Brugada syndrome: current concepts and genetic background / Síndrome de Brugada: conceitos atuais e antecedentes genéticos

BACKGROUNG: Brugada syndrome (BrS) is a hereditary clinical-electrocardiographic arrhythmic entity with low worldwide prevalence. The syndrome is caused by changes in the structure and function of certain cardiac ion channels and reduced expression of Connexin 43 (Cx43) in the Right Ventricle (RV), predominantly in the Right Ventricular Outflow Tract (VSVD), causing electromechanical abnormalities. The diagnosis is based on the presence of spontaneous or medicated ST elevation, characterized by boost of the J point and the ST segment ≥2 mm, of superior convexity "hollow type" (subtype 1A) or descending rectilinear model (subtype 1B). BrS is associated with an increased risk of syncope, palpitations, chest pain, convulsions, difficulty in breathing (nocturnal agonal breathing) and/or Sudden Cardiac Death (SCD) secondary to PVT/VF, unexplained cardiac arrest or documented PVT/VF or Paroxysmal atrial fibrillation (AF) in the absence of apparent macroscopic or structural heart disease, electrolyte disturbance, use of certain medications or coronary heart disease and fever. In less than three decades since the discovery of Brugada syndrome, the concept of Mendelian heredity has come undone. The enormous variants and mutations found mean that we are still far from being able to concretely clarify a genotype-phenotype relationship. There is no doubt that the entity is oligogenetic, associated with environmental factors, and that there are variants of uncertain significance, especially the rare variants of the SCN5A mutation, with European or Japanese ancestors, as well as a spontaneous type 1 or induced pattern, thanks to gnomAD (coalition) researchers who seek to aggregate and harmonize exome and genome sequencing data from a variety of large-scale sequencing projects and make summary data available to the scientific community at large). Thus, we believe that this in-depth analytical study of the countless mutations attributed to BrS may constitute a real cornerstone that will help to better understand this intriguing syndrome.

INTRODUÇÃO: A Síndrome de Brugada (SBr) é uma entidade arrítmica clínico-eletrocardiográfica hereditária com baixa prevalência mundial. A síndrome é causada por alterações na estrutura e função de certos canais iônicos cardíacos e redução da expressão da Connexina 43 (Cx43) no Ventrículo Direito (VD), predominantemente no Trato de Saída do Ventricular Direito (VSVD), causando anormalidades eletromecânicas. O diagnóstico é baseado na presença de supradesnivelamento de ST espontâneo ou medicamentoso caracterizado por supradesnivelamento do ponto J e do segmento ST ≥2 mm, de convexidade superior "tipo covado" (subtipo 1A) ou modelo retilíneo descendente (subtipo 1B). A SBr está associado a um risco aumentado de síncope, palpitações, dor precordial, convulsões, dificuldade em respirar (respiração agonal noturna) e/ou Morte Cardíaca Súbita (MSC) secundária a PVT/VF, parada cardíaca inexplicada ou PVT/VF documentado ou Fibrilação atrial paroxística (FA) na ausência de doença cardíaca macroscópica ou estrutural aparente, distúrbio eletrolítico, uso de certos medicamentos ou coração coronário e febre. Em menos de três décadas desde a descoberta da síndrome de Brugada, o conceito de hereditariedade mendeliana se desfez. As enormes variantes e mutações encontradas significam que ainda estamos longe de sermos capazes de esclarecer concretamente uma relação genótipo-fenótipo. Não há dúvida de que a entidade é oligogenética associada a fatores ambientais, e que há variantes de significado incerto, principalmente as raras variantes da mutação SCN5A, com ancestrais europeus ou japoneses, bem como padrão espontâneo tipo 1 ou induzido, graças ao gnomAD (coalizão de pesquisadores que buscam agregar e harmonizar dados de sequenciamento de exoma e genoma de uma variedade de projetos de sequenciamento em grande escala e disponibilizar dados resumidos para a comunidade científica em geral). As enormes variantes e mutações encontradas significam que ainda estamos longe de sermos capazes de esclarecer concretamente uma relação genótipo-fenótipo. Assim, acreditamos que este estudo analítico em profundidade das inúmeras mutações atribuídas à BrS pode constituir uma verdadeira pedra angular que ajudará a compreender melhor esta síndrome intrigante.

MDSGene: Closing Data Gaps in Genotype-Phenotype Correlations of Monogenic Parkinson's Disease.

Given the rapidly increasing number of reported movement disorder genes and clinical-genetic desciptions of mutation carriers, the International Parkinson's Disease and Movement Disorder Society Gene Database (MDSGene) initiative has been launched in 2016 and grown to become a large international project (http://www.mdsgene.org). MDSGene currently contains >1150 variants described in ∼5700 movement disorder patients in almost 1000 publications including monogenic forms of PD clinically resembling idiopathic (PARK-PINK1, PARK-Parkin, PARK-DJ-1, PARK-SNCA, PARK-VPS35, PARK-LRRK2), as well as of atypical PD (PARK-SYNJ1, PARK-DNAJC6, PARK-ATP13A2, PARK-FBXO7). Inclusion of genes is based on standardized published criteria for determining causation. Clinical and genetic information can be filtered according to demographic, clinical or genetic criteria and summary statistics are automatically generated by the MDSGene online tool. Despite MDSGene's novel approach and features, it also faces several challenges: i) The criteria for designating genes as causative will require further refinement, as well as time and support to replace the faulty list of 'PARKs'. ii) MDSGene has uncovered extensive clinical data gaps. iii) The quickly growing body of clinical and genetic data require a large number of experts worldwide posing logistic challenges. iv) MDSGene currently captures published data only, i.e., a small fraction of the available information on monogenic PD available. Thus, an important future aim is to extend MDSGene to unpublished cases in order to provide the broad data base to the PD community that is necessary to comprehensively inform genetic counseling, therapeutic approaches and clinical trials, as well as basic and clinical research studies in monogenic PD.

Lack of meaningful genotype-phenotype association in SCN1A-related infantile-onset epileptic encephalopathies

Background & Objective: SCN1A gene which encodes for sodium channel alpha 1 subunit has been found to be the most common mutated gene in patients with epilepsy. This study aims to characterize the SCN1A mutations as well as to describe genotype and phenotype association in children with SCN1Arelated infantile-onset epileptic encephalopathies in Malaysia. Methods: Children with infantile-onset epileptic encephalopathy mostly suspected to have Dravet syndrome who had mutational analysis for SCN1A gene from hospitals all over Malaysia were included in the study. Their epilepsy syndrome diagnosis was classified into severe myoclonic epilepsy in infancy and its variants. Polymerase chain reaction and bidirectional sequencing were used to identify SCN1A mutations. Results: A total of 38 children with heterozygous mutations were analysed, 22 (57.9%) of which were novel mutations. Truncated mutations were the most common mutation type (19, 50%). Other mutation types were missense mutations (14, 36.8%), splice site mutations (4, 10.5%) and in-frame deletion (1, 2.6%). The mean age of seizure onset was 4.7 months. Seizure following vaccination was observed in 26.3% of the children. All of them had drug resistant epilepsy. There was no significant association between the type of mutation with the syndromic diagnosis, age of seizure onset, tendency of the seizures to cluster or having status epilepticus, mean age when developmental delay was observed and response to various antiepileptic drugs. Conclusion: This study expands the spectrum of SCN1A mutations and proves the importance of SCN1A gene testing in diagnosing infantile-onset epileptic encephalopathies patients. Although, our study does not support any clinically meaningful genotype-phenotype association for SCN1A-related infantile-onset epileptic encephalopathies, the clinical characteristics of our cohort are similar to those that have been described in previous studies.