were aggravated in the R558 background, mainly due to the reduced steady-state availability of mutant channels. The electrophysiological properties of the remaining SSS-related hNav1.5 mutants including the missense mutants (L212P, T220I, DelF1617, T187I, R878C, G1408R), and the truncated mutants (W1421X, K1578fs/52, R1623X) were not significantly affected by H558R. Conclusion: We conclude that polymorphism H558R has mutation-specific effects on SCN5A-related SSS. Our data highlight the importance of common genetic variants in modulating phenotypes of genetic diseases. (J Cardiovasc Electrophysiol, Vol. 21, pp. 564-573, May 2010) [ABSTRACT FROM AUTHOR]

Cardiac Diseases Caused by SCN5A Mutations. A prerequisite for a normal cardiac function is a proper generation and propagation of electrical impulses. Contraction of the heart is obtained through a delicate matched transmission of the electrical impulses. A pivotal element of the impulse propagation is the depolarizing sodium current, responsible for the initial depolarization of the cardiomyocytes. Recent research has shown that mutations in the SCN5A gene, encoding the cardiac sodium channel Nav1.5, are associated with both rare forms of ventricular arrhythmia, as well as the most frequent form of arrhythmia, atrial fibrillation (AF). In this comprehensive review, we describe the functional role of Nav1.5 and its associated proteins in propagation and depolarization both in a normal- and in a pathophysiological setting. Furthermore, several of the arrhythmogenic diseases, such as long-QT syndrome, Brugada syndrome, and AF, reported to be associated with mutations in SCN5A, are thoroughly described. (J Cardiovasc Electrophysiol, Vol. 21, pp. 107–115, January 2010) [ABSTRACT FROM AUTHOR]

Sodium channels play a crucial role in initiation, propagation, and maintenance of cardiac excitation throughout the heart. Indeed, dysfunctional sodium channels have been shown to be responsible for several inherited cardiac electrical disorders, such as Long QT and Brugada syndromes (BrS), potentially leading to fatal arrhythmic events. Genetic approaches and functional experiments using heterologous systems have enabled the characterization of the molecular determinants involved in these disorders and their consequences on ion channel function. The improved understanding of the mechanisms leading to these cardiac arrhythmic events represents a first step in the development of therapeutic treatments. [ABSTRACT FROM AUTHOR]

Background: The potential pathophysiological role of common SCN5A polymorphisms in cardiac arrhythmias has been increasingly recognized. However, little is known about the impact of those polymorphisms on the pharmocological response of hNav1.5 to various antiarrhythmic agents. Methods and Results: The known SCN5A polymorphism, S524Y, was studied in comparison with the wild type (WT) define the SCN5A-Q1077del variant. The ion channel gating kinetics and pharmacology were evaluated using whole-cell patch-clamp methods in HEK-293 cells. Consistent with a previous report, the basal ion channel gating kinetics of S524Y were indistinguishable from the WT. Quinidine (20 μM) caused similar extent of tonic block reduction of sodium currents at –120 mV in WT and S524Y. Surprisingly, quinidine (20 μM) exerted a more use-dependent block by a 10 Hz pulse train in S524Y than in WT at 22°C ( Ki: WT, 51.3 μM; S524Y, 20.3 μM). S524Y significantly delayed recovery from the use-dependent block, compared with the WT (τ= 88.6 ± 7.9 s vs 41.9 ± 6.6 s, P < 0.005). Under more physiological conditions using a 2 Hz pulse train at 37°C, S524Y similarly enhanced the use-dependent block by quinidine. In addition, S524Y enhanced the use-dependent block by flecainide (12.5 μM), but not by mexiletine (100 μM). Conclusion: A common SCN5A polymorphism, S524Y, can enhance a use-dependent block by class Ia and Ic antiarrhythmic agents. Our findings may have clinical implications in pharmacological management of cardiac arrhythmias since this common SCN5A polymorphism might be a contributing factor to the variable antiarrhythmic response. [ABSTRACT FROM AUTHOR]

Introduction: We aimed at identifying the molecular defect underlying the clinical phenotype of a Finnish family with a cardiac conduction defect and atrial arrhythmias. Methods and Results: A large Finnish family was clinically evaluated (ECG, 24-hour ambulatory ECG, echocardiography). We performed linkage analysis with markers flanking the SCN5A gene and subsequently sequenced the SCN5A gene. Five family members had atrial arrhythmias and intracardiac conduction defects, and due to bradycardia needed a pacemaker when adolescents. No heart failure or sudden cardiac death was observed. Left ventricle dilatation was seen in one individual and three individuals had a slightly enlarged right ventricle. Premature death due to stroke occurred in one subject during the study, and two other members had suffered from stroke at young age. Linkage analysis favored the role of the SCN5A gene in disease pathogenesis, and direct sequencing disclosed D1275N mutation. This alteration was present not only in all six affected individuals, but also in two young individuals lacking clinical symptoms. Conclusions: Cardiac conduction defect and atrial arrhythmias in a large Finnish family appear to result from the SCN5A D1275N mutation. Although no sudden cardiac death was recorded in the family, at least three affected members had encountered brain infarction at the age of 30 or younger. [ABSTRACT FROM AUTHOR]

Mutations in the SCN5A gene can cause Brugada syndrome, a genetically inherited form of idiopathic ventricular fibrillation. We describe the case of a 3-year-old child with a structurally normal heart presenting with monomorphic ventricular tachycardia. Her electrocardiogram suggested a Brugada syndrome and the diagnosis was confirmed by the identification of a Brugada syndrome in her mother and in two other family members. Genetic study led to the identification of a c.2516T→C SCN5A mutation. The child was treated with quinidine therapy without recurrence of arrhythmic events for a time period of 16 months. [ABSTRACT FROM AUTHOR]

Brugada Syndrome and Sodium Channel Blockade. Brugada syndrome is an inherited cardiac disorder caused by mutations in theSCN5Agene encoding the cardiac sodium channelα subunit, which can lead ventricular fibrillation and sudden death. Inattentive use of antiarrhythmic drugs potentially triggers fatal cardiac arrhythmias through further reduction of sodium current (INa). We studied the molecular mechanism underlying a case of Brugada syndrome that showed no response to a class Ic antiarrhythmic drug. Molecular genetic studies of a patient with Brugada syndrome identified a novel mutation inSCN5A, which causes substitution of serine for asparagine (N406S) in S6 of domain I (IS6). The provocation test with pilsicainide, a class Ic antiarrhythmic drug, failed to exacerbate ST-segment elevation in this case. Electrophysiological analyses of the N406S-mutant channel expressed together with theβ1 subunit in HEK293 cells showed that the voltage dependence of activation was positively shifted by 16 mV and that intermediate inactivation was enhanced. Whereas tonic block by pilsicainide was not changed in the N406S channel, use-dependent block by pilsicainide was almost completely abolished, consistent with the clinical findings of the negative provocation test. In contrast, the N406S channel showed stronger use-dependent block by quinidine than the wild-type channel. We demonstrate a novel Brugada mutation N406S, which is associated with the discordant effects on blocking actions of antiarrhythmic drugs as well as the multiple channel gating defects. We emphasis that an antiarrhythmic drug may exert unpredicted effects in patients with channel mutations.(J Cardiovasc Electrophysiol, Vol. 16, pp. 486-493, May 2005) [ABSTRACT FROM AUTHOR]

Brugada Syndrome with an S5-Pore Mutation ofSCN5A. Brugada syndrome is an inherited cardiac disorder caused by mutations in theSCN5Agene encoding the cardiac sodium channelα-subunit, and potentially leads to ventricular fibrillation and sudden death. We report a case of a novelSCN5Amutation associated with Brugada syndrome. A 51-year-old man suffered from recurrent nocturnal syncopal attacks due to polymorphic ventricular tachycardia. His electrocardiogram showed ST-segment elevation in V1–V3 leads, but there was no evidence of structural heart disease. DNA sequence analysis ofSCN5Ain this patient revealed a missense mutation (R282H) in the S5-pore region of domain I. This mutational change was not present in 100 healthy Japanese controls. In the patient's family, a 36-year-old brother had died suddenly. Genetic analysis identified two other carriers of the R282H mutation, who had ST-segment elevation and slightly increased QRS widths, but they experienced no syncopal episodes or ventricular fibrillation. Electrophysiological investigation of the R282H mutant channel expressed in cultured cells showed a severe reduction in sodium current density and a mild positive shift of activation curve. R282H did not enhance intermediate inactivation. Single-channel conductance of R282H was slightly decreased compared with WT. The electrophysiological characteristics of the R282H channel are suggested to be closely related to the clinical phenotype of Brugada syndrome.(J Cardiovasc Electrophysiol, Vol. 16, pp. 1-6, April 2005) [ABSTRACT FROM AUTHOR]

Brugada Syndrome. Introduction: Brugada syndrome is characterized by sudden death secondary to malignant arrhythmias and the presence of ST segment elevation in leads V1 to V3 of patients with structurally normal hearts. This ECG pattern often is concealed but can be unmasked using potent sodium channel blockers. Like congenital long QT syndrome type 3 (LQT3) and sudden unexpected death syndrome, Brugada syndrome has been linked to mutations in SCN5A. Methods and Results: We screened a large European family with Brugada syndrome. Three members (two female) had suffered malignant ventricular arrhythmias. Ten members showed an ECG pattern characteristic of Brugada syndrome at baseline, and eight showed the pattern only after administration of ajmaline (total 12 female). Haplotype analysis revealed that all individuals with positive ECG at baseline shared the SCN5A locus. Sequencing of SCN5A identified a missense mutation, R367H, previously associated with sudden unexpected death syndrome. Two of the eight individuals who displayed a positive ECG after the administration of ajmaline, but not before, did not have the R367H mutation, and sequencing analysis failed to identify any other mutation in SCN5A. The R367H mutation failed to generate any current when heterologously expressed in HEK cells. Conclusion: Our results support the hypothesis that (1) sudden unexpected death syndrome and Brugada syndrome are the same disease; (2) male predominance of the phenotype observed in sudden unexpected death syndrome does not apply to this family, suggesting that factors other than the specific mutation determine the gender distinction; and (3) ajmaline may provide false-positive results. These findings have broad implications relative to the diagnosis and risk stratification of family members of patients with the Brugada syndrome. (J Cardiovasc Electrophysiol, Vol. 15, pp. 64-69, January 2004) [ABSTRACT FROM AUTHOR]

The congenital long QT syndromes (LQTSs) are a group of inherited cardiac disorders that increase the risk of sudden death from ventricular arrhythmias. Individuals with LQTS show abnormalities in cardiac repolarization. Mutations that cause LQTSs are distributed throughout the human genome on chromosomes 347, 11, and 21. Recent molecular genetic studies established that LQT3 results from mutations In the cardiac sodium ion channel gene (SCN5A). Research efforts are aimed at elucidating molecular mechanisms, determining the links between clinical phenotypes and the individual gene mutations, and pharmacologic targeting of the phenotypes. This approach will ultimately guide rational therapy. In addition, LQT3 serves as a model for Inherited molecular-based disorders, as well as a paradigm for understanding the genesis and control of other cardiac arrhythmias. [ABSTRACT FROM AUTHOR]

The Na current (INa) in human ventricle is carried through a specific isoform of the voltage gated Na channel in heart. The pore forming α-subunit is encoded by the gene SCN5A. Up to four β-subunits may be associated, and the larger macromolecular complex may include attachments to cytoskeleton and scaffolding proteins, all of which may affect the gating kinetics of the current. INa underlies initiation and propagation of action potentials in the heart and plays a prominent role in cardiac electrophysiology and arrhythmia. In addition, INa also loads the ventricular cell with Na+ ions and plays an important role in intracellular Na homeostasis. This review considers the structure and function of the human cardiac Na channel that carries INa with a particular consideration of the implications of alterations in INa in acquired cardiac diseases such as hypertrophy, failure, and ischemia, which affect Na loading. [ABSTRACT FROM AUTHOR]