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The following case series presents three different pediatric patients with SCN5A- related disease. In addition, family members are presented to demonstrate the variable penetrance that is commonly seen. Identifying features of this disease is important, because even in the very young, SCN5A disorders can cause lethal arrhythmias and sudden death. [ABSTRACT FROM AUTHOR]

Brugada syndrome (BrS) is an inherited cardiac arrhythmogenic disease that predisposes patients to sudden cardiac death. It is associated with mutations in SCN5A , which encodes the cardiac sodium channel alpha subunit (Na V 1.5). BrS-related mutations have incomplete penetrance and variable expressivity within families. The purpose of this study was to determine the role of patient-specific genetic background on the cellular and clinical phenotype among carriers of Na V 1.5_p.V1525M. We studied sodium currents from patient-specific human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) and heterologously transfected human embryonic kidney (HEK) tsA201 cells using the whole-cell patch-clamp technique. We determined gene and protein expression by quantitative polymerase chain reaction, RNA sequencing, and western blot and performed a genetic panel for arrhythmogenic diseases. Our results showed a large reduction in I Na density in hiPSC-CM derived from 2 V1525M single nucleotide variant (SNV) carriers compared with hiPSC-CM derived from a noncarrier, suggesting a dominant-negative effect of the Na V 1.5_p.V1525M channel. I Na was not affected in hiPSC-CMs derived from a V1525M SNV carrier who also carries the Na V 1.5_p.H558R polymorphism. Heterozygous expression of V1525M in HEK-293T cells produced a loss of I Na function, not observed when this variant was expressed together with H558R. In addition, the antiarrhythmic drug mexiletine rescued I Na function in hiPSC-CM. SCN5A expression was increased in the V1525M carrier who also expresses Na V 1.5_p.H558R. Our results in patient-specific hiPSC-CM point to a dominant-negative effect of Na V 1.5_p.V1525M, which can be reverted by the presence of Na V 1.5_p.H558R. Overall, our data points to a role of patient-specific genetic background as a determinant for incomplete penetrance in BrS. [ABSTRACT FROM AUTHOR]

The efficacy of beta-blocker treatment in type 3 long QT syndrome (LQT3) remains debated. The purpose of this study was to test the hypothesis that beta-blocker use is associated with cardiac events (CEs) in a French cohort of LQT3 patients. All patients with a likely pathogenic/pathogenic variant in the SCN5A gene (linked to LQT3) were included and followed-up. Documented ventricular tachycardia/ventricular fibrillation, torsades de pointes, aborted cardiac arrest, sudden death, and appropriate shocks were considered as severe cardiac events (SCEs). CEs also included syncope. We included 147 patients from 54 families carrying 23 variants. Six of the patients developed symptoms before the age of 1 year and were analyzed separately. The 141 remaining patients (52.5% male; median age at diagnosis 24.0 years) were followed-up for a median of 11 years. The probabilities of a CE and an SCE from birth to the age of 40 were 20.5% and 9.9%, respectively. QTc prolongation (hazard ratio [HR] 1.12 [1.0–1.2]; P =.005]) and proband status (HR 4.07 [1.9–8.9]; P <.001) were independently associated with the occurrence of CEs. Proband status (HR 8.13 [1.7–38.8]; P =.009) was found to be independently associated with SCEs, whereas QTc prolongation (HR 1.11 [1.0–1.3]; P =.108) did not reach statistical significance. The cumulative probability of the age at first CE/SCE was not lower in patients treated with a beta-blocker. In agreement with the literature, proband status and lengthened QTc were associated with a higher risk of CEs. Our data do not show a protective effect of beta-blocker treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Pathogenic variants in the SCN5A -encoded Nav1.5 sodium channel cause type 3 long QT syndrome (LQT3). We present the case of an infant with severe LQT3 who was refractory to multiple pharmacologic therapies as well as bilateral stellate ganglionectomy. The patient's novel variant, p.F1760C-SCN5A, involves a critical residue of the Nav1.5's local anesthetic binding domain. The purpose of this study was to characterize functionally the p.F1760C-SCN5A variant using TSA-201 and patient-specific induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). Whole-cell patch clamp was used to assess p.F1760C-SCN5A associated sodium currents with/without lidocaine (Lido), flecainide, and phenytoin (PHT) in TSA-201 cells. p.F1760C-SCN5A and CRISPR-Cas9 variant-corrected isogenic control (IC) iPSC-CMs were generated. FluoVolt voltage dye was used to measure the action potential duration (APD) with/without mexiletine or PHT. V 1/2 of inactivation was right-shifted significantly in F1760C cells (–72.2 ± 0.7 mV) compared to wild-type (WT) cells (–86.3 ± 0.9 mV; P <.0001) resulting in a marked increase in window current. F1760C increased sodium late current 2-fold from 0.18% ± 0.04% of peak in WT to 0.49% ± 0.07% of peak in F1760C (P =.0005). Baseline APD to 90% repolarization (APD 90) was increased markedly in F1760C iPSC-CMs (601 ± 4 ms) compared to IC iPSC-CMs (423 ± 15 ms; P <.0001). However, 4-hour treatment with 10 μM mexiletine failed to shorten APD 90 , and treatment with 5μM PHT significantly decreased APD 90 of F1760C iPSC-CMs (453 ± 6 ms; P <.0001). PHT rescued electrophysiological phenotype and APD of a novel p.F1760C-SCN5A variant. The antiepileptic drug PHT may be an effective alternative therapeutic for the treatment of LQT3, especially for variants that disrupt the Lido/mexiletine binding site. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) is a disorder of cardiac ventricular dilation and contractile dysfunction that often progresses to heart failure. Multiple genes have been associated with DCM, including SCN5A which has been linked to 2 % of all DCM cases. Peripheral mononuclear blood cells from DCM patients with SCN5A variants (c.2440C>T and c.665G>A) were utilized to generate two human induced pluripotent stem cell (iPSC) lines. Both lines exhibited typical iPSC morphology, expressed pluripotency markers, normal karyotypes, and trilineage differentiation capabilities. These lines offer valuable resources for investigating the mechanism of SCN5A-associated DCM, facilitating studies of ion channel protein involvement in the disease. [ABSTRACT FROM AUTHOR]

Background: Severe acute respiratory syndrome coronavirus 2 vaccination reduces morbidity and mortality associated with coronavirus disease 2019 (COVID-19); unfortunately, it is associated with serious adverse events, including sudden unexplained death (SUD).Objective: We aimed to study the genetic basis of SUD after COVID-19 vaccination in Thailand.Methods: From April to December 2021, cases with natural but unexplained death within 7 days of COVID-19 vaccination were enrolled for whole exome sequencing.Results: Thirteen were recruited, aged between 23 and 72 years; 10 (77%) were men, 12 were Thai; and 1 was Australian. Eight (61%) died after receiving the first dose of vaccine, and 7 (54%) died after receiving ChAdOx1 nCoV-19; however, there were no significant correlations between SUD and either the number or the type of vaccine. Fever was self-reported in 3 cases. Ten (77%) and 11 (85%) died within 24 hours and 3 days of vaccination, respectively. Whole exome sequencing analysis revealed that 5 cases harbored SCN5A variants that had previously been identified in patients with Brugada syndrome, giving an SCN5A variant frequency of 38% (5 of 13). This is a significantly higher rate than that observed in Thai SUD cases occurring 8-30 days after COVID-19 vaccination during the same period (10% [1 of 10]), in a Thai SUD cohort studied before the COVID-19 pandemic (12% [3 of 25]), and in our in-house exome database (12% [386 of 3231]).Conclusion: These findings suggest that SCN5A variants may be associated with SUD within 7 days of COVID-19 vaccination, regardless of vaccine type, number of vaccine dose, and presence of underlying diseases or postvaccine fever. [ABSTRACT FROM AUTHOR]

Background: Sudden unexpected infant death (SUID) occurs unpredictably and remains unexplained after scene investigation and autopsy. Approximately 1 in 7 cases of SUID can be related to a cardiac cause, and developmental regulation of cardiac ion channel genes may contribute to SUID.Objective: The goal of this study was to investigate the developmental changes in the spliceoforms of SCN5A and KCNQ1, 2 genes implicated in SUID.Methods: Using reverse transcription quantitative real-time polymerase chain reaction, we quantified expression of SCN5A (adult and fetal) and KCNQ1 (KCNQ1a and b) spliceoforms in 153 human cardiac tissue samples from decedents that succumbed to SUID ("unexplained") and other known causes of death ("explained noncardiac").Results: There is a stepwise increase in the adult/fetal SCN5A spliceoform ratio from <2 months (4.55 ± 0.36; n = 51) through infancy and into adulthood (17.41 ± 3.33; n = 5). For KCNQ1, there is a decrease in the ratio of KCNQ1b to KCNQ1a between the <2-month (0.37 ± 0.02; n = 46) and the 2- to 4-month (0.28 ± 0.02; n = 52) age groups. When broken down by sex, race, or cause of death, there were no differences in SCN5A or KCNQ1 spliceoform expression, except for a higher ratio of KCNQ1b to KCNQ1a at 5-12 months of age for SUID females (0.40 ± 0.04; n = 9) than for males (0.25 ± 0.03; n = 6) and at <2 months of age for SUID white (0.42 ± 0.03; n = 19) than for black (0.33 ± 0.05; n = 9) infants.Conclusion: This study documents the developmental changes in SCN5A and KCNQ1 spliceoforms in humans. Our data suggest that spliceoform expression ratios change significantly throughout the first year of life. [ABSTRACT FROM AUTHOR]

Background: Mutations in cardiac sodium channel Nav1.5 cause Brugada syndrome (BrS). MOG1 is a chaperone that binds to Nav1.5, facilitates Nav1.5 trafficking to the cell surface, and enhances the amplitude of sodium current INa.Objective: The purpose of this study was to identify structural elements involved in MOG1-Nav1.5 interaction and their relevance to the pathogenesis of BrS.Methods: Systematic analyses of large deletions, microdeletions, and point mutations, and glutathione S-transferases pull-down, co-immunoprecipitation, cell surface protein quantification, and patch-clamping of INa were performed.Results: Large deletion analysis defined the MOG1-Nav1.5 interaction domain to amino acids S476-H585 of Nav1.5 Loop I connecting transmembrane domains I and II. Microdeletion and point mutation analyses further defined the domain to F530T531F532R533R534R535. Mutations F530A, F532A, R533A, and R534A, but not T531A and R535A, significantly reduced MOG1-Nav1.5 interaction and eliminated MOG1-enhanced INa. Mutagenesis analysis identified D24, E36, D44, E53, and E101A of MOG1 as critical residues for interaction with Nav1.5 Loop I. We then characterized 3 mutations at the MOG1-Nav1.5 interaction domain: p.F530V, p.F532C, and p.R535Q reported from patients with long QT syndrome and BrS. We found that p.F532C reduced MOG1-Nav1.5 interaction and eliminated MOG1 function on INa; p.R535Q is also a loss-of-function mutation that reduces INa amplitude in a MOG1-independent manner, whereas p.F530V is benign as it does not have an apparent effect on MOG1 and INa.Conclusion: Our findings define the MOG1-Nav1.5 interaction domain to a 5-amino-acid motif of F530T531F532R533R534 in Loop I. Mutation p.F532C associated with BrS abolishes Nav1.5 interaction with MOG1 and reduces MOG1-enhanced INa density, thereby uncovering a novel molecular mechanism for the pathogenesis of BrS. [ABSTRACT FROM AUTHOR]

We present the case of a patient with recurrent episodes of ventricular fibrillation without evidence of structural cardiac diseases on imaging techniques and negative genetic testing for the most common primary arrhythmia syndromes. A new variant c.6023C>T p.Pro2008Leu of the SCN5A protein, responsible for the sodium inward current (INa) through the cardiomyocytes, was found. A likely pathogenic effect of this gene variant was hypothesized. [ABSTRACT FROM AUTHOR]

Background: SCN5A mutations are associated with multiple arrhythmic and cardiomyopathic phenotypes including Brugada syndrome (BrS), sinus node dysfunction (SND), atrioventricular block, supraventricular tachyarrhythmias (SVTs), long QT syndrome (LQTS), dilated cardiomyopathy and left ventricular noncompaction. Several single SCN5A mutations have been associated with overlap of some of these phenotypes, but never with overlap of all the phenotypes.Objective: We encountered two pedigrees with multiple arrhythmic phenotypes with or without cardiomyopathic phenotypes, and sought to identify a responsible mutation and reveal its functional abnormalities.Methods: Target panel sequencing of 72 genes, including inherited arrhythmia syndromes- and cardiomyopathies-related genes, was employed in two probands. Cascade screening was performed by Saner sequencing. Wild-type or identified mutant SCN5A were expressed in tsA201 cells, and whole-cell sodium currents (INa) were recorded using patch-clamp techniques.Results: We identified an SCN5A A735E mutation in these probands, but did not identify any other mutations. All eight mutation carriers exhibited at least one of the arrhythmic phenotypes. Two patients exhibited multiple arrhythmic phenotypes: one (15-year-old girl) exhibited BrS, SND, and exercise and epinephrine-induced QT prolongation, the other (4-year-old boy) exhibited BrS, SND, and SVTs. Another one (30-year-old male) exhibited all arrhythmic and cardiomyopathic phenotypes, except for LQTS. One male suddenly died at age 22. Functional analysis revealed that the mutant did not produce functional INa.Conclusions: A non-functional SCN5A A735E mutation could be associated with multiple arrhythmic and cardiomyopathic phenotypes, although there remains a possibility that other unidentified factors may be involved in the phenotypic variability of the mutation carriers. [ABSTRACT FROM AUTHOR]

Background: Mutations in SCN5A are rarely found in Thai patients with Brugada syndrome (BrS). Recent evidence suggested that common genetic variations may underlie BrS in a complex inheritance model.Objective: The purpose of this study was to find common and rare/low-frequency genetic variants predisposing to BrS in persons in Thailand.Methods: We conducted a genome-wide association study (GWAS) to explore the association of common variants in 154 Thai BrS cases and 432 controls. We sequenced SCN5A in 131 cases and 205 controls. Variants were classified according to current guidelines, and case-control association testing was performed for rare and low-frequency variants.Results: Two loci were significantly associated with BrS. The first was near SCN5A/SCN10A (lead marker rs10428132; odds ratio [OR] 2.4; P = 3 × 10-10). Conditional analysis identified a novel independent signal in the same locus (rs6767797; OR 2.3; P = 2.7 × 10-10). The second locus was near HEY2 (lead marker rs3734634; OR 2.5; P = 7 × 10-9). Rare (minor allele frequency [MAF] <0.0001) coding variants in SCN5A were found in 8 of the 131 cases (6.1% in cases vs 2.0% in controls; P = .046; OR 3.3; 95% confident interval [CI] 1.0-11.1), but an enrichment of low-frequency (MAF<0.001 and >0.0001) variants also was observed in cases, with 1 variant (SCN5A: p.Arg965Cys) detected in 4.6% of Thai BrS patients vs 0.5% in controls (P = 0.015; OR 9.8; 95% CI 1.2-82.3).Conclusion: The genetic basis of BrS in Thailand includes a wide spectrum of variant frequencies and effect sizes. As previously shown in European and Japanese populations, common variants near SCN5A and HEY2 are associated with BrS in the Thai population, confirming the transethnic transferability of these 2 major BrS loci. [ABSTRACT FROM AUTHOR]

Congenital long-QT syndrome type 3 (LQT3) with SCN5A -V411M mutation has been reported as a malignant case of LQT3 with highest risk for sudden cardiac death (SCD). Here, we present two cases of LQT3 with SCN5A -V411M who had been implanted with subcutaneous (S-) or transvenous (TV-) implantable cardioverter defibrillators (ICD). Case 1, a 2-year-old boy, although he had no symptoms, was diagnosed as having LQT3 (V411M- SCN5A) due to family history. The QTc interval was still longer than 500 ms during follow-up even under oral mexiletine. Case 2 (his aunt) diagnosed as LQT3 suffered from syncope caused by ventricular fibrillation at 35-years-old despite taking mexiletine. Furthermore, case 1's father and half-brother, both had the V411M mutation with LQT3, had suddenly died. Thus, case 1 was recommended S-ICD when he was 15-years-old for primary prevention of SCD but not necessary for pacing therapy, while, case 2 had been implanted TV-ICD for secondary prevention of SCD. They had no event after ICD implantation, however, case 2 had to have added an extra ICD-lead due to lead failure when she was 44-years-old. The S-ICD may be a potent therapeutic option for high-risk LQTS when patients are younger and do not need pacing therapy. < Learning objective: In congenital long-QT syndrome (LQTS) type 3, some of the first events are lethal, particularly, LQT3 with V411M- SCN5A mutation is the highest risk for sudden cardiac death (SCD). Which implantable cardioverter defibrillator (ICD), transvenous (TV-ICD) or subcutaneous (S-ICD) is better for primary prevention of SCD in LQTS is still controversial. The S-ICD rather than TV-ICD may have a potent benefit for high-risk LQTS when patients are younger and do not need pacing therapy.> [ABSTRACT FROM AUTHOR]

Background: The cardiac sodium channel (SCN5A) mutation R222Q neutralizes a positive charge in the domain I voltage sensor. Mutation carriers display very frequent ectopy and dilated cardiomyopathy.Objectives: To describe the effect of SCN5A R222Q on murine myocyte and Purkinje fiber electrophysiology, and identify underlying mechanisms.Methods: We generated mice carrying humanized wild-type (H) and mutant (RQ) SCN5A channels. We characterized whole-heart and isolated ventricular and Purkinje myocyte properties.Results: RQ/RQ mice were not viable. INa from RQ/H ventricular myocytes displayed increased "window current" and hyperpolarizing shifts in both inactivation and activation compared to H/H, as previously reported in heterologous expression systems. Surprisingly, action potentials were markedly abbreviated in RQ/H myocytes (action potential durations at 90% repolarization: 12.6 ± 1.3 ms vs 29.1 ± 1.0 ms in H/H, P < .01, n = 10 each). We identified a large [K+]o-dependent outward gating pore current in RQ/H but not H/H myocytes, and decreasing [K+]o elicited early afterdepolarizations (EADs) and triggered activity in isolated myocytes and ectopic beats in whole hearts. Further, RQ/H Purkinje cells displayed striking, consistent low-voltage EADs. In vivo, however, RQ/H mice displayed little ectopy and contractile function was normal.Conclusion: While SCN5A R222Q increases plateau inward sodium current, action potentials were unexpectedly shortened, likely reflecting an outward gating-pore current. Low extracellular potassium increased this pore current, and was arrhythmogenic in vitro and ex vivo. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this study was to analyze the correlations of the sodium channel, voltage-gated, type V, alpha subunit (SCN5A) gene polymorphisms with the onset of atrial fibrillation (AF), and its clinical significance. PATIENTS AND METHODS: The quantitative Real Time-Polymerase Chain Reaction (QRTPCR) amplification and the TaqMan analysis were utilized to analyze the composition of SCN5A genotypes and alleles in the peripheral blood mononuclear cells of 48 normal controls and 115 AF patients. Meanwhile, the differences in single nucleotide polymorphisms (SNPs), 1673 A>G, and 3666+69 G>C, between the AF group and the control group were analyzed using the χ²-test. The high-risk factors influencing the AF attack were analyzed via logistic regression analysis, as well as univariate and multivariate analyses. In addition, the correlations of gene polymorphisms with high-risk factors (drinking and hypertension) for AF were verified by the χ²-test. RESULTS: There were statistically significant differences in the incidence rate of hypertension, the times of smoking and drinking, and the frequencies of palpitation and syncope between the AF group and the control group (p<0.05). The composition of genotypes and alleles of 1673 A>G and 3666+69 G>C in the AF group was significantly different from that of the control group (p<0.05). According to the results of the logistic regression analysis, as well as the univariate and multivariate analyses, drinking, and hypertension were associated with the occurrence of AF (p<0.05). Furthermore, statistically significant differences were observed in the composition of the gene polymorphisms 1673 A>G and 3666+69 G>C between patients with and without histories of drinking and hypertension (p<0.05). CONCLUSIONS: There are significant differences in SCN5A gene polymorphisms 1673 A>G and 3666+69 G>C between AF patients and normal controls. Moreover, drinking and hypertension can influence the changes in the gene polymorphisms. [ABSTRACT FROM AUTHOR]

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Background: Brugada syndrome (BrS) is a primary arrhythmia syndrome affecting 1 in 2000 of the general population. Genetic testing identifies pathogenic variants in the sodium voltage-gated channel α-subunit 5 gene (SCN5A) in up to 25% of familial BrS. Balanced translocations, which involve the exchange of the ends of 2 different chromosomes, are found in approximately 1 in 500 people. They usually are benign and only rarely are reported to cause arrhythmogenic disorders.Objective: The purpose of this study was to identify the genetic mechanism underlying a family with BrS, sick sinus syndrome, cardiac hypertrophy, sudden cardiac death, and multiple miscarriages.Methods: We clinically evaluated family members with an electrocardiogram, 2-dimensional echocardiogram, and provocation testing with ajmaline challenge. Cytogenetic testing included karyotype and fluorescent in situ hybridization (FISH) analysis. We performed gene panel, exome, and genome sequencing analysis.Results: Sequencing of 128 cardiac genes and exome sequencing of a family with BrS, sick sinus syndrome, cardiac hypertrophy, sudden cardiac death, and multiple miscarriages did not reveal a pathogenic variant. Karyotype and FISH analysis identified a balanced translocation breaking the SCN5A gene on chromosome 3 and the multiple chromosome maintenance 10 gene (MCM10) on chromosome 10 t(3;10)(p22.2;p13). We characterized both translocation breakpoint junctions using genome sequencing and found no regions of sequence homology.Conclusion: A balanced translocation breaking SCN5A is a novel mechanism underlying disease in a family with BrS, sick sinus syndrome, cardiac hypertrophy, and sudden cardiac death. Genome sequencing can identify rare chromosomal aberrations causing inherited diseases that may otherwise be missed using gene panel and exome sequencing-based approaches. [ABSTRACT FROM AUTHOR]

Background: Loss-of-function mutations in SCN5A are associated in ∼20% of Brugada syndrome (BrS) patients. Copy number variations (CNVs) have been shown to be associated with several inherited arrhythmia syndromes.Objective: The purpose of this study was to investigate SCN5A CNVs among BrS probands.Methods: The study cohort consisted of 151 BrS probands who were symptomatic or had a family history of BrS, sudden death, syncope, or arrhythmic diseases. We performed sequence analysis of SCN5A by the Sanger method. For detecting CNVs in SCN5A, we performed multiplex ligation-dependent probe amplification analysis of the 151 BrS probands.Results: We identified pathogenic SCN5A mutations in 20 probands by the Sanger method. In 140 probands in whom multiplex ligation-dependent probe amplification was successfully performed, 4 probands were found to present different CNVs (deletion in 3 and duplication in 1). Three of them had fatal arrhythmia events; the remaining 1 was asymptomatic but had a family history. Mean age at diagnosis was 23 ± 14 years. All of the baseline 12-lead electrocardiograms showed PQ-interval prolongation. The characteristics of these 4 probands with CNVs were similar to those of the probands with mutations leading to premature truncation of the protein or missense mutations causing peak INa reduction >90%.Conclusion: We identified SCN5A CNVs in 2.9% of BrS probands who were symptomatic or had a family history. [ABSTRACT FROM AUTHOR]

Introduction: Mutations within SCN5A are found in a significant proportion (15-30%) of Brugada syndrome (BrS) cases and impair sodium transport across excitable cardiac cells that mediate ventricular contractions. Genetic testing offers a means to clinically assess and manage affected individuals and their family members.Methods and Results: The proband at age 44 years old exhibited a syncopal event during exercise, and presented later with a spontaneous type-I BrS pattern on 12‑lead resting electrocardiogram (ECG). Mutational analysis performed across all SCN5A exons revealed a unique three base-pair deletion p.M741_T742delinsI (c.2223_2225delGAC), in a heterozygous state in the proband and 2 siblings. This mutation was not seen in a cohort of 105 ethnicity-matched controls or in public genome databases. Patch clamp electrophysiology study conducted in TSA201 cells showed an abolishment of sodium current (INa). The proband, and several relatives, also harboured a known SCN5A variant, p.R1193Q (c.3578G>A).Conclusion: Our study has demonstrated the deleterious effect of a novel SCN5A mutation p.M741_T742delinsI (c.2223_2225delGAC). The findings highlight the complex effects of gender and age in phenotype manifestation. It also offers insights into improving the long-term management of BrS, and the utility of cascade genetic screening for risk stratification. [ABSTRACT FROM AUTHOR]

Background: Heritable cardiac-sodium channel dysfunction is associated with various arrhythmia syndromes, some predisposing to ventricular fibrillation. Phenotypic diversity among carriers of identical-by-descent mutations is often remarkable, suggesting influences of genetic modifiers.Objective: The purpose of this study was to identify a unique SCN5A-mutation founder population with mixed clinical phenotypes and sudden cardiac death, and to investigate the heritability of electromechanical traits besides the SCN5A-mutation effect.Methods: The 16-generation founder population segregating SCN5A c.4850_4852delTCT, p.(Phe1617del), was comprehensively phenotyped. Variance component analysis was used to evaluate the mutation's effects and assess heritability.Results: In 45 p.(Phe1617del) positives, the mutation associated strongly with QTc prolongation (472 ± 60 ms vs 423 ± 35 ms in 26 mutation negatives; P <.001; odds ratio for long-QT syndrome 22.4; 95% confidence interval 4.5-224.2; P <.001) and electromechanical window (EMW) negativity (-29 ± 47 ms vs 34 ± 26 ms; P <.001). Overlapping phenotypes including conduction delay and Brugada syndrome were noted in 19. Polymorphic ventricular tachyarrhythmias occurred mostly in the daytime, after arousal-evoked heart-rate acceleration and repolarization prolongation. Cox proportional hazards regression analysis revealed female gender as an independent risk factor for cardiac events (hazard ratio 5.1; 95% confidence interval 1.6-16.3; P = .006). p.(Phe1617del) was an important determinant of QTcbaseline, QTcmax, and EMW, explaining 18%, 28%, and 37%, respectively, of the trait's variance. Significant heritability was observed for PQ interval (P = .003) after accounting for the p.(Phe1617del) effect.Conclusion: This SCN5A-p.(Phe1617del) founder population with phenotypic divergence and overlap reveals long-QT syndrome-related and arousal-evoked ventricular tachyarrhythmias with a female preponderance. Variance component analysis indicates additional genetic variance for PQ interval hidden in the genome, besides a dominant p.(Phe1617del) effect on QTc and EMW. [ABSTRACT FROM AUTHOR]

Background: Long QT syndrome type 3 (LQT3) accounts for 5%-10% of long QT syndrome and results from gain-of-function mutations in the SCN5A-encoded sodium channel. Approximately 2% of healthy individuals host rare SCN5A variants of uncertain significance (VUS). Distinction of true LQT3-causative mutations from background genetic noise is essential.Objective: The purpose of this study was to assess the use of the lidocaine attenuation test (LAT) in evaluating patients with possible LQT3.Methods: We reviewed the LAT results and medical records for 25 patients with a possible LQT3-associated SCN5A variant. The LAT involved a loading dose of 1 mg/kg of intravenous lidocaine followed by continuous infusion at 50 μg/(kg⋅min) for 20 minutes. If the corrected QT interval shortened by ≥30 ms, the LAT was defined as positive.Results: Sixteen patients (64%) had a positive LAT, 6 of which demonstrated the E1784K variant. A positive LAT correlated in 86% of cases with abnormal in vitro channel function (mean corrected QT interval attenuation 43 ± 3 ms vs 25 ± 5 ms for wild-type variants; P = .03). Four of 5 patients (80%) with a VUS had a positive LAT (T1304M [2 patients], L1786P, and R800L). The T1304M variant demonstrated abnormal in vitro function and a positive LAT, opening the door for a potential variant promotion from VUS to likely pathogenic.Conclusion: The LAT may help distinguish true LQT3-causative mutations from an otherwise noncontributory VUS. Given that lidocaine acts as a late sodium current blocker, a positive LAT may enable the early identification of a pathological accentuation of the late sodium current that could be targeted therapeutically. [ABSTRACT FROM AUTHOR]

Background: Familial sick sinus syndrome (SSS) is often attributable to mutations in genes encoding the cardiac Na channel SCN5A and pacemaker channel HCN4. We previously found that SSS with SCN5A mutations shows early onset of manifestations and male predominance. Despite recent reports on the complications of atrial fibrillation (AF) and left ventricular noncompaction (LVNC) in patients with SSS caused by HCN4 mutations, their overall clinical spectrum remains unknown.Objective: The purpose of this study was to investigate the clinical and demographic features of SSS patients carrying HCN4 mutations.Methods: We genetically screened 38 unrelated SSS families and functionally analyzed the mutant SCN5A and HCN4 channels by patch clamping. We also evaluated the clinical features of familial SSS by a meta-analysis of 48 SSS probands with mutations in HCN4 (n = 16) and SCN5A (n = 32), including previously reported cases, and 538 sporadic SSS cases.Results: We identified two HCN4 and three SCN5A loss-of-function mutations in our familial SSS cohort. Meta-analysis of HCN4 mutation carriers showed a significantly younger age at diagnosis (39.1 ± 21.7 years) than in sporadic SSS (74.3 ± 0.4 years; P <.001), but a significantly older age than in SCN5A mutation carriers (20.0 ± 17.6 years; P = .003). Moreover, HCN4 mutation carriers were more frequently associated with AF (43.8%) and LVNC (50%) and with older age at pacemaker implantation (43.5 ± 22.1 years) than were SCN5A mutation carriers (17.8 ± 16.5 years; P <.001).Conclusion: SSS with HCN4 mutations may form a distinct SSS subgroup characterized by early clinical manifestation after adolescence and frequent association with AF and LVNC. [ABSTRACT FROM AUTHOR]

Background Phenotypes often differ even within family members carrying the same SCN5A mutation. We aimed to evaluate the genetic modifiers in a family with Brugada syndrome (BrS) and sick sinus syndrome (SSS) with an SCN5A mutation that causes the truncated alpha-subunit of cardiac Na channel protein. Methods To detect the genetic modifiers, we performed targeted panel sequencing of the coding region of 46 genes that are related to primary arrhythmia syndrome, by using a bench-top, next generation sequencer. Phenotype–genotype relationships were evaluated among the family members. Results Index proband was a 13-year old (yo) boy with cardiac conduction defect as well as BrS. Genetic analysis revealed that he and his three asymptomatic family members carried a novel nonsense mutation: SCN5A -Q779X. Both genotype-positive mother and sister exhibited coved type ST elevation and his sister had SSS, whereas his elder brother exhibited saddleback type ST elevation induced by pilsicainide administration. We detected four non-synonymous variants ( DSG2 -R773K, SCN1B -L210P, -S248R, and -R250T) in the proband, his mother and his sister, but not in his brother. Conclusion Phenotypic differences between the proband and his brother carrying the same nonsense SCN5A mutation could be explained by modifiers such as SCN1 B, and DSG2 gene variants. [ABSTRACT FROM AUTHOR]

Background—Several compounds have been reported to induce translational readthrough of premature stop codons resulting in the production of full-length protein by interfering with ribosomal proofreading. Here we examined the effect of 2 of these compounds, gentamicin and PTC124, in human-induced pluripotent stem cell (hiPSC)–derived cardiomyocytes bearing nonsense mutations in the sodium channel gene SCN5A, which are associated with conduction disease and potential lethal arrhythmias.Methods and Results—We generated hiPSC from 2 patients carrying the mutations R1638X and W156X. hiPSC-derived cardiomyocytes from both patients recapitulated the expected electrophysiological phenotype, as evidenced by reduced Na+ currents and action potential upstroke velocities compared with hiPSC-derived cardiomyocytes from 2 unrelated control individuals. While we were able to confirm the readthrough efficacy of the 2 drugs in Human Embryonic Kidney 293 cells, we did not observe rescue of the electrophysiological phenotype in hiPSC-derived cardiomyocytes from the patients.Conclusions—We conclude that these drugs are unlikely to present an effective treatment for patients carrying the loss-of-function SCN5A gene mutations examined in this study. [ABSTRACT FROM AUTHOR]

Background: Long-QT syndrome (LQTS) is an inherited arrhythmia characterized by prolonged ventricular repolarization and malignant tachyarrhythmias. LQT1, LQT2, and LQT3 are caused by mutations in KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3), which account for approximately 90% of genotyped LQTS patients. Most cardiac events in LQT1 patients occur during exercise, whereas patients with LQT3 tend to have arrhythmic events during rest or asleep.Objective: The study aimed to identify a genetic mutation in a Japanese man who presented with sinus node dysfunction and prolonged QT interval on exercise and epinephrine stress tests, as well as to clarify the electrophysiological properties of mutant channels.Methods: LQTS-related genes were screened in this patient. Electrophysiological functional assays were conducted with a heterologous expression system.Results: We identified a heterozygous missense SCN5A mutation, V2016M, which changes the last amino acid of the cardiac sodium channel. Electrophysiological analyses revealed that the mutant channels exhibited a loss-of-function feature, decreased peak sodium current densities (wild type 175.2 ± 17.6 pA/pF; V2016M 97.2 ± 16.0 pA/pF; P < .01). In addition, the mutant channels showed gain-of-function features: increased late sodium currents by protein kinase A activation (wild type 0.07 ± 0.01%; V2016M 0.17 ± 0.03%; P < .05) and impaired inactivation of sodium channels by protein kinase A or C activation.Conclusion: We identified an SCN5A mutation in a patient with sinus node dysfunction and epinephrine-induced QT prolongation, which was an atypical phenotype for LQT3. The electrophysiological properties of the mutant channels might be associated with the overlapping clinical features of the patient. [ABSTRACT FROM AUTHOR]

Background: Mutations in SCN5A, which encodes the cardiac voltage-gated sodium channels, can be associated with multiple electrophysiological phenotypes. A novel SCN5A R1632C mutation, located in the domain IV-segment 4 voltage sensor, was identified in a young male patient who had a syncopal episode during exercise and presented with atrial tachycardia, sinus node dysfunction, and Brugada syndrome.Objective: We sought to elucidate the functional consequences of the R1632C mutation.Methods: The wild-type (WT) or R1632C SCN5A mutation was coexpressed with β1 subunit in tsA201 cells, and whole-cell sodium currents (INa) were recorded using patch-clamp methods.Results: INa density, measured at -20 mV from a holding potential of -120 mV, for R1632C was significantly lower than that for WT (R1632C: -433 ± 52 pA/pF, n = 14; WT: -672 ± 90 pA/pF, n = 15; P < .05); however, no significant changes were observed in the steady-state activation and fast inactivation rate. The steady-state inactivation curve for R1632C was remarkably shifted to hyperpolarizing potentials compared with that for WT (R1632C: V1/2 = -110.7 ± 0.8 mV, n = 16; WT: V1/2 = -85.9 ± 2.5 mV, n = 17; P < .01). The steady-state fast inactivation curve for R1632C was also shifted to the same degree. Recovery from fast inactivation after a 20-ms depolarizing pulse for R1632C was remarkably delayed compared with that for WT (R1632C: τ = 246.7 ± 14.3 ms, n = 8; WT: τ = 3.7 ± 0.3 ms, n = 8; P < .01). Repetitive depolarizing pulses at various cycle lengths greatly attenuated INa for R1632C than that for WT.Conclusion: R1632C showed a loss of function of INa by an enhanced fast-inactivated state stability because of a pronounced impairment of recovery from fast inactivation, which may explain the phenotypic manifestation observed in our patient. [ABSTRACT FROM AUTHOR]

Background The human cardiac action potential in atrial and ventricular cells is initiated by a fast-activating, fast-inactivating sodium current generated by the SCN5A/ Na v 1.5 channel in association with its β1/ SCN1B subunit. The role of Na v 1.5 in the etiology of many cardiac diseases strongly suggests that proper regulation of cell biology and function of the channel is critical for normal cardiac function. Hence, numerous recent studies have focused on the regulatory mechanisms of Na v 1.5 biosynthetic and degradation processes as well as its subcellular localization. Objective The purpose of this study was to investigate the role of microRNAs in the Scn5a /Na v 1.5 posttranscriptional regulation. Methods Quantitative polymerase chain reaction, immunohistochemical and electrophysiological measurements of distinct microRNA gain-of-function experiments in cardiomyocytes for the assessment of Scn5a expression. Results Functional studies of HL-1 cardiomyocytes and luciferase assays in fibroblasts demonstrate that Scn5a is directly (miR-98, miR-106, miR-200, and miR-219) and indirectly (miR-125 and miR-153) regulated by multiple microRNAs displaying distinct time-dependent profiles. Cotransfection experiments demonstrated that miR-219 and miR-200 have independent opposite effects on Scn5a expression modulation. Of all the microRNAs studied, only miR-219 increases Scn5a expression levels, leading to altered contraction rhythm of HL-1 cardiomyocytes. Electrophysiological analyses in HL-1 cells revealed that miR-219 increases the sodium current. In vivo administration of miR-219 does not alter normal cardiac rhythm, but abolishes some of the effects of flecainide intoxication in mice, particularly QRS prolongation. Conclusion This study demonstrates the involvement of multiple microRNAs in the regulation of Scn5a . Particularly, miR-219 increases Scn5a /Na v 1.5 transcript and protein expression. Our data suggest that microRNAs, such as miR-219, constitute a promising therapeutical tool to treat sodium cardiac arrhythmias. [ABSTRACT FROM AUTHOR]

Background In enhanced atrioventricular (A-V) nodal conduction (EAVNC) syndrome, patients have short A-V conduction times. Multiple mechanisms have been proposed to explain EAVNC; however, the electrophysiological or molecular substrate responsible for it remains unclear. Objective The purpose of this study was to test the hypothesis that overexpression of SCN5A in the mouse heart may provide an animal model mimicking EAVNC. Methods Electrocardiogram, atrial, His bundle, and ventricular electrograms were recorded from wild-type (WT) and transgenic (TG) mice overexpressing human SCN5A . The sodium current and Na V 1.5 expression were measured using patch-clamp and immunohistochemistry techniques. Results The P-R interval in TG mice (13.6 ± 1.2 ms) was much shorter than that in WT mice (40.2 ± 0.59 ms). In TG isolated hearts, the A-V conduction time (14.4 ± 0.81 ms) during right atrial pacing was also shorter than that in WT hearts (39.5 ± 0.62 ms). Records of His bundle electrograms revealed that atrial-to-His and His-to-ventricular intervals were shorter in TG than in WT hearts. In addition, TG hearts had a shorter Wenckebach cycle length and A-V effective refractory period. The sodium current was 2-fold greater in TG ventricular myocytes than in WT ventricular myocytes. Flecainide prolonged the A-V conduction time in TG hearts to a value close to that in WT hearts. Nifedipine prolonged the atrial-to-His interval in WT hearts but not in TG hearts. Immunohistochemistry studies revealed increased Na V 1.5 labeling in TG atrial and ventricular tissues, and Na V 1.5 expression in A-V junction and A-V ring regions in TG hearts. Conclusion Enhanced A-V conduction in mice overexpressing SCN5A in the heart mimics the human syndrome of EAVNC. Thus, variants in sodium channel expression in the A-V nodal region may be an electrophysiological substrate responsible for EAVNC. [ABSTRACT FROM AUTHOR]

The article presents a study that investigates and identifies the functional and genetic determinants of polymorphic exercise-induced ventricular arrhythmia of numerous multigenerational family in Finland. Researchers carried out cardiological examination and cardiac ultrasonography of the 31 family members of four generation Finnish family from 2002 to 2003. They found that mutation of gain-of-function of sodium channel protein type 5 subunit alpha gene (SCN5A) is the cause of their ailments.

Background: Long QT syndrome (LQTS) is associated with sudden cardiac death and the prolongation of the QT interval on the electrocardiogram. A comprehensive screening of all genes previously associated with this disease leaves 30% of the patients without a genetic diagnosis. Pathogenic mutations in the sodium channel β subunits have been associated with cardiac channelopathies, including SCN4B mutations in LQTS. Objective: To evaluate the role of mutations in the sodium channel β subunits in LQTS. Methods: We screened for mutations in the genes encoding the 5 sodium β subunits (SCN1B isoforms a and b, SCN2B, SCN3B, and SCN4B) from 30 nonrelated patients who were clinically diagnosed with LQTS without mutations in common LQTS-related genes. We used the patch-clamp technique to study the properties of sodium currents and the action potential duration in human embryonic kidney and HL-1 cells, respectively, in the presence of β1b subunits. Results: The genetic screening revealed a novel mutation in the SCN1Bb gene (β1bP213T) in an 8-year-old boy. Our electrophysiological analysis revealed that β1bP213T increases late sodium current. In addition, β1bP213T subtly altered Nav1.5 function by shifting the window current, accelerating recovery from inactivation, and decreasing the slow inactivation rate. Moreover, experiments using HL-1 cells revealed that the action potential duration significantly increases when the mutant β1b was overexpressed compared with β1bWT. Conclusion: These data revealed SCN1Bb as a susceptibility gene responsible for LQTS, highlighting the importance of continuing the search for new genes and mechanisms to decrease the percentage of patients with LQTS remaining without genetic diagnosis. [Copyright &y& Elsevier]

Background: The debate on the diagnostic value of high intercostal spaces (ICSs) and of the number of diagnostic leads in Brugada syndrome (BrS) has been settled by a recent expert consensus statement. Objective: To test the validity, and the underlying anatomy, of the new electrocardiographic (ECG) diagnostic criteria using echocardiographic, molecular, and clinical evidence in 1 clinical study population with BrS. Methods: We analyzed 114 patients with BrS and with a spontaneous or drug-induced type 1 ECG pattern recorded in 1 or more right precordial leads in fourth, third, and second ICSs. The right ventricular outflow tract (RVOT) was localized by using echocardiography. All probands were screened on the SCN5A gene. Results: The percentage of mutation carriers (MCs) and the event rate were similar regardless of the diagnostic ICS (fourth vs high ICSs: MCs 23% vs 19%; event rate 22% vs 28%) and the number of diagnostic leads (1 vs ≥2: MCs 20% vs 22%; event rate 22% vs 27%). The concordance between RVOT anatomical location and the diagnostic ICSs was 86%. The percentage of the diagnostic ECG pattern recorded was significantly increased by the exploration of the ICSs showing RVOT by echocardiography (echocardiography-guided approach vs conventional approach 100% vs 43%; P < .001). Conclusion: The high ICSs are not inferior to the standard fourth ICS for the ECG diagnosis of BrS, and the interindividual variability depends on the anatomical location of the RVOT as assessed by using echocardiography. This approach significantly increases diagnostic sensitivity without decreasing specificity and fully supports the recently published new diagnostic criteria. [Copyright &y& Elsevier]

Background: Mutations in the SCN5A gene, encoding the α subunit of the cardiac Na+ channel, Nav1.5, can result in several life-threatening arrhythmias. Objective: To characterize a distal truncating SCN5A mutation, R1860Gfs*12, identified in a family with different phenotypes including sick sinus syndrome, atrial fibrillation (AF), atrial flutter, and atrioventricular block. Methods: Patch-clamp and biochemical analyses were performed in human embryonic kidney 293 cells transfected with wild-type (WT) and/or mutant channels. Results: The mutant channel expressed alone caused a 70% reduction in inward sodium current (INa) density compared to WT currents, which was consistent with its partial proteasomal degradation. It also led to a negative shift of steady-state inactivation and to a persistent current. When mimicking the heterozygous state of the patients by coexpressing WT and R1860Gfs*12 channels, the biophysical properties of INa were still altered and the mutant channel α subunits still interacted with the WT channels. Since the proband developed paroxysmal AF at a young age, we screened 17 polymorphisms associated with AF risk in this family and showed that the proband carries at-risk polymorphisms upstream of PITX2, a gene widely associated with AF development. In addition, when mimicking the difference in resting membrane potentials between cardiac atria and ventricles in human embryonic kidney 293 cells or when using computer model simulations, R1860Gfs*12 induced a more drastic decrease in INa at the atrial potential. Conclusion: We have identified a distal truncated SCN5A mutant associated with gain- and loss-of-function effects, leading to sick sinus syndrome and atrial arrhythmias. A constitutively higher susceptibility to arrhythmias of atrial tissues and genetic variability could explain the complex phenotype observed in this family. [Copyright &y& Elsevier]

Background: A high prevalence of atrial fibrillation/atrial flutter (AF/AFl) has been reported in small series of Brugada patients, with discordant data. Objective: The purpose of this study was to analyze, in a large population of Brugada patients, the prevalence of AF/AFl, its correlation with prognosis, and the efficacy of hydroquinidine (HQ) treatment. Methods: Among 560 patients with Brugada type 1 ECG (BrECG), 48 (9%) had AF/AFl. Three groups were considered: 23 patients with BrECG pattern recognized before AF/AFl (group 1); 25 patients first diagnosed with AF/AFl in whom Class IC antiarrhythmic drugs administered for cardioversion/prophylaxis unmasked BrECG (group 2); and 512 patients without AF/AFl (group 3). Recurrence of AF/AFl and occurrence of ventricular arrhythmias were evaluated at follow-up. Results: Mean age was 47 ± 15 years, 59 ± 11 years, and 44 ± 14 years in groups 1, 2, and 3, respectively. Seven subjects (32%) in group 1 had syncope/aborted sudden death, 1 (4%) in group 2, and 122 (24%) in group 3. Ventricular arrhythmia occurred in three patients in group 1, none in group 2, and 10 in group 3 at median follow-up of 51, 68, and 41 months, respectively. Nine patients in group 1 and nine in group 2 received HQ for AF/AFl prophylaxis; on therapy, none had AF/AFl recurrence. Conclusion: Prevalence of AF/AFl in Brugada patients is higher than in the general population of the same age. Patients in group 1 are younger than those in group 2 and have a worse prognosis compared to both groups 2 and 3. HQ therapy has proved useful and safe in patients with AF/AFl and BrECG. [Copyright &y& Elsevier]

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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. [ABSTRACT FROM AUTHOR]

Brugada syndrome (BrS) is associated with the familial sudden death syndrome, and more than 10 genes have been reported as causative for or modifiers of BrS. All gene mutations are related to functional changes of inward sodium or calcium currents or outward potassium currents. SCN5A was the first gene known to be associated with BrS; it encodes the α‐subunit of the cardiac sodium channel. Approximately 20% of BrS patients in genotyped cases were found to carry SCN5A mutations. The frequency for other BrS‐associated gene mutations is so low that genotype–phenotype correlations for these genes have not been studied to the same extent as SCN5A‐related BrS. In some families with SCN5A mutations, the penetrance of the mutations is low, and pathophysiological changes in the right ventricular outflow tract were reported in patients with SCN5A mutations. Furthermore, the phenotypes of SCN5A‐related BrS can overlap with other phenotypes, including long QT and sick sinus syndrome, thereby suggesting that SCN5A mutations might be modifiers for BrS, but they do not direct cause BrS. Here, we summarize the genetic background of BrS, with a particular focus on recent progress in this field. [ABSTRACT FROM AUTHOR]

Long QT syndrome (LQTs) is an uncommon genetic disease causing sudden cardiac death with Torsade de Pointes (TdP). The first line drug treatment has been known to be Β-blocker. We encountered a 15-year-old female student with LQTs who had prolonged QTc and multiple episodes of syncope or agonal respiration during sleep. Although her T wave morphology in surface electrocardiography resembled LQTs type 1, her clinical presentation was unusual. During the epinephrine test, TdP was aggravated during Β-blocker medication, but alleviated by sodium channel blocker (mexiletine). Therefore, she underwent implantable cardioverter defibrillator implantation. [ABSTRACT FROM AUTHOR]

The article describes the character and mechanism of a novel loss of function mutation in SCN5A encoding the cardiac sodium channel Nav1.5 channel mutation associated with Brugada Syndrome. Findings showed that Nav1.5-S1218I and R811H are novel loss of function mutation in the SCN5A gene causing Brugada Sydrome. These findings have significant implications in the risk assessment of unaffected at-risk family members.

The article presents a study which explained the high prevalence of long QT syndrome-associated SCN5A variants in patients with early-onset lone atrial fibrillation (AF). The researchers studied 192 patients with onset of AF ranging from 16 to 39 years without any related disease in eight hospitals in Copenhagen, Denmark. Results identified 8 mutations and 2 rare variants in SCN5A and showed that both gain- and loss-of-function alterations in the electrophysiological properties may lead to AF.

Background: Congenital long-QT syndrome (LQTS) may present during fetal development and can be life-threatening. The molecular mechanism for the unusual early onset of LQTS during fetal development is unknown. Objective: We sought to elucidate the molecular basis for severe fetal LQTS presenting at 19 weeks'' gestation, the earliest known presentation of this disease. Methods: Fetal magnetocardiography was used to demonstrated torsades de pointes and a prolonged rate-corrected QT interval. In vitro electrophysiological studies were performed to determine functional consequences of a novel SCN5A mutation found in the fetus. Results: The fetus presented with episodes of ventricular ectopy progressing to incessant ventricular tachycardia and hydrops fetalis. Genetic analysis disclosed a novel, de novo heterozygous mutation (L409P) and a homozygous common variant (R558 in SCN5A). In vitro electrophysiological studies demonstrated that the mutation in combination with R558 caused significant depolarized shifts in the voltage dependence of inactivation and activation, faster recovery from inactivation, and a 7-fold higher level of persistent current. When the mutation was engineered in a fetal-expressed SCN5A splice isoform, channel dysfunction was markedly potentiated. Also, R558 alone in the fetal splice isoform evoked a large persistent current, and hence both alleles were dysfunctional. Conclusion: We report the earliest confirmed diagnosis of symptomatic LQTS and present evidence that mutant cardiac sodium channel dysfunction is potentiated by a developmentally regulated alternative splicing event in SCN5A. Our findings provide a plausible mechanism for the unusual severity and early onset of cardiac arrhythmia in fetal LQTS. [Copyright &y& Elsevier]

Background: Considering that approximately 2% of Caucasian controls host rare, nonsynonymous variants in the SCN5A-encoded cardiac sodium channel, caution must be exercised when interpreting SCN5A genetic test results for long QT syndrome (LQTS). Objective: The purpose of this study was to determine if A572D-SCN5A is a pathogenic mutation, a possible functional modifier, or background “genetic noise.” Methods: The frequency of A572D was compared between 3,741 LQTS referral cases (mostly Caucasian) and 1,437 Caucasian controls. A572D-SCN5A was engineered into SCN5A using the most commonly spliced transcript (Q1077del, hH1c clone) in the setting of either H558 or R558 for heterologous expression/patch clamp studies in HEK293 cells. Results: A572D-SCN5A was detected in 17 (0.45%) of 3,741 cases compared with 7 (0.49%) of 1,437 controls (P = .82). Among the 17 A572D-positive LQTS referrals, 10 (59%) hosted definite LQTS-causing mutations elsewhere (5 KCNQ1, 3 KCNH2, 2 SCN5A). Functional studies showed no gating kinetic or current density differences compared with wild-type channels in the context of H558 but showed moderate dysfunction when expressed in H558R-SCN5A, with which it is invariably associated. Conclusion: There is sufficient evidence to conclude that A572D-SCN5A is not an independent, LQT3-causative mutation. A572D is present in approximately 0.5% of both cases and controls and has a wild-type phenotype when expressed in HEK293 cells. However, in the context of H558R-SCN5A, persistent late sodium current emerges, indicating that A572D/H558R could be a proarrhythmic factor akin to S1103Y. These findings underscore the scrutiny necessary to distinguish truly pathogenic mutations from functional polymorphisms and otherwise innocuous, rare genetic variants in SCN5A. These results also question how much cellular dysfunction for a mutation is required in vitro to support pathogenicity. [Copyright &y& Elsevier]