1932

Abstract

Brugada syndrome is a heritable channelopathy characterized by a peculiar electrocardiogram (ECG) pattern and increased risk of cardiac arrhythmias and sudden death. The arrhythmias originate because of an imbalance between the repolarizing and depolarizing currents that modulate the cardiac action potential. Even if an overt structural cardiomyopathy is not typical of Brugada syndrome, fibrosis and structural changes in the right ventricle contribute to a conduction slowing, which ultimately facilitates ventricular arrhythmias. Currently, Mendelian autosomal dominant transmission is detected in less than 25% of all clinical confirmed cases. Although 23 genes have been associated with the condition, only , encoding the cardiac sodium channel, is considered clinically actionable and disease causing. The limited monogenic inheritance has pointed toward new perspectives on the possible complex genetic architecture of the disease, involving polygenic inheritance and a polygenic risk score that can influence penetrance and risk stratification.

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2022-08-31
2024-12-10
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Literature Cited

  1. 1.
    Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R et al. 2011. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm 8:1308–39
    [Google Scholar]
  2. 2.
    Andorin A, Gourraud J-B, Mansourati J, Fouchard S, le Marec H et al. 2017. The QUIDAM study: hydroquinidine therapy for the management of Brugada syndrome patients at high arrhythmic risk. Heart Rhythm 14:1147–54
    [Google Scholar]
  3. 3.
    Antzelevitch C. 2001. The Brugada syndrome: ionic basis and arrhythmia mechanisms. J. Cardiovasc. Electrophysiol. 12:268–72
    [Google Scholar]
  4. 4.
    Antzelevitch C. 2006. Brugada syndrome. Pacing Clin. Electrophysiol 29:1130–59
    [Google Scholar]
  5. 5.
    Antzelevitch C. 2012. Genetic, molecular and cellular mechanisms underlying the J wave syndromes. Circ. J. 76:1054–65
    [Google Scholar]
  6. 6.
    Antzelevitch C, Patocskai B. 2016. Brugada syndrome: clinical, genetic, molecular, cellular, and ionic aspects. Curr. Probl. Cardiol. 41:7–57
    [Google Scholar]
  7. 7.
    Antzelevitch C, Yan G-X, Ackerman MJ, Borggrefe M, Corrado D et al. 2017. J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. Europace 19:665–94
    [Google Scholar]
  8. 8.
    Barajas-Martínez H, Hu D, Ferrer T, Onetti CG, Wu Y et al. 2012. Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8. Heart Rhythm 9:548–55
    [Google Scholar]
  9. 9.
    Baranchuk A, Nguyen T, Ryu MH, Femenía F, Zareba W et al. 2012. Brugada phenocopy: new terminology and proposed classification: Brugada phenocopy. Ann. Noninvasive Electrocardiol. 17:299–314
    [Google Scholar]
  10. 10.
    Bayés de Luna A, Brugada J, Baranchuk A, Borggrefe M, Breithardt G et al. 2012. Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. J. Electrocardiol. 45:433–42
    [Google Scholar]
  11. 11.
    Bezzina CR, Barc J, Mizusawa Y, Remme CA, Gourraud J-B et al. 2013. Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nat. Genet. 45:1044–49 Corrigendum 2013. Nat. Genet. 45:1409
    [Google Scholar]
  12. 12.
    Bezzina CR, Veldkamp MW, van den Berg MP, Postma AV, Rook MB et al. 1999. A single Na+ channel mutation causing both long-QT and Brugada syndromes. Circ. Res. 85:1206–13
    [Google Scholar]
  13. 13.
    Brugada J, Campuzano O, Arbelo E, Sarquella-Brugada G, Brugada R. 2018. Present status of Brugada syndrome. J. Am. Coll. Cardiol. 72:1046–59
    [Google Scholar]
  14. 14.
    Burashnikov E, Pfeiffer R, Barajas-Martínez H, Delpón E, Hu D et al. 2010. Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm 7:1872–82
    [Google Scholar]
  15. 15.
    Calò L, Giustetto C, Martino A, Sciarra L, Cerrato N et al. 2016. A new electrocardiographic marker of sudden death in Brugada syndrome. J. Am. Coll. Cardiol. 67:1427–40
    [Google Scholar]
  16. 16.
    Campuzano O, Sarquella-Brugada G, Cesar S, Arbelo E, Brugada J, Brugada R 2020. Update on genetic basis of Brugada syndrome: monogenic, polygenic or oligogenic?. Int. J. Mol. Sci. 21:7155
    [Google Scholar]
  17. 17.
    Catalano O, Antonaci S, Moro G, Mussida M, Frascaroli M et al. 2009. Magnetic resonance investigations in Brugada syndrome reveal unexpectedly high rate of structural abnormalities. Eur. Heart J. 30:2241–48
    [Google Scholar]
  18. 18.
    Cerrone M. 2018. Controversies in Brugada syndrome. Trends Cardiovasc. Med. 28:284–92
    [Google Scholar]
  19. 19.
    Cerrone M, Lin X, Zhang M, Agullo-Pascual E, Pfenniger A et al. 2014. Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype. Circulation 129:1092–103
    [Google Scholar]
  20. 20.
    Cerrone M, Montnach J, Lin X, Zhao Y-T, Zhang M et al. 2017. Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm. Nat. Commun. 8:106
    [Google Scholar]
  21. 21.
    Cerrone M, Remme CA, Tadros R, Bezzina CR, Delmar M. 2019. Beyond the one gene–one disease paradigm: complex genetics and pleiotropy in inheritable cardiac disorders. Circulation 140:595–610
    [Google Scholar]
  22. 22.
    Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J et al. 1998. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 392:293–96
    [Google Scholar]
  23. 23.
    Cordeiro JM, Barajas-Martínez H, Hong K, Burashnikov E, Pfeiffer R et al. 2006. Compound heterozygous mutations P336L and I1660V in the human cardiac sodium channel associated with the Brugada syndrome. Circulation 114:2026–33
    [Google Scholar]
  24. 24.
    Cordeiro JM, Marieb M, Pfeiffer R, Calloe K, Burashnikov E, Antzelevitch C. 2009. Accelerated inactivation of the L-type calcium current due to a mutation in CACNB2b underlies Brugada syndrome. J. Mol. Cell. Cardiol. 46:695–703
    [Google Scholar]
  25. 25.
    Coronel R, Casini S, Koopmann TT, Wilms-Schopman FJG, Verkerk AO et al. 2005. Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study. Circulation 112:2769–77
    [Google Scholar]
  26. 26.
    Corrado D, Basso C, Buja G, Nava A, Rossi L, Thiene G. 2001. Right bundle branch block, right precordial ST-segment elevation, and sudden death in young people. Circulation 103:710–17
    [Google Scholar]
  27. 27.
    Curcio A, Santarpia G, Indolfi C. 2017. The Brugada syndrome: from gene to therapy. Circ. J. 81:290–97
    [Google Scholar]
  28. 28.
    Daimi H, Khelil AH, Neji A, Ben Hamda K, Maaoui S et al. 2019. Role of SCN5A coding and non-coding sequences in Brugada syndrome onset: What's behind the scenes?. Biomed. J. 42:252–60
    [Google Scholar]
  29. 29.
    Delpón E, Cordeiro JM, Núñez L, Thomsen PEB, Guerchicoff A et al. 2008. Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. Circ. Arrhythm. Electrophysiol. 1:209–18
    [Google Scholar]
  30. 30.
    Di Resta C, Pietrelli A, Sala S, Della Bella P, De Bellis G et al. 2015. High-throughput genetic characterization of a cohort of Brugada syndrome patients. Hum. Mol. Genet. 24:5828–35
    [Google Scholar]
  31. 31.
    Fazi F, Nervi C. 2008. MicroRNA: basic mechanisms and transcriptional regulatory networks for cell fate determination. Cardiovasc. Res. 79:553–61
    [Google Scholar]
  32. 32.
    Frustaci A, Priori SG, Pieroni M, Chimenti C, Napolitano C et al. 2005. Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome. Circulation 112:3680–87
    [Google Scholar]
  33. 33.
    Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN et al. 2003. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424:443–47
    [Google Scholar]
  34. 34.
    Ghouse J, Have CT, Skov MW, Andreasen L, Ahlberg G et al. 2017. Numerous Brugada syndrome–associated genetic variants have no effect on J-point elevation, syncope susceptibility, malignant cardiac arrhythmia, and all-cause mortality. Genet. Med. 19:521–28
    [Google Scholar]
  35. 35.
    Giustetto C, Cerrato N, Gribaudo E, Scrocco C, Castagno D et al. 2014. Atrial fibrillation in a large population with Brugada electrocardiographic pattern: prevalence, management, and correlation with prognosis. Heart Rhythm 11:259–65
    [Google Scholar]
  36. 36.
    Gollob MH, Blier L, Brugada R, Champagne J, Chauhan V et al. 2011. Recommendations for the use of genetic testing in the clinical evaluation of inherited cardiac arrhythmias associated with sudden cardiac death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society joint position paper. Can. J. Cardiol. 27:232–45
    [Google Scholar]
  37. 37.
    Hennessey JA, Marcou CA, Wang C, Wei EQ, Wang C et al. 2013. FGF12 is a candidate Brugada syndrome locus. Heart Rhythm 10:1886–94
    [Google Scholar]
  38. 38.
    Hoogendijk MG, Potse M, Linnenbank AC, Verkerk AO, den Ruijter HM et al. 2010. Mechanism of right precordial ST-segment elevation in structural heart disease: excitation failure by current-to-load mismatch. Heart Rhythm 7:238–48
    [Google Scholar]
  39. 39.
    Hosseini SM, Kim R, Udupa S, Costain G, Jobling R et al. 2018. Reappraisal of reported genes for sudden arrhythmic death: evidence-based evaluation of gene validity for Brugada syndrome. Circulation 138:1195–205
    [Google Scholar]
  40. 40.
    Hu D, Barajas-Martínez H, Burashnikov E, Springer M, Wu Y et al. 2009. A mutation in the β3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype. Circ. Cardiovasc. Genet. 2:270–78
    [Google Scholar]
  41. 41.
    Hu D, Barajas-Martínez H, Medeiros-Domingo A, Crotti L, Veltmann C et al. 2012. A novel rare variant in SCN1Bb linked to Brugada syndrome and SIDS by combined modulation of Nav1.5 and Kv4.3 channel currents. Heart Rhythm 9:760–69
    [Google Scholar]
  42. 42.
    Hu D, Barajas-Martínez H, Pfeiffer R, Dezi F, Pfeiffer J et al. 2014. Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome. J. Am. Coll. Cardiol. 64:66–79
    [Google Scholar]
  43. 43.
    Hu D, Barajas-Martínez H, Terzic A, Park S, Pfeiffer R et al. 2014. ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene. Int. J. Cardiol. 171:431–42
    [Google Scholar]
  44. 44.
    Ishikawa T, Kimoto H, Mishima H, Yamagata K, Ogata S et al. 2021. Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome. Eur. Heart J. 42:2854–63
    [Google Scholar]
  45. 45.
    Juang J-MJ, Binda A, Lee S-J, Hwang J-J, Chen W-J et al. 2020. GSTM3 variant is a novel genetic modifier in Brugada syndrome, a disease with risk of sudden cardiac death. EBioMedicine 57:102843
    [Google Scholar]
  46. 46.
    Kapplinger JD, Giudicessi JR, Ye D, Tester DJ, Callis TE et al. 2015. Enhanced classification of Brugada syndrome–associated and long-QT syndrome–associated genetic variants in the SCN5A-encoded Nav1.5 cardiac sodium channel. Circ. Cardiovasc. Genet. 8:582–95
    [Google Scholar]
  47. 47.
    Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M et al. 2010. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm 7:33–46
    [Google Scholar]
  48. 48.
    Kattygnarath D, Maugenre S, Neyroud N, Balse E, Ichai C et al. 2011. MOG1: a new susceptibility gene for Brugada syndrome. Circ. Cardiovasc. Genet. 4:261–68
    [Google Scholar]
  49. 49.
    Kroncke BM, Glazer AM, Smith DK, Blume JD, Roden DM. 2018. SCN5A (NaV1.5) variant functional perturbation and clinical presentation: variants of a certain significance. Circ. Genom. Precis. Med. 11:e002095
    [Google Scholar]
  50. 50.
    Kyndt F, Probst V, Potet F, Demolombe S, Chevallier J-C et al. 2001. Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family. Circulation 104:3081–86
    [Google Scholar]
  51. 51.
    Laurent G, Saal S, Amarouch MY, Béziau DM, Marsman RFJ et al. 2012. Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy. J. Am. Coll. Cardiol. 60:144–56
    [Google Scholar]
  52. 52.
    Leo-Macias A, Agullo-Pascual E, Delmar M 2016. The cardiac connexome: non-canonical functions of connexin43 and their role in cardiac arrhythmias. Semin. Cell Dev. Biol. 50:13–21
    [Google Scholar]
  53. 53.
    Li W, Yin L, Shen C, Hu K, Ge J, Sun A. 2018. SCN5A variants: association with cardiac disorders. Front. Physiol. 9:1372
    [Google Scholar]
  54. 54.
    London B, Michalec M, Mehdi H, Zhu X, Kerchner L et al. 2007. Mutation in glycerol-3-phosphate dehydrogenase 1-like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias. Circulation 116:2260–68
    [Google Scholar]
  55. 55.
    Makarawate P, Chaosuwannakit N, Vannaprasaht S, Sahasthas D, Koo SH et al. 2017. SCN5A genetic polymorphisms associated with increased defibrillator shocks in Brugada syndrome. J. Am. Heart Assoc. 6:e005009
    [Google Scholar]
  56. 56.
    Makita N, Behr E, Shimizu W, Horie M, Sunami A et al. 2008. The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. J. Clin. Investig. 6:2219–29
    [Google Scholar]
  57. 57.
    Malhotra JD, Chen C, Rivolta I, Abriel H, Malhotra R et al. 2001. Characterization of sodium channel α- and β-subunits in rat and mouse cardiac myocytes. Circulation 103:1303–10
    [Google Scholar]
  58. 58.
    Matsumura H, Nakano Y, Ochi H, Onohara Y, Sairaku A et al. 2017. H558R, a common SCN5A polymorphism, modifies the clinical phenotype of Brugada syndrome by modulating DNA methylation of SCN5A promoters. J. Biomed. Sci. 24:91
    [Google Scholar]
  59. 59.
    Mazzanti A, Tenuta E, Marino M, Pagan E, Morini M et al. 2019. Efficacy and limitations of quinidine in patients with Brugada syndrome. Circ. Arrhythm. Electrophysiol. 12:e007143
    [Google Scholar]
  60. 60.
    McNair WP, Sinagra G, Taylor MRG, Di Lenarda A, Ferguson DA et al. 2011. SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism. J. Am. Coll. Cardiol. 57:2160–68
    [Google Scholar]
  61. 61.
    Meregalli PG, Tan HL, Probst V, Koopmann TT, Tanck MW et al. 2009. Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. Heart Rhythm 6:341–48
    [Google Scholar]
  62. 62.
    Meregalli PG, Wilde A, Tan H. 2005. Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more?. Cardiovasc. Res. 67:367–78
    [Google Scholar]
  63. 63.
    Miles C, Asimaki A, Ster IC, Papadakis M, Gray B et al. 2021. Biventricular myocardial fibrosis and sudden death in patients with Brugada syndrome. J. Am. Coll. Cardiol. 78:1511–21
    [Google Scholar]
  64. 64.
    Milman A, Andorin A, Gourraud J-B, Postema PG, Sacher F et al. 2018. Profile of patients with Brugada syndrome presenting with their first documented arrhythmic event: data from the Survey on Arrhythmic Events in BRUgada Syndrome (SABRUS). Heart Rhythm 15:716–24
    [Google Scholar]
  65. 65.
    Milman A, Behr ER, Gray B, Johnson DC, Andorin A et al. 2021. Genotype-phenotype correlation of SCN5A genotype in patients with Brugada syndrome and arrhythmic events: insights from the SABRUS in 392 probands. Circ. Genom. Precis. Med. 14:e003222
    [Google Scholar]
  66. 66.
    Nademanee K. 2021. Radiofrequency ablation in Brugada syndrome. Heart Rhythm 18:1805–6
    [Google Scholar]
  67. 67.
    Nademanee K, Raju H, de Noronha SV, Papadakis M, Robinson L et al. 2015. Fibrosis, connexin-43, and conduction abnormalities in the Brugada syndrome. J. Am. Coll. Cardiol. 66:1976–86
    [Google Scholar]
  68. 68.
    Nademanee K, Veerakul G, Chandanamattha P, Chaothawee L, Ariyachaipanich A et al. 2011. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation 123:1270–79
    [Google Scholar]
  69. 69.
    Nielsen MW, Holst AG, Olesen S-P, Olesen MS. 2013. The genetic component of Brugada syndrome. Front. Physiol. 4:179
    [Google Scholar]
  70. 70.
    Pieroni M, Notarstefano P, Oliva A, Campuzano O, Santangeli P et al. 2018. Electroanatomic and pathologic right ventricular outflow tract abnormalities in patients with Brugada syndrome. J. Am. Coll. Cardiol. 72:2747–57
    [Google Scholar]
  71. 71.
    Poli S, Toniolo M, Maiani M, Zanuttini D, Rebellato L et al. 2018. Management of untreatable ventricular arrhythmias during pharmacologic challenges with sodium channel blockers for suspected Brugada syndrome. Europace 20:234–42
    [Google Scholar]
  72. 72.
    Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M et al. 2015. 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Eur. Heart J. 36:2793–867
    [Google Scholar]
  73. 73.
    Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E et al. 2003. Risk stratification in the long-QT syndrome. N. Engl. J. Med. 348:1866–74
    [Google Scholar]
  74. 74.
    Priori SG, Wilde AA, Horie M, Cho Y, Behr ER et al. 2013. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 10:e85–108
    [Google Scholar]
  75. 75.
    Priori SG, Wilde AA, Horie M, Cho Y, Behr ER et al. 2013. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 10:1932–63
    [Google Scholar]
  76. 76.
    Probst V, Veltmann C, Eckardt L, Meregalli PG, Gaita F et al. 2010. Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada syndrome registry. Circulation 121:635–43
    [Google Scholar]
  77. 77.
    Probst V, Wilde AAM, Barc J, Sacher F, Babuty D et al. 2009. SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome. Circ. Cardiovasc. Genet. 2:552–57
    [Google Scholar]
  78. 78.
    Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP et al. 2015. ClinGen—the Clinical Genome Resource. N. Engl. J. Med. 372:2235–42
    [Google Scholar]
  79. 79.
    Remme CA. 2013. Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects: cardiac sodium channelopathy associated with SCN5A mutations. J. Physiol. 591:4099–116
    [Google Scholar]
  80. 80.
    Ritchie MD, Denny JC, Zuvich RL, Crawford DC, Schildcrout JS et al. 2013. Genome- and phenome-wide analyses of cardiac conduction identifies markers of arrhythmia risk. Circulation 127:1377–85
    [Google Scholar]
  81. 81.
    Riuró H, Beltran-Alvarez P, Tarradas A, Selga E, Campuzano O et al. 2013. A missense mutation in the sodium channel β2 subunit reveals SCN2B as a new candidate gene for Brugada syndrome. Hum. Mutat. 34:961–66
    [Google Scholar]
  82. 82.
    Rizzo S, Lodder EM, Verkerk AO, Wolswinkel R, Beekman L et al. 2012. Intercalated disc abnormalities, reduced Na+ current density, and conduction slowing in desmoglein-2 mutant mice prior to cardiomyopathic changes. Cardiovasc. Res. 95:409–18
    [Google Scholar]
  83. 83.
    Sato PY, Coombs W, Lin X, Nekrasova O, Green KJ et al. 2011. Interactions between Ankyrin-G, Plakophilin-2, and Connexin43 at the cardiac intercalated disc. Circ. Res. 109:193–201
    [Google Scholar]
  84. 84.
    Sato PY, Musa H, Coombs W, Guerrero-Serna G, Patiño GA et al. 2009. Loss of plakophilin-2 expression leads to decreased sodium current and slower conduction velocity in cultured cardiac myocytes. Circ. Res. 105:523–26
    [Google Scholar]
  85. 85.
    Shinlapawittayatorn K, Du XX, Liu H, Ficker E, Kaufman ES, Deschênes I. 2011. A common SCN5A polymorphism modulates the biophysical defects of SCN5A mutations. Heart Rhythm 8:455–62
    [Google Scholar]
  86. 86.
    Shinlapawittayatorn K, Dudash LA, Du XX, Heller L, Poelzing S et al. 2011. A novel strategy using cardiac sodium channel polymorphic fragments to rescue trafficking-deficient SCN5A mutations. Circ. Cardiovasc. Genet. 4:500–9
    [Google Scholar]
  87. 87.
    Smits JPP, Eckardt L, Probst V, Bezzina CR, Schott JJ et al. 2002. Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J. Am. Coll. Cardiol. 40:350–56
    [Google Scholar]
  88. 88.
    Sonoda K, Ohno S, Ozawa J, Hayano M, Hattori T et al. 2018. Copy number variations of SCN5A in Brugada syndrome. Heart Rhythm 15:1179–88
    [Google Scholar]
  89. 89.
    Tadros R, Tan HL ESCAPE-NET Investig ., el Mathari S, Kors JA et al. 2019. Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores. Eur. Heart J. 40:3097–107
    [Google Scholar]
  90. 90.
    Tarradas A, Pinsach-Abuin M, Mackintosh C, Llorà-Batlle O, Pérez-Serra A et al. 2017. Transcriptional regulation of the sodium channel gene (SCN5A) by GATA4 in human heart. J. Mol. Cell. Cardiol. 102:74–82
    [Google Scholar]
  91. 91.
    te Riele ASJM, Agullo-Pascual E, James CA, Leo-Macias A, Cerrone M et al. 2017. Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis. Cardiovasc. Res. 113:102–11
    [Google Scholar]
  92. 92.
    Veerman CC, Podliesna S, Tadros R, Lodder EM, Mengarelli I et al. 2017. The Brugada syndrome susceptibility gene HEY2 modulates cardiac transmural ion channel patterning and electrical heterogeneity. Circ. Res. 121:537–48
    [Google Scholar]
  93. 93.
    Verbanck M, Chen C-Y, Neale B, Do R 2018. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat. Genet. 50:693–98
    [Google Scholar]
  94. 94.
    Watanabe H, Koopmann TT, Le Scouarnec S, Yang T, Ingram CR et al. 2008. Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. J. Clin. Investig. 118:2260–68
    [Google Scholar]
  95. 95.
    Wijeyeratne YD, Tanck MW, Mizusawa Y, Batchvarov V, Barc J et al. 2020. SCN5A mutation type and a genetic risk score associate variably with Brugada syndrome phenotype in SCN5A families. Circ. Genom. Precis. Med. 13:e002911
    [Google Scholar]
  96. 96.
    Wilde AAM, Amin AS. 2018. Clinical spectrum of SCN5A mutations. JACC Clin. Electrophysiol. 4:569–79
    [Google Scholar]
  97. 97.
    Wilde AAM, Brugada R. 2011. Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac sodium channel. Circ. Res. 108:884–97
    [Google Scholar]
  98. 98.
    Wilde AAM, Postema PG, Di Diego JM, Viskin S, Morita H et al. 2010. The pathophysiological mechanism underlying Brugada syndrome. J. Mol. Cell. Cardiol. 49:543–53
    [Google Scholar]
  99. 99.
    Yagihara N, Watanabe H, Barnett P, Duboscq-Bidot L, Thomas AC et al. 2016. Variants in the SCN5A promoter associated with various arrhythmia phenotypes. J. Am. Heart Assoc. 5:e003644
    [Google Scholar]
  100. 100.
    Yang P, Kupershmidt S, Roden DM. 2004. Cloning and initial characterization of the human cardiac sodium channel (SCN5A) promoter. Cardiovasc. Res. 61:56–65
    [Google Scholar]
  101. 101.
    Zhang Z-S, Tranquillo J, Neplioueva V, Bursac N, Grant AO. 2007. Sodium channel kinetic changes that produce Brugada syndrome or progressive cardiac conduction system disease. Am. J. Physiol. Heart Circ. Physiol. 292:H399–407
    [Google Scholar]
  102. 102.
    Zumhagen S, Spieker T, Rolinck J, Baba HA, Breithardt G et al. 2009. Absence of pathognomonic or inflammatory patterns in cardiac biopsies from patients with Brugada syndrome. Circ. Arrhythm. Electrophysiol. 2:16–23
    [Google Scholar]
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