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Thirty years ago, a distinctly new clinical-electrocardiographic syndrome was described, today known as Brugada Syndrome (BrS). Typical treatment for this type of syndrome is electrocardiography with ST-segment elevation in the direct precordial derivations. The clinical presentation of the disease is highly variable: the patients can remain completely asymptomatic, but they can also develop episodes of syncope, atrial fibrillation (AF), sinus node dysfunction (SNF), conduction disorders, asystole, and ventricular fibrillation (VF). This disease is caused by mutations in the genes responsible for the potential action of cardiac cells. The most commonly involved gene is SCN5A, which controls the structure and function of the heart's sodium channel. The description of this new syndrome has shown highly positive implications in all fields of medicine.

Trinta anos atrás, uma nova síndrome clínico-eletrocardiográfica distinta foi descrita, agora conhecida como síndrome de Brugada (SBr). Típico para essa síndrome é o eletrocardiograma com supradesnivelamento do segmento ST nas derivações precordiais direitas. A apresentação clínica da doença é altamente variável: os pacientes podem permanecer completamente assintomáticos, mas também podem desenvolver episódios de síncope, fibrilação atrial (FA), síndrome do nódulo sinusal (SNS), distúrbios de condução, assistolia e fibrilação ventricular (FV). A doença é causada por mutações nos genes responsáveis pelo potencial de ação das células do coração. O gene mais frequentemente envolvido é o SCN5A, que controla a estrutura e função do canal de sódio cardíaco. A descrição dessa nova síndrome teve implicações muito positivas em todos os campos da medicina.

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BACKGROUND: The Brugada syndrome (BrS) is a heart rhythm condition that is commonly associated with a strong predisposition for sudden cardiac death. Malignant ventricular arrhythmias could occur secondary to the dysfunction of the cardiac sodium voltage-gated Na(v)1.5 channel (SCN5A). OBJECTIVE: This study aimed to perform a multiparametric computational analysis of the physicochemical properties of SCN5A mutants associated with BrS using a set of bioinformatics tools. METHODS: In-house algorithms were calibrated to calculate, in a double-blind test, the Polarity Index Method (PIM) profile and protein intrinsic disorder predisposition (PIDP) profile of each sequence, and computer programs specialized in the genomic analysis were used. RESULTS: Specific regularities in the charge/polarity and PIDP profile of the SCN5A mutant proteins enabled the re-creation of the taxonomy, allowing us to propose a bioinformatics method that takes advantage of the PIM profile to identify this group of proteins from their sequence. CONCLUSION: Bioinformatics programs could reproduce characteristic PIM and PIDP profiles of the BrS-related SCN5A mutant proteins. This information can contribute to a better understanding of these altered proteins.

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Cardiac channelopathies are a heterogeneous group of inherited cardiac diseases that are associated with mutations in the genes that encode the expression of cardiac ion channels. In view of this, it can be mentioned that the main hereditary arrhythmias in children and adolescents, caused by dysfunction of the ion channels, are Brugada Syndrome (BrS) and Long QT Syndrome (LQTS). However, few studies address the physiological effects of these conditions on children and adolescents. Thus, the aim of this study is to describe the mutation phenotype related to voltage-gated sodium channels in children and adolescents. A search was performed in the literature of PubMed, Scielo, and Google scholar. The search was limited to articles written in the last 5 years, so articles published between 2014 and 2019 were included. Among 2196 studies identified through a systematic literature review, 30 studies related to the theme were identified for a complete review and after applying exclusion criteria, 4 articles were included in the results of this study. As the most frequently observed channelopathy, BrS was also more identified in children and adolescents, characterized by episodes of syncope or sudden cardiac death. LQTS shows clinical manifestations with a mild phenotype and good prognosis, although it is necessary to monitor and correct serum electrolyte disturbances to prevent ventricular arrhythmias and, consequently, sudden death in patients with the pathology. The aim of this study is to find the general phenotypes related to genetic mutations of voltage-gated sodium channels, in a population aged from 7- to 14-year-old.

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AIMS: SCN5A gene encodes the α-subunit of Nav1.5, mainly found in the human heart. SCN5A variants are the most common genetic alterations associated with Brugada syndrome (BrS). In rare cases, compound heterozygosity is observed; however, its functional consequences are poorly understood. We aimed to analyze the functional impact of de novo Nav1.5 mutations in compound heterozygosity in distinct alleles (G400R and T1461S positions) previously found in a patient with BrS. Moreover, we evaluated the potential benefits of quinidine to improve the phenotype of mutant Na+ channels in vitro. MATERIALS AND METHODS: The functional properties of human wild-type and Nav1.5 variants were evaluated using whole-cell patch-clamp and immunofluorescence techniques in transiently expressed human embryonic kidney (HEK293) cells. KEY FINDINGS: Both variants occur in the highly conservative positions of SCN5A. Although all variants were expressed in the cell membrane, a significant reduction in the Na+ current density (except for G400R alone, which was undetected) was observed along with abnormal biophysical properties, once the variants were expressed in homozygosis and heterozygosis. Interestingly, the incubation of transfected cells with quinidine partially rescued the biophysical properties of the mutant Na+ channel. SIGNIFICANCE: De novo compound heterozygosis mutations in SNC5A disrupt the Na+ macroscopic current. Quinidine could partially reverse the in vitro loss-of-function phenotype of Na+ current. Thus, our data provide, for the first time, a detailed biophysical characterization of dysfunctional Na+ channels linked to compound heterozygosity in BrS as well as the benefits of the pharmacological treatment using quinidine on the biophysical properties of Nav1.5.

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Sodium voltage-gated channel α subunit 5 (SCN5A)-mutations may cause an array of arrhythmogenic syndromes most frequently as an autosomal dominant trait, with incomplete penetrance, variable expressivity and male predominance. In the present study, we retrospectively describe a group of Mexican patients with SCN5A-disease causing variants in whom the onset of symptoms occurred in the pediatric age range. The study included 17 patients with clinical diagnosis of primary electrical disease, at least one SCN5A pathogenic or likely pathogenic mutation and age of onset <18 years, and all available first- and second-degree relatives. Fifteen patients (88.2%) were male, and sixteen independent variants were found (twelve missense, three truncating and one complex inframe deletion/insertion). The frequency of compound heterozygosity was remarkably high (3/17, 17.6%), with early childhood onset and severe disease. Overall, 70.6% of pediatric patients presented with overlap syndrome, 11.8% with isolated sick sinus syndrome, 11.8% with isolated Brugada syndrome (BrS) and 5.9% with isolated type 3 long QT syndrome (LQTS). A total of 24/45 SCN5A mutation carriers were affected (overall penetrance 53.3%), and penetrance was higher in males (63.3%, 19 affected/30 mutation carriers) than in females (33.3%, 5 affected/15 carriers). In conclusion, pediatric patients with SCNA-disease causing variants presented mainly as overlap syndrome, with predominant loss-of-function phenotypes of sick sinus syndrome (SSS), progressive cardiac conduction disease (PCCD) and ventricular arrhythmias.

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BACKGROUND: Brugada syndrome (BrS) has diagnostic challenges and controversial risk assessment. We aimed to investigate invasive and noninvasive parameters in symptomatic and asymptomatic patients from a Brazilian cohort of type-1 BrS. METHODS: Patients with spontaneous and drug-induced type-1 BrS were classified into two groups, asymptomatic (n = 116, 84.1%) and symptomatic (n = 22, 15.9%; 13 with arrhythmogenic syncope, 9 with aborted sudden cardiac death). Genetic testing, EPS parameters, and electrocardiogram (ECG) parameters were analyzed. RESULTS: A total of 138 consecutive patients were eligible, 101 men (73.2%), mean 41.4 years, mostly probands (79%). Spontaneous pattern, observed in 77.5% of the patients, was associated with symptoms only if expressed in V1 and V2 standard position (not high precordial leads; p = .014). All symptomatic patients were probands. The presence of right ventricular outflow tract conduction delay (RVOTcd) signs, positive EPS, and SCN5A status was similar between symptomatic and asymptomatic subjects. During the mean 75-month follow-up, eight patients had appropriate therapies. All had spontaneous type-1 ECG pattern and 2/8 (25%) were asymptomatic, with positive EPS. The overall LAE incidence of 1.1% per year dropped to 0.27% in asymptomatic patients. RVOTcd occurred more frequently in SCN5A carriers (QRS-f 33.3% vs. 7.7%; p = .005, AVR sign 58.3% vs. 13.6%; p < .001; deep S in lead I 75% vs. 48.5%, p = .025%), as well as longer HV interval (66 vs. 49 ms; p < .001). CONCLUSIONS: Spontaneous type-1 Brugada pattern in standard leads and proband status were more frequent in symptomatic subjects. RVOTcd, more common in SCN5A carriers, did not predict symptoms in BrS patients. EPS exhibited limited prognostic value for this low-risk population.

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Inheritable and de novo variants in the cardiac voltage-gated sodium channel, Nav1.5, are responsible for both long-QT syndrome type 3 (LQT3) and Brugada syndrome type 1 (BrS1). Interestingly, a subset of Nav1.5 variants can cause both LQT3 and BrS1. Many of these variants are found in channel structures that form the channel fast inactivation machinery, altering the rate, voltage dependence, and completeness of the fast inactivation process. We used a series of mutants at position 1784 to show that the most common inheritable Nav1.5 variant, E1784K, alters fast inactivation through two separable mechanisms: (1) a charge-dependent interaction that increases the noninactivating current characteristic of E1784K; and (2) a hyperpolarized voltage dependence and accelerated rate of fast inactivation that decreases the peak sodium current. Using a homology model built on the NavPaS structure, we find that the charge-dependent interaction is between E1784 and K1493 in the DIII-DIV linker of the channel, five residues downstream of the putative inactivation gate. This interaction can be disrupted by a positive charge at position 1784 and rescued with the K1493E/E1784K double mutant that abolishes the noninactivating current. However, the double mutant does not restore either the voltage dependence or rates of fast inactivation. Conversely, a mutant at the bottom of DIVS4, K1641D, causes a hyperpolarizing shift in the voltage dependence of fast inactivation and accelerates the rate of fast inactivation without causing an increase in noninactivating current. These findings provide novel mechanistic insights into how the most common inheritable arrhythmogenic mixed syndrome variant, E1784K, simultaneously decreases transient sodium currents and increases noninactivating currents, leading to both BrS1 and LQT3.

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INTRODUÇÃO: A Síndrome de Brugada é uma cardiopatia de origem genética (autossómica dominante) que predispõe a arritmias ventriculares que podem ser fatais. É provocada geralmente por uma mutação do gene SCN5A. Tem especial prevalência em indivíduos adultos e do sexo masculino. Também ocorre com mais frequência em indivíduos de origem asiática. Pode provocar morte súbita (através de taquicardia ventricular polimórfica), principalmente em indivíduos em repouso ou durante o sono. Em raras descrições na literatura, há relatos de mutação do gene CACNA1C como causador da síndrome. Descrição: Indivíduo do sexo masculino, nascido em 1954, hipertenso, dislipidêmico, tabagista, histórico familiar rico em morte súbita (mãe, irmãos e tios maternos, todos durante o sono). Encaminhado ao serviço em 2009 para estratificação de risco de morte súbita. Apresentava dor torácica tipo angina. Coronariografia apenas demonstrou lesão de 20% em artéria circunflexa. Eletrocardiograma com padrão típico de Síndrome de Brugada (tipo 1). Submetido a Estudo Eletrofisiológico no mesmo ano, sendo induzida Fibrilação Ventricular com um único extraestímulo em ápice de ventrículo direito. Indicado então implante de Cardioversor Desfibrilador Implantável (CDI). Medicado para doença coronariana, manteve-se assintomático do ponto de vista cardiovascular e permanece desta forma até hoje. Em 2017 obtivemos sua análise genética, evidenciando mutação no gene CACNA1C (que é mais descrita como causadora da síndrome de QT Longo tipo 8 ou Síndrome de Timothy). Sua última avaliação ambulatorial foi em janeiro de 2019, onde se encontrava estável clinicamente, sem registros de terapias do CDI, mantendo eletrocardiograma típico de Síndrome de Brugada. CONCLUSÕES: Descrevemos um caso raro de Síndrome de Brugada causada pela mutação no gene CACNA1C. (AU)

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Compound heterozygosity has been described in inherited arrhythmias, and usually associated with a more severe phenotype. Reports of this occurrence in Brugada syndrome patients are still rare. We report a study of genotype-phenotype correlation after the identification of new variants by genetic testing. We describe the case of an affected child with a combination of two different likely pathogenic SCN5A variants, presenting sinus node dysfunction, flutter and atrial fibrillation, prolonged HV interval, spontaneous type 1 Brugada pattern in the prepubescent age and familiar history of sudden death.

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Abstract Compound heterozygosity has been described in inherited arrhythmias, and usually associated with a more severe phenotype. Reports of this occurrence in Brugada syndrome patients are still rare. We report a study of genotype-phenotype correlation after the identification of new variants by genetic testing. We describe the case of an affected child with a combination of two different likely pathogenic SCN5A variants, presenting sinus node dysfunction, flutter and atrial fibrillation, prolonged HV interval, spontaneous type 1 Brugada pattern in the prepubescent age and familiar history of sudden death.

Resumo A heterozigose composta é descrita em arritmias hereditárias, geralmente associada a um fenótipo mais grave. Relatos dessa ocorrência em pacientes com síndrome de Brugada ainda são raros. Neste estudo, descrevemos o caso de uma criança com a combinação de duas novas variantes distintas no gene SCN5A, apresentando disfunção do nó sinusal, flutter e fibrilação atrial, intervalo HV prolongado, padrão tipo 1 espontâneo de Brugada na idade pré-puberal e história familiar de morte súbita.

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J-wave syndromes are disorders of ventricular repolarization characterized by prominent J waves on the ECG and have the potential to predispose affected individuals to lethal ventricular arrhythmias. These disorders share a common cellular mechanism with prominent Ito in ventricular epicardium. This current causes transmural dispersion of repolarization and the generation of phase 2 reentry, leading to short-coupled extrasystoles and VF. Several autonomic, chemical, and hormonal factors modulate Ito and are therefore vital in attenuating or increasing the arrhythmic potential of these syndromes. Future research should focus on evaluating the arrhythmogenic potential of patients with pathogenic genotypes and/or J waves and no history of VF.

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El síndrome de Brugada es una enfermedad hereditaria caracterizada por una anormalidad electrocardiográfica y un aumento del riesgo de muerte súbita cardiaca. El síndrome de Brugada puede ser causado por la presencia de mutaciones en el gen SCN5A en aproximadamente el 20% de los casos familiares. El gen SCN5A codifica la subunidad a del canal iónico de sodio en las células cardiacas. Estudios realizados durante la última década en genética molecular han permitido identificar 11 nuevos genes con susceptibilidad para síndrome de Brugada además del SCN5A, lo que lleva a pensar que es una enfermedad con heterogeneidad genética y compleja de identificar en la clínica y a nivel molecular en el laboratorio. Una manera de heredar el síndrome de Brugada es por medio de un patrón de transmisión hereditaria autosómica dominante. Esta breve revisión se enfoca a describir el proceso de diagnóstico de marcadores genéticos en un caso reportado de síndrome de Brugada guiando al lector a través del proceso de identificación de las variantes genéticas responsables del síndrome y a determinar la consecuencia funcional de las mutaciones del canal de sodio sobre la alteración electrocardiográfica.

Brugada syndrome is a genetic disease that is characterized by abnormal electrocardiogram findings and an increased risk of sudden cardiac death. This syndrome is linked to mutations in the SCN5A gene in approximately 20% of Brugada syndrome probands. SCN5A encodes the a subunit of the cardiac sodium channel. Studies conducted over the past decade have identified 11 other Brugada syndrome susceptibility genes besides to SCN5A, pointing to genetic heterogeneity of the syndrome. Transmission of the disease shows an autosomal dominant inheritance pattern. This brief review focuses on a reported case of sodium channel-mediated Brugada syndrome, guiding the reader through the process of identification of the genetic variants responsible for the clinically-diagnosed syndrome, mutagenesis to clone SCN5A with and without the 2 variants identified and transfection of the 2 variants into TSA201 cells to determine the functional consequence of these genetic variants on sodium channel expression and function.

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Brugada syndrome is a genetic disease that is characterized by abnormal electrocardiogram findings and an increased risk of sudden cardiac death. This syndrome is linked to mutations in the SCN5A gene in approximately 20% of Brugada syndrome probands. SCN5A encodes the α subunit of the cardiac sodium channel. Studies conducted over the past decade have identified 11 other Brugada syndrome susceptibility genes besides to SCN5A, pointing to genetic heterogeneity of the syndrome. Transmission of the disease shows an autosomal dominant inheritance pattern. This brief review focuses on a reported case of sodium channel-mediated Brugada syndrome, guiding the reader through the process of identification of the genetic variants responsible for the clinically-diagnosed syndrome, mutagenesis to clone SCN5A with and without the 2 variants identified and transfection of the 2 variants into TSA201 cells to determine the functional consequence of these genetic variants on sodium channel expression and function.

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A novel SCN5A mutation was found in a child with congenital sick sinus disease, a Brugada-like electrocardiogram and recurrent aborted sudden death. The mutation (L1821fs/10) is a 4 base pair deletion (TCTG) at position 5464-5467 in exon 28 of the gene. The novel mutation is predicted to produce a frameshift leading to a premature stop codon after ten missense amino acids upstream that did not allow the generation of the complete protein, and probably producing an incomplete and therefore non functional protein. The resulting alteration in sodium current could explain the clinical phenotype observed in this patient.

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