Brugada syndrome: current concepts and genetic background

Authors

  • Andrés Ricardo Pérez-Riera Laboratório de Delineamento de Estudos e Escrita Científica. Centro Universitário FMABC, Santo André, São Paulo, Brazil.
  • Joseane Elza Tonussi Mendes Laboratório de Delineamento de Estudos e Escrita Científica. Centro Universitário FMABC, Santo André, São Paulo, Brazil.
  • Fabiola Ferreira da Silva Laboratório de Delineamento de Estudos e Escrita Científica. Centro Universitário FMABC, Santo André, São Paulo, Brazil.
  • Frank Yanowitz Intermountain Medical Center, Intermountain Heart Institute, Salt Lake City, UT, United States; The University of Utah, Department of Internal Medicine, Salt Lake City, UT, United States
  • Luiz Carlos de Abreu Professor. Department of Integrated Health Education and Graduate Program in Collective Health. Federal University of Espírito Santo, ES, Brazil.
  • José Luiz Figueiredo Department of Surgery, Experimental Surgery Unit, Federal University of Pernambuco, Recife, Pernambuco, Brazil.
  • Rodrigo Daminello Raimundo Laboratório de Delineamento de Estudos e Escrita Científica. Centro Universitário FMABC, Santo André, São Paulo, Brazil.
  • Raimundo Barbosa-Barros Coronary Center of the Hospital de Messejana Dr. Carlos Alberto Studart Gomes, Fortaleza, Ceará, Brazil
  • Kjell Nikus Heart Center, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Finland.
  • Pedro Brugada Scientific Director, Cardiovascular Division, Free University of Brussels (UZ Brussel) VUB, Brussels, Belgium

DOI:

https://doi.org/10.36311/jhgd.v31.11074

Keywords:

Brugada Syndrome, arrhythmic, environmental, genotype, phenotyp

Abstract

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.

Downloads

Download data is not yet available.

References

Monasky MM, Micaglio E, Ciconte G, Pappone C. Brugada syndrome: oligogenic or mendelian disease? International Journal of Molecular Sciences. janeiro de 2020; 21(5): 1687.

Wang Q, Ohno S, Ding W-G, Fukuyama M, Miyamoto A, Itoh H, et al. Gain-of-function kcnh2 mutations in patients with brugada syndrome: novel kcnh2 mutations in brugada syndrome. J Cardiovasc Electrophysiol. maio de 2014; 25(5): 522–30.

Portero V, Le Scouarnec S, Es-Salah-Lamoureux Z, Burel S, Gourraud J, Bonnaud S, et al. Dysfunction of the voltage-gated k + channel β2 subunit in a familial case of brugada syndrome. JAHA [Internet]. 13 de junho de 2016 [citado 26 de fevereiro de 2021]; 5(6). Disponível em: https://www.ahajournals.org/doi/10.1161/JAHA.115.003122

Chen C-YJ, Lu T-P, Lin L-Y, Liu Y-B, Ho L-T, Huang H-C, et al. Impact of ancestral differences and reassessment of the classification of previously reported pathogenic variants in patients with brugada syndrome in the genomic era: a sads-tw brs registry. Front Genet. 4 de janeiro de 2019; 9:680.

Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proceedings of the National Academy of Sciences. 1o de dezembro de 1977; 74(12): 5463–7.

Jimmy Juang J-M, Liu Y-B, Julius Chen C-Y, Yu Q-Y, Chattopadhyay A, Lin L-Y, et al. Validation and disease risk assessment of previously reported genome-wide genetic variants associated with brugada syndrome: sads-tw brs registry. Circ: Genomic and Precision Medicine [Internet]. agosto de 2020 [citado 26 de fevereiro de 2021]; 13(4). Disponível em: https://www.ahajournals.org/doi/10.1161/CIRCGEN.119.002797

Chen CJ, Chuang EY. The puzzle of genetics in Brugada syndrome: a disease with a high risk of sudden cardiac death in young people. Ann Palliat Med. novembro de 2020; 9(6): 4394–7.

Chen C-YJ, Juang J-MJ, Lin L-Y, Liu Y-B, Ho L-T, Yu C-C, et al. Gender difference in clinical and genetic characteristics of Brugada syndrome: SADS-TW BrS registry. QJM: An International Journal of Medicine. 1o de maio de 2019;112(5):343–50.

Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature. setembro de 2009; 461(7261): 272–6.

Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, et al. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. janeiro de 2010; 42(1): 30–5.

Wang DG. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science. 15 de maio de 1998; 280(5366): 1077–82.

Teer JK, Mullikin JC. Exome sequencing: the sweet spot before whole genomes. Human Molecular Genetics. 15 de outubro de 2010; 19(R2): R145–51.

Rauch A, Hoyer J, Guth S, Zweier C, Kraus C, Becker C, et al. Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am J Med Genet. 1o de outubro de 2006; 140A (19): 2063–74.

Mooney SD. Progress towards the integration of pharmacogenomics in practice. Hum Genet. maio de 2015; 134(5): 459–65.

on behalf of the ESHG Public and Professional Policy Committee, van El CG, Cornel MC, Borry P, Hastings RJ, Fellmann F, et al. Whole-genome sequencing in health care: recommendations of the european society of human genetics. Eur J Hum Genet. junho de 2013; 21(6): 580–4.

Nantes Referral Center for inherited cardiac arrhythmia, Walsh R, Lahrouchi N, Tadros R, Kyndt F, Glinge C, et al. Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. Genet Med. janeiro de 2021; 23(1): 47–58.

Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. março de 1998; 392(6673): 293–6.

Hosseini SM, Kim R, Udupa S, Costain G, Jobling R, Liston E, et al. Reappraisal of reported genes for sudden arrhythmic death: evidence-based evaluation of gene validity for brugada syndrome. Circulation. 18 de setembro de 2018; 138(12): 1195–205.

Pérez-Riera AR, Raimundo RD, Watanabe RA, Figueiredo JL, Abreu LC de. Cardiac sodium channel, its mutations and their spectrum of arrhythmia phenotypes. J Hum Growth Dev. 28 de novembro de 2016; 26(3): 281.

Bezzina C, Veldkamp MW, van den Berg MP, Postma AV, Rook MB, Viersma J-W, et al. A single na + channel mutation causing both long-qt and brugada syndromes. Circulation Research. 3 de dezembro de 1999; 85(12): 1206–13.

Clancy CE, Tateyama M, Kass RS. Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome. J Clin Invest. 1o de novembro de 2002; 110(9): 1251–62.

Rivolta I, Abriel H, Tateyama M, Liu H, Memmi M, Vardas P, et al. Inherited brugada and long qt-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes. Journal of Biological Chemistry. agosto de 2001; 276(33): 30623–30.

Doisne N, Waldmann V, Redheuil A, Waintraub X, Fressart V, Ader F, et al. A novel gain-of-function mutation in SCN5A responsible for multifocal ectopic Purkinje-related premature contractions. Human Mutation. abril de 2020; 41(4): 850–9.

Kyndt F, Probst V, Potet F, Demolombe S, Chevallier J-C, Baro I, et al. Novel scn5a mutation leading either to isolated cardiac conduction defect or brugada syndrome in a large french family. Circulation. 17 de dezembro de 2001; 104(25): 3081–6.

Wilde AAM, Amin AS. Clinical spectrum of scn5a mutations. JACC: Clinical Electrophysiology. maio de 2018; 4(5): 569–79.

Amin AS, Boink GJJ, Atrafi F, Spanjaart AM, Asghari-Roodsari A, Molenaar RJ, et al. Facilitatory and inhibitory effects of SCN5A mutations on atrial fibrillation in Brugada syndrome. Europace. 1o de julho de 2011; 13(7): 968–75.

Han D, Tan H, Sun C, Li G. Dysfunctional Nav1.5 channels due to SCN5A mutations. Exp Biol Med (Maywood). junho de 2018; 243(10): 852–63.

Remme CA, Wilde AAM, Bezzina CR. Cardiac sodium channel overlap syndromes: different faces of scn5a mutations. Trends in Cardiovascular Medicine. abril de 2008; 18(3): 78–87.

Wilde AAM, Garan H, Boyden PA. Role of the Purkinje system in heritable arrhythmias. Heart Rhythm. julho de 2019; 16(7): 1121–6.

Haïssaguerre M, Duchateau J, Dubois R, Hocini M, Cheniti G, Sacher F, et al. Idiopathic ventricular fibrillation. JACC: Clinical Electrophysiology. junho de 2020; 6(6): 591–608.

Robyns T, Nuyens D, Vandenberk B, Kuiperi C, Corveleyn A, Breckpot J, et al. Genotype–phenotype relationship and risk stratification in loss-of-function SCN 5A mutation carriers. Ann Noninvasive Electrocardiol [Internet]. setembro de 2018 [citado 26 de fevereiro de 2021]; 23(5). Disponível em: https://onlinelibrary.wiley.com/doi/abs/10.1111/anec.12548

Amin AS, Reckman YJ, Arbelo E, Spanjaart AM, Postema PG, Tadros R, et al. SCN5A mutation type and topology are associated with the risk of ventricular arrhythmia by sodium channel blockers. International Journal of Cardiology. setembro de 2018; 266: 128–32.

Rao AS, Knowles JW. Polygenic risk scores in coronary artery disease. Current Opinion in Cardiology. julho de 2019; 34(4): 435–40.

Khera AV, Chaffin M, Aragam KG, Haas ME, Roselli C, Choi SH, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. setembro de 2018; 50(9): 1219–24.

Micaglio E, Monasky MM, Ciconte G, Vicedomini G, Conti M, Mecarocci V, et al. Novel scn5a frameshift mutation in brugada syndrome associated with complex arrhythmic phenotype. Front Genet. 6 de junho de 2019; 10: 547.

Monasky M, Micaglio E, Giachino D, Ciconte G, Giannelli L, Locati E, et al. Genotype–phenotype correlation in a family with brugada syndrome harboring the novel p. Gln371* nonsense variant in the scn5a gene. IJMS. 6 de novembro de 2019; 20(22): 5522.

Monasky MM, Micaglio E, Ciconte G, Benedetti S, Di Resta C, Vicedomini G, et al. Genotype/phenotype relationship in a consanguineal family with brugada syndrome harboring the r1632c missense variant in the scn5a gene. Front Physiol. 28 de maio de 2019; 10: 666.

Micaglio E, Monasky MM, Ciconte G, Vicedomini G, Conti M, Mecarocci V, et al. Scn5a nonsense mutation and nf1 frameshift mutation in a family with brugada syndrome and neurofibromatosis. Front Genet. 15 de fevereiro de 2019; 10: 50.

Micaglio E, Monasky M, Resta N, Bagnulo R, Ciconte G, Giannelli L, et al. Novel scn5a p. W697x nonsense mutation segregation in a family with brugada syndrome. IJMS. 4 de outubro de 2019; 20(19): 4920.

Veltmann C, Barajas-Martinez H, Wolpert C, Borggrefe M, Schimpf R, Pfeiffer R, et al. Further insights in the most common scn5a mutation causing overlapping phenotype of long qt syndrome, brugada syndrome, and conduction defect. JAHA [Internet]. 6 de julho de 2016 [citado 26 de fevereiro de 2021]; 5(7). Disponível em: https://www.ahajournals.org/doi/10.1161/JAHA.116.003379

Samani K, Ai T, Towbin JA, Brugada R, Shuraih M, Xi Y, et al. A nonsense scn5a mutation associated with brugada-type electrocardiogram and intraventricular conduction defects. Pacing and Clinical Electrophysiology. setembro de 2009; 32(9): 1231–6.

Probst V, Allouis M, Sacher F, Pattier S, Babuty D, Mabo P, et al. Progressive cardiac conduction defect is the prevailing phenotype in carriers of a brugada syndrome scn5a mutation. J Cardiovasc Electrophysiol. março de 2006; 17(3): 270–5.

Keller DI, Barrane FZ, Gouas L, Martin J, Pilote S, Suarez V, Osswald S, Brink M, Guicheney P, Schwick N, Chahine M. A novel nonsense mutation in the SCN5A gene leads to Brugada syndrome and a silent gene mutation carrier state. Can J Cardiol. 2005; 21: 925-931.

Ackerman MJ, Splawski I, Makielski JC, Tester DJ, Will ML, Timothy KW, et al. Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: Implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. Heart Rhythm. novembro de 2004; 1(5): 600–7.

Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm. janeiro de 2010; 7(1): 33–46.

Ohkubo K, Watanabe I, Okumura Y, Ashino S, Kofune M, Nagashima K, et al. Prolonged qrs duration in lead v2 and risk of life-threatening ventricular arrhythmia in patients with brugada syndrome. Int Heart J. 2011; 52(2): 98–102.

Nademanee K, Raju H, de Noronha SV, Papadakis M, Robinson L, Rothery S, et al. Fibrosis, connexin-43, and conduction abnormalities in the brugada syndrome. Journal of the American College of Cardiology. novembro de 2015; 66(18): 1976–86.

Ingles J, Macciocca I, Morales A, Thomson K. Genetic testing in inherited heart diseases. Heart, Lung and Circulation. abril de 2020; 29(4): 505–11.

London B, Michalec M, Mehdi H, Zhu X, Kerchner L, Sanyal S, et al. Mutation in glycerol-3-phosphate dehydrogenase 1–like gene (gpd1-l) decreases cardiac na + current and causes inherited arrhythmias. Circulation. 13 de novembro de 2007; 116(20): 2260–8.

Antzelevitch C, Patocskai B. Brugada syndrome: clinical, genetic, molecular, cellular, and ionic aspects. Current Problems in Cardiology. janeiro de 2016; 41(1): 7–57.

Van Norstrand DW, Valdivia CR, Tester DJ, Ueda K, London B, Makielski JC, et al. Molecular and functional characterization of novel glycerol-3-phosphate dehydrogenase 1–like gene (gpd1-l) mutations in sudden infant death syndrome. Circulation. 13 de novembro de 2007; 116(20): 2253–9.

Béziau DM, Barc J, O’Hara T, Le Gloan L, Amarouch MY, Solnon A, et al. Complex Brugada syndrome inheritance in a family harbouring compound SCN5A and CACNA1C mutations. Basic Res Cardiol. novembro de 2014; 109(6): 446.

Bozarth X, Dines JN, Cong Q, Mirzaa GM, Foss K, Lawrence Merritt J, et al. Expanding clinical phenotype in CACNA1C related disorders: From neonatal onset severe epileptic encephalopathy to late-onset epilepsy. Am J Med Genet. dezembro de 2018; 176(12): 2733–9.

Ou X, Crane DE, MacIntosh BJ, Young LT, Arnold P, Ameis S, et al. CACNA1C rs1006737 genotype and bipolar disorder: Focus on intermediate phenotypes and cardiovascular comorbidity. Neuroscience & Biobehavioral Reviews. agosto de 2015; 55: 198–210.

Tesli M, Skatun KC, Ousdal OT, Brown AA, Thoresen C, Agartz I, et al. Cacna1c risk variant and amygdala activity in bipolar disorder, schizophrenia and healthy controls. Fatemi H, organizador. PLoS ONE. 20 de fevereiro de 2013; 8(2): e56970.

Chernyavskaya Y, Ebert AM, Milligan E, Garrity DM. Voltage-gated calcium channel CACNB2 ( β2.1) protein is required in the heart for control of cell proliferation and heart tube integrity. Dev Dyn. abril de 2012; 241(4): 648–62.

Wallace RH, Wang DW, Singh R, Scheffer IE, George AL, Phillips HA, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel ß1 subunit gene SCN1B. Nat Genet. agosto de 1998; 19(4): 366–70.

Singh R, Andermann E, Whitehouse WPA, Harvey AS, Keene DL, Seni M-H, et al. Severe myoclonic epilepsy of infancy: extended spectrum of gefs+? Epilepsia. 20 de dezembro de 2001; 42(7): 837–44.

Watanabe H, Darbar D, Kaiser DW, Jiramongkolchai K, Chopra S, Donahue BS, et al. Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation. Circ Arrhythm Electrophysiol. junho de 2009; 2(3): 268–75.

Scheffer IE, Harkin LA, Grinton BE, Dibbens LM, Turner SJ, Zielinski MA, et al. Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. Brain. 21 de novembro de 2006; 130(1): 100–9.

Ogiwara I, Nakayama T, Yamagata T, Ohtani H, Mazaki E, Tsuchiya S, et al. A homozygous mutation of voltage-gated sodium channel β I gene SCN1B in a patient with Dravet syndrome: Homozygous SCN1B Mutation in Epilepsy. Epilepsia. dezembro de 2012; 53(12): e200–3.

Delpón E, Cordeiro JM, Núñez L, Thomsen PEB, Guerchicoff A, Pollevick GD, et al. Functional effects of kcne3 mutation and its role in the development of brugada syndrome. Circ Arrhythm Electrophysiol. agosto de 2008; 1(3): 209–18.

Nakajima T, Wu J, Kaneko Y, Ashihara T, Ohno S, Irie T, et al. Kcne3 t4a as the genetic basis of brugada-pattern electrocardiogram. Circ J. 2012; 76(12): 2763–72.

Hu D, Barajas-Martinez H, Burashnikov E, Springer M, Wu Y, Varro A, et al. A mutation in the β3 subunit of the cardiac sodium channel associated with brugada ecg phenotype. Circ Cardiovasc Genet. junho de 2009; 2(3): 270–8.

Nielsen MW, Holst AG, Olesen S-P, Olesen MS. The genetic component of Brugada syndrome. Front Physiol [Internet]. 2013 [citado 26 de fevereiro de 2021]; 4. Disponível em: http://journal.frontiersin.org/article/10.3389/fphys.2013.00179/abstract

Ishikawa T, Takahashi N, Ohno S, Sakurada H, Nakamura K, On YK, et al. Novel scn3b mutation associated with brugada syndrome affects intracellular trafficking and function of nav1. 5. Circ J. 2013; 77(4): 959–67.

Ueda K, Hirano Y, Higashiuesato Y, Aizawa Y, Hayashi T, Inagaki N, et al. Role of HCN4 channel in preventing ventricular arrhythmia. J Hum Genet. fevereiro de 2009; 54(2): 115–21.

Barajas-Martínez H, Hu D, Ferrer T, Onetti CG, Wu Y, Burashnikov E, et al. Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8. Heart Rhythm. abril de 2012; 9(4): 548–55.

Giudicessi JR, Ye D, Tester DJ, Crotti L, Mugione A, Nesterenko VV, et al. Transient outward current (Ito) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome. Heart Rhythm. julho de 2011; 8(7): 1024–32.

Templin C, Ghadri J-R, Rougier J-S, Baumer A, Kaplan V, Albesa M, et al. Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (Sqts6). European Heart Journal. 1o de maio de 2011;3 2(9): 1077–88.

Hancox JC, Whittaker DG, Du C, Stuart AG, Zhang H. Emerging therapeutic targets in the short QT syndrome. Expert Opinion on Therapeutic Targets. 4 de maio de 2018; 22(5): 439–51.

Iles DE, Lehmann-Horn F, Scherer SW, Tsui L-C, Weghuis DO, Suijkerbuijk RF, et al. Localization of the gene encoding the α 2 /δ-subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families. Hum Mol Genet. 1994; 3(6): 969–75.

Portero V, Wilders R, Casini S, Charpentier F, Verkerk AO, Remme CA. Kv4. 3 expression modulates nav1. 5 sodium current. Front Physiol. 12 de março de 2018; 9: 178.

Campuzano O, Berne P, Selga E, Allegue C, Iglesias A, Brugada J, Brugada R. Brugada syndrome and p.E61X_RANGRF. Cardiol J. 2014; 21: 121-127.

Olesen MS, Jensen NF, Holst AG, Nielsen JB, Tfelt-Hansen J, Jespersen T, et al. A novel nonsense variant in nav1. 5 cofactor mog1 eliminates its sodium current increasing effect and may increase the risk of arrhythmias. Canadian Journal of Cardiology. julho de 2011; 27(4): 523.e17-523.e23.

Wu L, Yong SL, Fan C, Ni Y, Yoo S, Zhang T, et al. Identification of a new co-factor, mog1, required for the full function of cardiac sodium channel nav1. 5. Journal of Biological Chemistry. março de 2008; 283(11): 6968–78.

Chakrabarti S, Wu X, Yang Z, Wu L, Yong SL, Zhang C, et al. Mog1 rescues defective trafficking of na v 1. 5 mutations in brugada syndrome and sick sinus syndrome. Circ Arrhythm Electrophysiol. abril de 2013; 6(2): 392–401.

Mlynarova J, Trentin-Sonoda M, Gaisler da Silva F, Major JL, Salih M, Carneiro-Ramos MS, et al. SLMAP3 isoform modulates cardiac gene expression and function. Backx PH, organizador. PLoS ONE. 1o de abril de 2019; 14(4): e0214669.

Ishikawa T, Sato A, Marcou CA, Tester DJ, Ackerman MJ, Crotti L, et al. A novel disease gene for brugada syndrome: sarcolemmal membrane–associated protein gene mutations impair intracellular trafficking of hnav1. 5. Circ Arrhythm Electrophysiol. dezembro de 2012; 5(6): 1098–107.

Hu D, Barajas-Martínez H, Terzic A, Park S, Pfeiffer R, Burashnikov E, et al. ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene. International Journal of Cardiology. fevereiro de 2014; 171(3): 431–42.

Riuró H, Beltran-Alvarez P, Tarradas A, Selga E, Campuzano O, Vergés M, et al. A missense mutation in the sodium channel β2 subunit reveals scn2b as a new candidate gene for brugada syndrome. Human Mutation. julho de 2013; 34(7): 961–6.

Bao Y, Willis BC, Frasier CR, Lopez-Santiago LF, Lin X, Ramos-Mondragón R, et al. scn2b deletion in mice results in ventricular and atrial arrhythmias. Circ Arrhythm Electrophysiol [Internet]. dezembro de 2016 [citado 26 de fevereiro de 2021]; 9(12). Disponível em: https://www.ahajournals.org/doi/10.1161/CIRCEP.116.003923

Huang L, Tang S, Peng L, Chen Y, Cheng J. Molecular autopsy of desmosomal protein plakophilin-2 in sudden unexplained nocturnal death syndrome. J Forensic Sci. maio de 2016; 61(3): 687–91.

Cerrone M, Delmar M. Desmosomes and the sodium channel complex: Implications for arrhythmogenic cardiomyopathy and Brugada syndrome. Trends in Cardiovascular Medicine. julho de 2014; 24(5): 184–90.

Papavassiliu T, Wolpert C, Flüchter S, Schimpf R, Neff W, Haase KK, et al. Magnetic resonance imaging findings in patients with brugada syndrome. Journal of Cardiovascular Electrophysiology. outubro de 2004; 15(10): 1133–8.

Cerrone M, Noorman M, Lin X, Chkourko H, Liang F-X, van der Nagel R, et al. Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency. Cardiovascular Research. 1o de setembro de 2012; 95(4): 460–8.

Wang C, Wang C, Hoch EG, Pitt GS. Identification of novel interaction sites that determine specificity between fibroblast growth factor homologous factors and voltage-gated sodium channels. Journal of Biological Chemistry. julho de 2011; 286(27): 24253–63.

Hennessey JA, Marcou CA, Wang C, Wei EQ, Wang C, Tester DJ, et al. FGF12 is a candidate Brugada syndrome locus. Heart Rhythm. dezembro de 2013; 10(12): 1886–94.

Villeneuve N, Abidi A, Cacciagli P, Mignon-Ravix C, Chabrol B, Villard L, et al. Heterogeneity of FHF1 related phenotype: Novel case with early onset severe attacks of apnea, partial mitochondrial respiratory chain complex II deficiency, neonatal onset seizures without neurodegeneration. European Journal of Paediatric Neurology. setembro de 2017; 21(5): 783–6.

Hu D, Barajas-Martínez H, Pfeiffer R, Dezi F, Pfeiffer J, Buch T, et al. Mutations in scn10a are responsible for a large fraction of cases of brugada syndrome. Journal of the American College of Cardiology. julho de 2014; 64(1): 66–79.

Sotoodehnia N, Isaacs A, de Bakker PIW, Dörr M, Newton-Cheh C, Nolte IM, et al. Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. Nat Genet. dezembro de 2010; (12): 1068–76.

Abriel H. Genetic background of Brugada syndrome is more complex than what we would like it to be! Cardiovascular Research. 1o de junho de 2015; 106(3): 351–2.

Behr ER, Savio-Galimberti E, Barc J, Holst AG, Petropoulou E, Prins BP, et al. Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study. Cardiovascular Research. 1o de junho de 2015; 106(3): 520–9.

Fukuyama M, Ohno S, Makiyama T, Horie M. Novel SCN10A variants associated with Brugada syndrome. Europace. junho de 2016; 18(6): 905–11.

El-Battrawy I, Albers S, Cyganek L, Zhao Z, Lan H, Li X, et al. A cellular model of Brugada syndrome with SCN10A variants using human-induced pluripotent stem cell-derived cardiomyocytes. EP Europace. 1o de setembro de 2019; 21(9): 1410–21.

Gray B, Hasdemir C, Ingles J, Aiba T, Makita N, Probst V, et al. Lack of genotype-phenotype correlation in Brugada Syndrome and Sudden Arrhythmic Death Syndrome families with reported pathogenic SCN1B variants. Heart Rhythm. julho de 2018; 15(7): 1051–7.

Leo S, D’Hooge R, Meert T. Exploring the role of nociceptor-specific sodium channels in pain transmission using Nav1.8 and Nav1.9 knockout mice. Behavioural Brain Research. março de 2010; 208(1): 149–57.

Leimeister C, Externbrink A, Klamt B, Gessler M. Hey genes: a novel subfamily of hairy - and Enhancer of split related genes specifically expressed during mouse embryogenesis. Mechanisms of Development. julho de 1999; 85(1–2): 173–7.

Bezzina CR, Barc J, Mizusawa Y, Remme CA, Gourraud J-B, Simonet F, et al. Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nat Genet. setembro de 2013; 45(9): 1044–9.

Veerman CC, Podliesna S, Tadros R, Lodder EM, Mengarelli I, de Jonge B, et al. The brugada syndrome susceptibility gene hey2 modulates cardiac transmural ion channel patterning and electrical heterogeneity. Circ Res. 18 de agosto de 2017; 121(5): 537–48.

Andreasen L, Nielsen JB, Darkner S, Christophersen IE, Jabbari J, Refsgaard L, et al. Brugada syndrome risk loci seem protective against atrial fibrillation. Eur J Hum Genet. dezembro de 2014; 22(12): 1357–61.

Nakano Y, Ochi H, Onohara Y, Toshishige M, Tokuyama T, Matsumura H, et al. Common variant near hey2 has a protective effect on ventricular fibrillation occurrence in brugada syndrome by regulating the repolarization current. Circ Arrhythm Electrophysiol [Internet]. janeiro de 2016 [citado 26 de fevereiro de 2021]; 9(1). Disponível em: https://www.ahajournals.org/doi/10.1161/CIRCEP.115.003436

Boczek NJ, Ye D, Johnson EK, Wang W, Crotti L, Tester DJ, et al. Characterization of sema3a -encoded semaphorin as a naturally occurring k v 4. 3 protein inhibitor and its contribution to brugada syndrome. Circ Res. agosto de 2014; 115(4): 460–9.

Turker I, Makiyama T, Ueyama T, Shimizu A, Yamakawa M, Chen P, et al. telethonin variants found in brugada syndrome, j-wave pattern ecg, and arvc reduce peak na v 1. 5 currents in hek-293 cells. Pacing Clin Electrophysiol. agosto de 2020; 43(8): 838–46.

Baskin B, Skinner JR, Sanatani S, Terespolsky D, Krahn AD, Ray PN, et al. TMEM43 mutations associated with arrhythmogenic right ventricular cardiomyopathy in non-Newfoundland populations. Hum Genet. novembro de 2013; 132(11): 1245–52.

Merner ND, Hodgkinson KA, Haywood AFM, Connors S, French VM, Drenckhahn J-D, et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the tmem43 gene. The American Journal of Human Genetics. abril de 2008; 82(4): 809–21.

Siragam V, Cui X, Masse S, Ackerley C, Aafaqi S, Strandberg L, et al. Tmem43 mutation p. S358l alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy. Ai X, organizador. PLoS ONE. 24 de outubro de 2014; 9(10): e109128.

Nakane T, Satoh T, Inada Y, Nakayama J, Itoh F, Chiba S. Molecular cloning and expression of HRLRRP, a novel heart-restricted leucine-rich repeat protein. Biochemical and Biophysical Research Communications. fevereiro de 2004; 314(4): 1086–92.

Chiamvimonvat N, Song L. Lrrc10 (Leucine-rich repeat containing protein 10) and reep5 (Receptor accessory protein 5) as novel regulators of cardiac excitation-contraction coupling structure and function. JAHA [Internet]. 6 de fevereiro de 2018 [citado 26 de fevereiro de 2021]; 7(3). Disponível em: https://www.ahajournals.org/doi/10.1161/JAHA.117.008260

Brody MJ, Hacker TA, Patel JR, Feng L, Sadoshima J, Tevosian SG, et al. Ablation of the cardiac-specific gene leucine-rich repeat containing 10 (Lrrc10) results in dilated cardiomyopathy. Peng T, organizador. PLoS ONE. 7 de dezembro de 2012; 7(12): e51621.

Huang L, Tang S, Chen Y, Zhang L, Yin K, Wu Y, et al. Molecular pathological study on LRRC10 in sudden unexplained nocturnal death syndrome in the Chinese Han population. Int J Legal Med. maio de 2017; 131(3): 621–8.

Brody MJ, Lee Y. The role of leucine-rich repeat containing protein 10 (Lrrc10) in dilated cardiomyopathy. Front Physiol [Internet]. 3 de agosto de 2016 [citado 26 de fevereiro de 2021]; 7. Disponível em: http://journal.frontiersin.org/Article/10.3389/fphys.2016.00337/abstract

Campuzano O, Sarquella-Brugada G, Cesar S, Arbelo E, Brugada J, Brugada R. Update on genetic basis of brugada syndrome: monogenic, polygenic or oligogenic? IJMS. 28 de setembro de 2020; 21(19): 7155.

Han D, Xue X, Yan Y, Li G. Dysfunctional Cav1.2 channel in Timothy syndrome, from cell to bedside. Exp Biol Med (Maywood). setembro de 2019; 244(12): 960–71.

Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by st-segment elevation, short qt intervals, and sudden cardiac death. Circulation. 30 de janeiro de 2007; 115(4): 442–9.

Chen Y, Barajas-Martinez H, Zhu D, Wang X, Chen C, Zhuang R, et al. Novel trigenic CACNA1C/DES/MYPN mutations in a family of hypertrophic cardiomyopathy with early repolarization and short QT syndrome. J Transl Med. dezembro de 2017; 15(1):7 8.

Pappone C, Monasky MM, Ciconte G. Epicardial ablation in genetic cardiomyopathies: a new frontier. European Heart Journal Supplements. 1o de março de 2019; 21(Supplement_B): B61–6.

Crotti L, Odening KE, Sanguinetti MC. Heritable arrhythmias associated with abnormal function of cardiac potassium channels. Cardiovascular Research. 15 de julho de 2020; 116(9): 1542–56.

Hegyi B, Chen-Izu Y, Izu LT, Rajamani S, Belardinelli L, Bers DM, et al. Balance between rapid delayed rectifier k + current and late na + current on ventricular repolarization: an effective antiarrhythmic target? Circ: Arrhythmia and Electrophysiology [Internet]. abril de 2020 [citado 26 de fevereiro de 2021]; 13(4). Disponível em: https://www.ahajournals.org/doi/10.1161/CIRCEP.119.008130

Liu D-W, Antzelevitch C. Characteristics of the delayed rectifier current (I Kr and I Ks) in canine ventricular epicardial, midmyocardial, and endocardial myocytes: a weaker i ks contributes to the longer action potential of the m cell. Circulation Research. março de 1995; 76(3): 351–65.

Caballero R, de la Fuente MG, Gómez R, Barana A, Amorós I, Dolz-Gaitón P, et al. In humans, chronic atrial fibrillation decreases the transient outward current and ultrarapid component of the delayed rectifier current differentially on each atria and increases the slow component of the delayed rectifier current in both. Journal of the American College of Cardiology. maio de 2010; 55(21): 2346–54.

Walsh KB. Screening technologies for inward rectifier potassium channels: discovery of new blockers and activators. SLAS DISCOVERY: Advancing the Science of Drug Discovery. junho de 2020; 25(5): 420–33.

Tonussi Mendes JE, Nikus K, Barbosa-Barros R, Pérez-Riera AR. The numerous denominations of the Brugada syndrome and proposal about how to put an end to an old controversy - a historical-critical perspective. J Hum Growth Dev. 2020; 30(3): 480-491.

Pérez-Riera AR, Raimundo RD, Watanabe RA, Abreu LC. The cardiac sodium channel its mutations and their spectrum arrhythmia phenotypes. J Hum Growth Dev. 2016; 26(3): 281-296. Doi: http://dx.doi.org/10.7322/jhgd.122759

Published

2021-04-28

Issue

Section

ORIGINAL ARTICLES