Advertisement

Heart Genomics pp 241-280 | Cite as

Progress of Genomics in Cardiac Conduction and Rhythm Disorders

  • Zhenyan Xu
  • Qinmei Xiong
  • Yang Shen
  • Jinzhu Hu
  • Kui Hong
Chapter
Part of the Translational Bioinformatics book series (TRBIO, volume 16)

Abstract

Genes and genetic loci linked thus far to cardiac electrical function and arrhythmia have been primarily uncovered through numerous studies. The contribution of epigenetics to heart rhythm disorders has also recently been highlighted in common pathologies. This chapter provides an overview to recent progress of genomics in cardiac conduction and rhythm disorders, including long QT syndrome (LQTS), Brugada syndrome (BrS), short QT syndrome (SQT), catecholaminergic polymorphic ventricular tachycardias (CPVT), early repolarization syndrome (ERS), atrial fibrillation (AF), idiopathic ventricular fibrillation (IVF), progressive cardiac conduction defect (PCCD), and sick sinus syndrome (SSS). After a brief introduction of each disorder, the disease-associated implication of genetic variations will be illustrated comprehensively. It can be found that there is marked genotype heterogeneity and cardiac phenotype heterogeneity in this field. Finally, the impact of genetics on clinical management of cardiac conduction and rhythm disorders will be summarized, including elucidation of an individual’s genetic predisposition and personalized approaches to treatment.

Keywords

Long QT syndrome Brugada syndrome Short QT syndrome Catecholaminergic polymorphic ventricular tachycardias Early repolarization syndrome Atrial fibrillation Idiopathic ventricular fibrillation Progressive cardiac conduction defect Sick sinus syndrome Genetic variation Genomics 

References

  1. Abriel H. Cardiac sodium channel Na(v)1.5 and interacting proteins: physiology and pathophysiology. J Mol Cell Cardiol. 2010;48(1):2–11.PubMedCrossRefGoogle Scholar
  2. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011;8(8):1308–39.PubMedCrossRefGoogle Scholar
  3. Akai J, Makita N, Sakurada H, Shirai N, Ueda K, Kitabatake A, Nakazawa K, Kimura A, Hiraoka M. A novel SCN5A mutation associated with idiopathic ventricular fibrillation without typical ECG findings of Brugada syndrome. FEBS Lett. 2000;479(1–2):29–34.PubMedCrossRefGoogle Scholar
  4. Alders M, Koopmann TT, Christiaans I, Postema PG, Beekman L, Tanck MW, Zeppenfeld K, Loh P, Koch KT, Demolombe S, Mannens MM, Bezzina CR, Wilde AA. Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation. Am J Hum Genet. 2009;84(4):468–76.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Angrist M, Chandrasekharan S, Heaney C, Cook-Deegan R. Impact of gene patents and licensing practices on access to genetic testing for long QT syndrome. Genet Med. 2010;12(4):S111–54.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez RA, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the second consensus conference. Heart Rhythm. 2005;2(4):429–40.PubMedCrossRefGoogle Scholar
  7. Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B, Gelber P, Bonaros EJ, Burashnikov E, Wu Y, Sargent JD, Schickel S, Oberheiden R, Bhatia A, Hsu LF, Haissaguerre M, Schimpf R, Borggrefe M, Wolpert C. 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. 2007;115(4):442–9.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Barajas-Martinez H, Hu D, Ferrer T, Onetti CG, Wu Y, Burashnikov E, Boyle M, Surman T, Urrutia J, Veltmann C, Schimpf R, Borggrefe M, Wolpert C, Ibrahim BB, Sanchez-Chapula JA, Winters S, Haissaguerre M, Antzelevitch C. Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8. Heart Rhythm. 2012;9(4):548–55.PubMedCrossRefGoogle Scholar
  9. Barsheshet A, Goldenberg I, O-Uchi J, Moss AJ, Jons C, Shimizu W, Wilde AA, McNitt S, Peterson DR, Zareba W, Robinson JL, Ackerman MJ, Cypress M, Gray DA, Hofman N, Kanters JK, Kaufman ES, Platonov PG, Qi M, Towbin JA, Vincent GM, Lopes CM. Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to beta-blocker therapy in type 1 long-QT syndrome. Circulation. 2012;125(16):1988–96.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Baruteau AE, Probst V, Abriel H. Inherited progressive cardiac conduction disorders. Curr Opin Cardiol. 2015;30(1):33–9.PubMedCrossRefGoogle Scholar
  11. Beavers DL, Wang W, Ather S, Voigt N, Garbino A, Dixit SS, Landstrom AP, Li N, Wang Q, Olivotto I, Dobrev D, Ackerman MJ, Wehrens X. Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization. J Am Coll Cardiol. 2013;62(21):2010–9.PubMedCrossRefGoogle Scholar
  12. Behr ER, Savio-Galimberti E, Barc J, Holst AG, Petropoulou E, Prins BP, Jabbari J, Torchio M, Berthet M, Mizusawa Y, Yang T, Nannenberg EA, Dagradi F, Weeke P, Bastiaenan R, Ackerman MJ, Haunso S, Leenhardt A, Kaab S, Probst V, Redon R, Sharma S, Wilde A, Tfelt-Hansen J, Schwartz P, Roden DM, Bezzina CR, Olesen M, Darbar D, Guicheney P, Crotti L, Jamshidi Y. Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study. Cardiovasc Res. 2015;106(3):520–9.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Bellocq C, van Ginneken AC, Bezzina CR, Alders M, Escande D, Mannens MM, Baro I, Wilde AA. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation. 2004;109(20):2394–7.PubMedCrossRefGoogle Scholar
  14. Berg KJ. Multifocal ventricular extrasystoles with Adams-Stokes syndrome in siblings. Am Heart J. 1960;60(6):965–70.CrossRefGoogle Scholar
  15. Bezzina CR, Barc J, Mizusawa Y, Remme CA, Gourraud JB, Simonet F, Verkerk AO, Schwartz PJ, Crotti L, Dagradi F, Guicheney P, Fressart V, Leenhardt A, Antzelevitch C, Bartkowiak S, Borggrefe M, Schimpf R, Schulze-Bahr E, Zumhagen S, Behr ER, Bastiaenen R, Tfelt-Hansen J, Olesen MS, Kaab S, Beckmann BM, Weeke P, Watanabe H, Endo N, Minamino T, Horie M, Ohno S, Hasegawa K, Makita N, Nogami A, Shimizu W, Aiba T, Froguel P, Balkau B, Lantieri O, Torchio M, Wiese C, Weber D, Wolswinkel R, Coronel R, Boukens BJ, Bezieau S, Charpentier E, Chatel S, Despres A, Gros F, Kyndt F, Lecointe S, Lindenbaum P, Portero V, Violleau J, Gessler M, Tan HL, Roden DM, Christoffels VM, Le Marec H, Wilde AA, Probst V, Schott JJ, Dina C, Redon R. Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nat Genet. 2013;45(9):1044–9.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Bhuiyan ZA, van den Berg MP, van Tintelen JP, Bink-Boelkens MT, Wiesfeld AC, Alders M, Postma AV, van Langen I, Mannens MM, Wilde AA. Expanding spectrum of human RYR2-related disease: new electrocardiographic, structural, and genetic features. Circulation. 2007;116(14):1569–76.PubMedCrossRefGoogle Scholar
  17. Boczek NJ, Ye D, Johnson EK, Wang W, Crotti L, Tester DJ, Dagradi F, Mizusawa Y, Torchio M, Alders M, Giudicessi JR, Wilde AA, Schwartz PJ, Nerbonne JM, Ackerman MJ. Characterization of SEMA3A-encoded semaphorin as a naturally occurring Kv4.3 protein inhibitor and its contribution to Brugada syndrome. Circ Res. 2014;115(4):460–9.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Bogarapu S, Bleyl SB, Calhoun A, Viskochil D, Saarel EV, Everitt MD, Frank DU. Phenotype of a patient with contiguous deletion of TBX5 and TBX3: expanding the disease spectrum. Am J Med Genet A. 2014;164A(5):1304–9.PubMedCrossRefGoogle Scholar
  19. Brugada R, Tapscott T, Czernuszewicz GZ, Marian AJ, Iglesias A, Mont L, Brugada J, Girona J, Domingo A, Bachinski LL, Roberts R. Identification of a genetic locus for familial atrial fibrillation. N Engl J Med. 1997;336(13):905–11.PubMedCrossRefGoogle Scholar
  20. Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M, Menendez TM, Brugada J, Pollevick GD, Wolpert C, Burashnikov E, Matsuo K, Wu YS, Guerchicoff A, Bianchi F, Giustetto C, Schimpf R, Brugada P, Antzelevitch C. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation. 2004;109(1):30–5.PubMedCrossRefGoogle Scholar
  21. Brugada R, Campuzano O, Sarquella-Brugada G, Brugada J, Brugada P. Brugada syndrome. Methodist Debakey Cardiovasc J. 2014;10(1):25–8.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Burashnikov E, Pfeiffer R, Barajas-Martinez H, Delpon E, Hu D, Desai M, Borggrefe M, Haissaguerre M, Kanter R, Pollevick GD, Guerchicoff A, Laino R, Marieb M, Nademanee K, Nam GB, Robles R, Schimpf R, Stapleton DD, Viskin S, Winters S, Wolpert C, Zimmern S, Veltmann C, Antzelevitch C. Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm. 2010;7(12):1872–82.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Cerrone M, Delmar M. Desmosomes and the sodium channel complex: implications for arrhythmogenic cardiomyopathy and Brugada syndrome. Trends Cardiovasc Med. 2014;24(5):184–90.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Cerrone M, Lin X, Zhang M, Agullo-Pascual E, Pfenniger A, Chkourko GH, Novelli V, Kim C, Tirasawadichai T, Judge DP, Rothenberg E, Chen HS, Napolitano C, Priori SG, Delmar M. Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype. Circulation. 2014;129(10):1092–103.PubMedCrossRefGoogle Scholar
  25. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R, Wang Z, Antzelevitch C, O’Brien RE, Schulze-Bahr E, Keating MT, Towbin JA, Wang Q. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998;392(6673):293–6.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY, Jin HW, Sun H, Su XY, Zhuang QN, Yang YQ, Li YB, Liu Y, Xu HJ, Li XF, Ma N, Mou CP, Chen Z, Barhanin J, Huang W. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003;299(5604):251–4.PubMedCrossRefGoogle Scholar
  27. Chen L, Marquardt ML, Tester DJ, Sampson KJ, Ackerman MJ, Kass RS. Mutation of an A-kinase-anchoring protein causes long-QT syndrome. Proc Natl Acad Sci U S A. 2007;104(52):20990–5.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Chen Y, Barajas-Martinez H, Zhu D, Wang X, Chen C, Zhuang R, Shi J, Wu X, Tao Y, Jin W, Wang X, Hu D. Novel trigenic CACNA1C/DES/MYPN mutations in a family of hypertrophic cardiomyopathy with early repolarization and short QT syndrome. J Transl Med. 2017;15(1):78.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Chinchilla A, Daimi H, Lozano-Velasco E, Dominguez JN, Caballero R, Delpon E, Tamargo J, Cinca J, Hove-Madsen L, Aranega AE, Franco D. PITX2 insufficiency leads to atrial electrical and structural remodeling linked to arrhythmogenesis. Circ Cardiovasc Genet. 2011;4(3):269–79.PubMedCrossRefGoogle Scholar
  30. Christophersen IE, Rienstra M, Roselli C, Yin X, Geelhoed B, Barnard J, Lin H, Arking DE, Smith AV, Albert CM, Chaffin M, Tucker NR, Li M, Klarin D, Bihlmeyer NA, Low SK, Weeke PE, Muller-Nurasyid M, Smith JG, Brody JA, Niemeijer MN, Dorr M, Trompet S, Huffman J, Gustafsson S, Schurmann C, Kleber ME, Lyytikainen LP, Seppala I, Malik R, Horimoto A, Perez M, Sinisalo J, Aeschbacher S, Theriault S, Yao J, Radmanesh F, Weiss S, Teumer A, Choi SH, Weng LC, Clauss S, Deo R, Rader DJ, Shah SH, Sun A, Hopewell JC, Debette S, Chauhan G, Yang Q, Worrall BB, Pare G, Kamatani Y, Hagemeijer YP, Verweij N, Siland JE, Kubo M, Smith JD, Van Wagoner DR, Bis JC, Perz S, Psaty BM, Ridker PM, Magnani JW, Harris TB, Launer LJ, Shoemaker MB, Padmanabhan S, Haessler J, Bartz TM, Waldenberger M, Lichtner P, Arendt M, Krieger JE, Kahonen M, Risch L, Mansur AJ, Peters A, Smith BH, Lind L, Scott SA, Lu Y, Bottinger EB, Hernesniemi J, Lindgren CM, Wong JA, Huang J, Eskola M, Morris AP, Ford I, Reiner AP, Delgado G, Chen LY, Chen YI, Sandhu RK, Li M, Boerwinkle E, Eisele L, Lannfelt L, Rost N, Anderson CD, Taylor KD, Campbell A, Magnusson PK, Porteous D, Hocking LJ, Vlachopoulou E, Pedersen NL, Nikus K, Orho-Melander M, Hamsten A, Heeringa J, Denny JC, Kriebel J, Darbar D, Newton-Cheh C, Shaffer C, Macfarlane PW, Heilmann-Heimbach S, Almgren P, Huang PL, Sotoodehnia N, Soliman EZ, Uitterlinden AG, Hofman A, Franco OH, Volker U, Jockel KH, Sinner MF, Lin HJ, Guo X, Dichgans M, Ingelsson E, Kooperberg C, Melander O, Loos R, Laurikka J, Conen D, Rosand J, van der Harst P, Lokki ML, Kathiresan S, Pereira A, Jukema JW, Hayward C, Rotter JI, Marz W, Lehtimaki T, Stricker BH, Chung MK, Felix SB, Gudnason V, Alonso A, Roden DM, Kaab S, Chasman DI, Heckbert SR, Benjamin EJ, Tanaka T, Lunetta KL, Lubitz SA, Ellinor PT. Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. Nat Genet. 2017;49(6):946–52.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Cordeiro JM, Marieb M, Pfeiffer R, Calloe K, Burashnikov E, Antzelevitch C. Accelerated inactivation of the L-type calcium current due to a mutation in CACNB2b underlies Brugada syndrome. J Mol Cell Cardiol. 2009;46(5):695–703.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Crotti L, Johnson CN, Graf E, De Ferrari GM, Cuneo BF, Ovadia M, Papagiannis J, Feldkamp MD, Rathi SG, Kunic JD, Pedrazzini M, Wieland T, Lichtner P, Beckmann BM, Clark T, Shaffer C, Benson DW, Kaab S, Meitinger T, Strom TM, Chazin WJ, Schwartz PJ, George AJ. Calmodulin mutations associated with recurrent cardiac arrest in infants. Circulation. 2013;127(9):1009–17.PubMedCrossRefGoogle Scholar
  33. Crozier IG, Loughnan A, Dow LJ, Low CJ, Ikram H. Congenital long QT syndrome in adults. N Z Med J. 1989;102(871):340–1.PubMedGoogle Scholar
  34. Daumy X, Amarouch MY, Lindenbaum P, Bonnaud S, Charpentier E, Bianchi B, Nafzger S, Baron E, Fouchard S, Thollet A, Kyndt F, Barc J, Le Scouarnec S, Makita N, Le Marec H, Dina C, Gourraud JB, Probst V, Abriel H, Redon R, Schott JJ. Targeted resequencing identifies TRPM4 as a major gene predisposing to progressive familial heart block type I. Int J Cardiol. 2016;207:349–58.PubMedCrossRefGoogle Scholar
  35. Delpon E, Cordeiro JM, Nunez L, Thomsen PE, Guerchicoff A, Pollevick GD, Wu Y, Kanters JK, Larsen CT, Hofman-Bang J, Burashnikov E, Christiansen M, Antzelevitch C. Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. Circ Arrhythm Electrophysiol. 2008;1(3):209–18.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Deo M, Ruan Y, Pandit SV, Shah K, Berenfeld O, Blaufox A, Cerrone M, Noujaim SF, Denegri M, Jalife J, Priori SG. KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia. Proc Natl Acad Sci U S A. 2013;110(11):4291–6.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Fukuyama M, Ohno S, Makiyama T, Horie M. Novel SCN10A variants associated with Brugada syndrome. Europace. 2016;18(6):905–11.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Giudicessi JR, Ye D, Tester DJ, Crotti L, Mugione A, Nesterenko VV, Albertson RM, Antzelevitch C, Schwartz PJ, Ackerman MJ. Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome. Heart Rhythm. 2011;8(7):1024–32.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Goldenberg I, Horr S, Moss AJ, Lopes CM, Barsheshet A, McNitt S, Zareba W, Andrews ML, Robinson JL, Locati EH, Ackerman MJ, Benhorin J, Kaufman ES, Napolitano C, Platonov PG, Priori SG, Qi M, Schwartz PJ, Shimizu W, Towbin JA, Vincent GM, Wilde AA, Zhang L. Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals. J Am Coll Cardiol. 2011;57(1):51–9.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Gudbjartsson DF, Arnar DO, Helgadottir A, Gretarsdottir S, Holm H, Sigurdsson A, Jonasdottir A, Baker A, Thorleifsson G, Kristjansson K, Palsson A, Blondal T, Sulem P, Backman VM, Hardarson GA, Palsdottir E, Helgason A, Sigurjonsdottir R, Sverrisson JT, Kostulas K, Ng MC, Baum L, So WY, Wong KS, Chan JC, Furie KL, Greenberg SM, Sale M, Kelly P, MacRae CA, Smith EE, Rosand J, Hillert J, Ma RC, Ellinor PT, Thorgeirsson G, Gulcher JR, Kong A, Thorsteinsdottir U, Stefansson K. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448(7151):353–7.PubMedCrossRefGoogle Scholar
  41. Guo Q, Ren L, Chen X, Hou C, Chu J, Pu J, Zhang S. A novel mutation in the SCN5A gene contributes to arrhythmogenic characteristics of early repolarization syndrome. Int J Mol Med. 2016;37(3):727–33.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Haissaguerre M, Chatel S, Sacher F, Weerasooriya R, Probst V, Loussouarn G, Horlitz M, Liersch R, Schulze-Bahr E, Wilde A, Kaab S, Koster J, Rudy Y, Le Marec H, Schott JJ. Ventricular fibrillation with prominent early repolarization associated with a rare variant of KCNJ8/KATP channel. J Cardiovasc Electrophysiol. 2009;20(1):93–8.PubMedCrossRefGoogle Scholar
  43. Harmer SC, Wilson AJ, Aldridge R, Tinker A. Mechanisms of disease pathogenesis in long QT syndrome type 5. Am J Phys Cell Phys. 2010;298(2):C263–73.CrossRefGoogle Scholar
  44. Hattori T, Makiyama T, Akao M, Ehara E, Ohno S, Iguchi M, Nishio Y, Sasaki K, Itoh H, Yokode M, Kita T, Horie M, Kimura T. A novel gain-of-function KCNJ2 mutation associated with short-QT syndrome impairs inward rectification of Kir2.1 currents. Cardiovasc Res. 2012;93(4):666–73.PubMedCrossRefGoogle Scholar
  45. Hayashi M, Denjoy I, Hayashi M, Extramiana F, Maltret A, Roux-Buisson N, Lupoglazoff JM, Klug D, Maury P, Messali A, Guicheney P, Leenhardt A. The role of stress test for predicting genetic mutations and future cardiac events in asymptomatic relatives of catecholaminergic polymorphic ventricular tachycardia probands. Europace. 2012;14(9):1344–51.PubMedCrossRefGoogle Scholar
  46. Hennessey JA, Marcou CA, Wang C, Wei EQ, Wang C, Tester DJ, Torchio M, Dagradi F, Crotti L, Schwartz PJ, Ackerman MJ, Pitt GS. FGF12 is a candidate Brugada syndrome locus. Heart Rhythm. 2013a;10(12):1886–94.PubMedCrossRefGoogle Scholar
  47. Hennessey JA, Wei EQ, Pitt GS. Fibroblast growth factor homologous factors modulate cardiac calcium channels. Circ Res. 2013b;113(4):381–8.PubMedCrossRefGoogle Scholar
  48. Holm H, Gudbjartsson DF, Sulem P, Masson G, Helgadottir HT, Zanon C, Magnusson OT, Helgason A, Saemundsdottir J, Gylfason A, Stefansdottir H, Gretarsdottir S, Matthiasson SE, Thorgeirsson GM, Jonasdottir A, Sigurdsson A, Stefansson H, Werge T, Rafnar T, Kiemeney LA, Parvez B, Muhammad R, Roden DM, Darbar D, Thorleifsson G, Walters GB, Kong A, Thorsteinsdottir U, Arnar DO, Stefansson K. A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nat Genet. 2011;43(4):316–20.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Hong K, Bjerregaard P, Gussak I, Brugada R. Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. J Cardiovasc Electrophysiol. 2005a;16(4):394–6.PubMedCrossRefGoogle Scholar
  50. Hong K, Piper DR, Diaz-Valdecantos A, Brugada J, Oliva A, Burashnikov E, Santos-de-Soto J, Grueso-Montero J, Diaz-Enfante E, Brugada P, Sachse F, Sanguinetti MC, Brugada R. De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero. Cardiovasc Res. 2005b;68(3):433–40.PubMedCrossRefGoogle Scholar
  51. Hong K, Hu J, Yu J, Brugada R. Concomitant Brugada-like and short QT electrocardiogram linked to SCN5A mutation. Eur J Hum Genet. 2012;20(11):1189–92.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Hu D, Barajas-Martinez H, Burashnikov E, Springer M, Wu Y, Varro A, Pfeiffer R, Koopmann TT, Cordeiro JM, Guerchicoff A, Pollevick GD, Antzelevitch C. A mutation in the beta 3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype. Circ Cardiovasc Genet. 2009;2(3):270–8.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Hu D, Barajas-Martinez H, Pfeiffer R, Dezi F, Pfeiffer J, Buch T, Betzenhauser MJ, Belardinelli L, Kahlig KM, Rajamani S, DeAntonio HJ, Myerburg RJ, Ito H, Deshmukh P, Marieb M, Nam GB, Bhatia A, Hasdemir C, Haissaguerre M, Veltmann C, Schimpf R, Borggrefe M, Viskin S, Antzelevitch C. Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome. J Am Coll Cardiol. 2014;64(1):66–79.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Ishikawa T, Sato A, Marcou CA, Tester DJ, Ackerman MJ, Crotti L, Schwartz PJ, On YK, Park JE, Nakamura K, Hiraoka M, Nakazawa K, Sakurada H, Arimura T, Makita N, Kimura A. A novel disease gene for Brugada syndrome: sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5. Circ Arrhythm Electrophysiol. 2012;5(6):1098–107.PubMedCrossRefGoogle Scholar
  55. Ishikawa T, Takahashi N, Ohno S, Sakurada H, Nakamura K, On YK, Park JE, Makiyama T, Horie M, Arimura T, Makita N, Kimura A. Novel SCN3B mutation associated with Brugada syndrome affects intracellular trafficking and function of Nav1.5. Circ J. 2013;77(4):959–67.PubMedCrossRefGoogle Scholar
  56. Ishikawa T, Jou CJ, Nogami A, Kowase S, Arrington CB, Barnett SM, Harrell DT, Arimura T, Tsuji Y, Kimura A, Makita N. Novel mutation in the alpha-myosin heavy chain gene is associated with sick sinus syndrome. Circ Arrhythm Electrophysiol. 2015;8(2):400–8.PubMedCrossRefGoogle Scholar
  57. Itoh H, Sakaguchi T, Ashihara T, Ding WG, Nagaoka I, Oka Y, Nakazawa Y, Yao T, Jo H, Ito M, Nakamura K, Ohe T, Matsuura H, Horie M. A novel KCNH2 mutation as a modifier for short QT interval. Int J Cardiol. 2009;137(1):83–5.PubMedCrossRefGoogle Scholar
  58. Jensen PN, Gronroos NN, Chen LY, Folsom AR, DeFilippi C, Heckbert SR, Alonso A. Incidence of and risk factors for sick sinus syndrome in the general population. J Am Coll Cardiol. 2014;64(6):531–8.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Jiang D, Xiao B, Yang D, Wang R, Choi P, Zhang L, Cheng H, Chen SR. RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR). Proc Natl Acad Sci U S A. 2004;101(35):13062–7.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Jiang D, Chen W, Wang R, Zhang L, Chen SR. Loss of luminal Ca2+ activation in the cardiac ryanodine receptor is associated with ventricular fibrillation and sudden death. Proc Natl Acad Sci U S A. 2007;104(46):18309–14.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Jons C, Moss AJ, Goldenberg I, Liu J, McNitt S, Zareba W, Qi M, Robinson JL. Risk of fatal arrhythmic events in long QT syndrome patients after syncope. J Am Coll Cardiol. 2010;55(8):783–8.PubMedCrossRefGoogle Scholar
  62. Kattygnarath D, Maugenre S, Neyroud N, Balse E, Ichai C, Denjoy I, Dilanian G, Martins RP, Fressart V, Berthet M, Schott JJ, Leenhardt A, Probst V, Le Marec H, Hainque B, Coulombe A, Hatem SN, Guicheney P. MOG1: a new susceptibility gene for Brugada syndrome. Circ Cardiovasc Genet. 2011;4(3):261–8.PubMedCrossRefGoogle Scholar
  63. Kawamura M, Ozawa T, Yao T, Ashihara T, Sugimoto Y, Yagi T, Itoh H, Ito M, Makiyama T, Horie M. Dynamic change in ST-segment and spontaneous occurrence of ventricular fibrillation in Brugada syndrome with a novel nonsense mutation in the SCN5A gene during long-term follow-up. Circ J. 2009;73(3):584–8.PubMedCrossRefGoogle Scholar
  64. Kazemian P, Gollob MH, Pantano A, Oudit GY. A novel mutation in the RYR2 gene leading to catecholaminergic polymorphic ventricular tachycardia and paroxysmal atrial fibrillation: dose-dependent arrhythmia-event suppression by beta-blocker therapy. Can J Cardiol. 2011;27(6):870–7.PubMedCrossRefGoogle Scholar
  65. Khera S, Jacobson JT. Short QT syndrome in current clinical practice. Cardiol Rev. 2016;24(4):190–3.PubMedCrossRefGoogle Scholar
  66. Krogh BA, Pedersen LN, Nielsen JC, Jensen HK. Ankyrin-2 variants associated with idiopathic ventricular fibrillation storm in patients with intermittent early repolarization pattern. Heart Rhythm Case Rep. 2015;1(5):337–41.CrossRefGoogle Scholar
  67. Kruse M, Pongs O. TRPM4 channels in the cardiovascular system. Curr Opin Pharmacol. 2014;15:68–73.PubMedCrossRefGoogle Scholar
  68. Kruse M, Schulze-Bahr E, Corfield V, Beckmann A, Stallmeyer B, Kurtbay G, Ohmert I, Schulze-Bahr E, Brink P, Pongs O. Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. J Clin Invest. 2009;119(9):2737–44.PubMedPubMedCentralCrossRefGoogle Scholar
  69. Lam L, Ingles J, Turner C, Kilborn M, Bagnall RD, Semsarian C. Exome sequencing identifies a novel mutation in the MYH6 gene in a family with early-onset sinus node dysfunction, ventricular arrhythmias, and cardiac arrest. Heart Rhythm Case Rep. 2015;1(3):141–5.CrossRefGoogle Scholar
  70. Le Scouarnec S, Bhasin N, Vieyres C, Hund TJ, Cunha SR, Koval O, Marionneau C, Chen B, Wu Y, Demolombe S, Song LS, Le Marec H, Probst V, Schott JJ, Anderson ME, Mohler PJ. Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease. Proc Natl Acad Sci U S A. 2008;105(40):15617–22.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Le Scouarnec S, Karakachoff M, Gourraud JB, Lindenbaum P, Bonnaud S, Portero V, Duboscq-Bidot L, Daumy X, Simonet F, Teusan R, Baron E, Violleau J, Persyn E, Bellanger L, Barc J, Chatel S, Martins R, Mabo P, Sacher F, Haissaguerre M, Kyndt F, Schmitt S, Bezieau S, Le Marec H, Dina C, Schott JJ, Probst V, Redon R. Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome. Hum Mol Genet. 2015;24(10):2757–63.PubMedCrossRefGoogle Scholar
  72. Lieve KV, van der Werf C, Wilde AA. Catecholaminergic polymorphic ventricular tachycardia. Circ J. 2016;80(6):1285–91.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Liu H, El ZL, Kruse M, Guinamard R, Beckmann A, Bozio A, Kurtbay G, Megarbane A, Ohmert I, Blaysat G, Villain E, Pongs O, Bouvagnet P. Gain-of-function mutations in TRPM4 cause autosomal dominant isolated cardiac conduction disease. Circ Cardiovasc Genet. 2010;3(4):374–85.PubMedCrossRefGoogle Scholar
  74. Liu H, Chatel S, Simard C, Syam N, Salle L, Probst V, Morel J, Millat G, Lopez M, Abriel H, Schott JJ, Guinamard R, Bouvagnet P. Molecular genetics and functional anomalies in a series of 248 Brugada cases with 11 mutations in the TRPM4 channel. PLoS One. 2013;8(1):e54131.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Liu M, Yang KC, Dudley SJ. Cardiac sodium channel mutations: why so many phenotypes? Nat Rev Cardiol. 2014;11(10):607–15.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Liu X, Shen Y, Xie J, Bao H, Cao Q, Wan R, Xu X, Zhou H, Huang L, Xu Z, Zhu W, Hu J, Cheng X, Hong K. A mutation in the CACNA1C gene leads to early repolarization syndrome with incomplete penetrance: a Chinese family study. PLoS One. 2017;12(5):e177532.Google Scholar
  77. London B, Michalec M, Mehdi H, Zhu X, Kerchner L, Sanyal S, Viswanathan PC, Pfahnl AE, Shang LL, Madhusudanan M, Baty CJ, Lagana S, Aleong R, Gutmann R, Ackerman MJ, McNamara DM, Weiss R, Dudley SJ. Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias. Circulation. 2007;116(20):2260–8.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Low SK, Takahashi A, Ebana Y, Ozaki K, Christophersen IE, Ellinor PT, Ogishima S, Yamamoto M, Satoh M, Sasaki M, Yamaji T, Iwasaki M, Tsugane S, Tanaka K, Naito M, Wakai K, Tanaka H, Furukawa T, Kubo M, Ito K, Kamatani Y, Tanaka T. Identification of six new genetic loci associated with atrial fibrillation in the Japanese population. Nat Genet. 2017;49(6):953–8.PubMedPubMedCentralCrossRefGoogle Scholar
  79. Makita N, Seki A, Sumitomo N, Chkourko H, Fukuhara S, Watanabe H, Shimizu W, Bezzina CR, Hasdemir C, Mugishima H, Makiyama T, Baruteau A, Baron E, Horie M, Hagiwara N, Wilde AA, Probst V, Le Marec H, Roden DM, Mochizuki N, Schott JJ, Delmar M. A connexin40 mutation associated with a malignant variant of progressive familial heart block type I. Circ Arrhythm Electrophysiol. 2012;5(1):163–72.PubMedPubMedCentralCrossRefGoogle Scholar
  80. Makita N, Yagihara N, Crotti L, Johnson CN, Beckmann BM, Roh MS, Shigemizu D, Lichtner P, Ishikawa T, Aiba T, Homfray T, Behr ER, Klug D, Denjoy I, Mastantuono E, Theisen D, Tsunoda T, Satake W, Toda T, Nakagawa H, Tsuji Y, Tsuchiya T, Yamamoto H, Miyamoto Y, Endo N, Kimura A, Ozaki K, Motomura H, Suda K, Tanaka T, Schwartz PJ, Meitinger T, Kaab S, Guicheney P, Shimizu W, Bhuiyan ZA, Watanabe H, Chazin WJ, George AJ. Novel calmodulin mutations associated with congenital arrhythmia susceptibility. Circ Cardiovasc Genet. 2014;7(4):466–74.PubMedPubMedCentralCrossRefGoogle Scholar
  81. Makiyama T, Akao M, Shizuta S, Doi T, Nishiyama K, Oka Y, Ohno S, Nishio Y, Tsuji K, Itoh H, Kimura T, Kita T, Horie M. A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation. J Am Coll Cardiol. 2008;52(16):1326–34.PubMedCrossRefGoogle Scholar
  82. Marsman RF, Bardai A, Postma AV, Res JC, Koopmann TT, Beekman L, van der Wal AC, Pinto YM, Lekanne DR, Wilde AA, Jordaens LJ, Bezzina CR. A complex double deletion in LMNA underlies progressive cardiac conduction disease, atrial arrhythmias, and sudden death. Circ Cardiovasc Genet. 2011;4(3):280–7.PubMedCrossRefGoogle Scholar
  83. Marsman RF, Barc J, Beekman L, Alders M, Dooijes D, van den Wijngaard A, Ratbi I, Sefiani A, Bhuiyan ZA, Wilde AA, Bezzina CR. A mutation in CALM1 encoding calmodulin in familial idiopathic ventricular fibrillation in childhood and adolescence. J Am Coll Cardiol. 2014;63(3):259–66.PubMedCrossRefGoogle Scholar
  84. McPate MJ, Duncan RS, Hancox JC, Witchel HJ. Pharmacology of the short QT syndrome N588K-hERG K+ channel mutation: differential impact on selected class I and class III antiarrhythmic drugs. Br J Pharmacol. 2008;155(6):957–66.PubMedPubMedCentralCrossRefGoogle Scholar
  85. Medeiros-Domingo A, Kaku T, Tester DJ, Iturralde-Torres P, Itty A, Ye B, Valdivia C, Ueda K, Canizales-Quinteros S, Tusie-Luna MT, Makielski JC, Ackerman MJ. SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome. Circulation. 2007;116(2):134–42.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Medeiros-Domingo A, Tan BH, Crotti L, Tester DJ, Eckhardt L, Cuoretti A, Kroboth SL, Song C, Zhou Q, Kopp D, Schwartz PJ, Makielski JC, Ackerman MJ. Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes. Heart Rhythm. 2010;7(10):1466–71.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Milanesi R, Bucchi A, Baruscotti M. The genetic basis for inherited forms of sinoatrial dysfunction and atrioventricular node dysfunction. J Interv Card Electrophysiol. 2015;43(2):121–34.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Mizusawa Y, Bezzina CR. Early repolarization pattern: its ECG characteristics, arrhythmogenicity and heritability. J Interv Card Electrophysiol. 2014;39(3):185–92.PubMedCrossRefGoogle Scholar
  89. Monfredi O, Boyett MR. Sick sinus syndrome and atrial fibrillation in older persons – a view from the sinoatrial nodal myocyte. J Mol Cell Cardiol. 2015;83:88–100.PubMedCrossRefGoogle Scholar
  90. Moss AJ, Zareba W, Kaufman ES, Gartman E, Peterson DR, Benhorin J, Towbin JA, Keating MT, Priori SG, Schwartz PJ, Vincent GM, Robinson JL, Andrews ML, Feng C, Hall WJ, Medina A, Zhang L, Wang Z. Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel. Circulation. 2002;105(7):794–9.PubMedCrossRefGoogle Scholar
  91. Moss AJ, Shimizu W, Wilde AA, Towbin JA, Zareba W, Robinson JL, Qi M, Vincent GM, Ackerman MJ, Kaufman ES, Hofman N, Seth R, Kamakura S, Miyamoto Y, Goldenberg I, Andrews ML, McNitt S. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007;115(19):2481–9.PubMedPubMedCentralCrossRefGoogle Scholar
  92. Nakano Y, Shimizu W. Genetics of long-QT syndrome. J Hum Genet. 2016;61(1):51–5.PubMedCrossRefGoogle Scholar
  93. Napolitano C, Antzelevitch C. Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac voltage-dependent L-type calcium channel. Circ Res. 2011;108(5):607–18.PubMedPubMedCentralCrossRefGoogle Scholar
  94. Nomikos M, Thanassoulas A, Beck K, Vassilakopoulou V, Hu H, Calver BL, Theodoridou M, Kashir J, Blayney L, Livaniou E, Rizkallah P, Nounesis G, Lai FA. Altered RyR2 regulation by the calmodulin F90L mutation associated with idiopathic ventricular fibrillation and early sudden cardiac death. FEBS Lett. 2014;588(17):2898–902.PubMedCrossRefGoogle Scholar
  95. Nyegaard M, Overgaard MT, Sondergaard MT, Vranas M, Behr ER, Hildebrandt LL, Lund J, Hedley PL, Camm AJ, Wettrell G, Fosdal I, Christiansen M, Borglum AD. Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death. Am J Hum Genet. 2012;91(4):703–12.PubMedPubMedCentralCrossRefGoogle Scholar
  96. Ohno S, Zankov DP, Ding WG, Itoh H, Makiyama T, Doi T, Shizuta S, Hattori T, Miyamoto A, Naiki N, Hancox JC, Matsuura H, Horie M. KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation. Circ Arrhythm Electrophysiol. 2011;4(3):352–61.PubMedCrossRefGoogle Scholar
  97. Olesen MS, Holst AG, Jabbari J, Nielsen JB, Christophersen IE, Sajadieh A, Haunso S, Svendsen JH. Genetic loci on chromosomes 4q25, 7p31, and 12p12 are associated with onset of lone atrial fibrillation before the age of 40 years. Can J Cardiol. 2012;28(2):191–5.PubMedCrossRefGoogle Scholar
  98. Olson TM, Alekseev AE, Liu XK, Park S, Zingman LV, Bienengraeber M, Sattiraju S, Ballew JD, Jahangir A, Terzic A. Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet. 2006;15(14):2185–91.PubMedCrossRefGoogle Scholar
  99. Paech C, Gebauer RA, Karstedt J, Marschall C, Bollmann A, Husser D. Ryanodine receptor mutations presenting as idiopathic ventricular fibrillation: a report on two novel familial compound mutations, c.6224T>C and c.13781A>G, with the clinical presentation of idiopathic ventricular fibrillation. Pediatr Cardiol. 2014;35(8):1437–41.PubMedCrossRefGoogle Scholar
  100. Pereira R, Campuzano O, Sarquella-Brugada G, Cesar S, Iglesias A, Brugada J, Cruz FF, Brugada R. Short QT syndrome in pediatrics. Clin Res Cardiol. 2017;106(6):393–400.PubMedCrossRefGoogle Scholar
  101. Pérez-Riera AR, Barbosa-Barros R, de Rezende Barbosa MPC, Daminello-Raimundo R, de Lucca AA Jr, de Abreu LC. Catecholaminergic polymorphic ventricular tachycardia, an update. Ann Noninvasive Electrocardiol. 2018 Jul;23(4):e12512.PubMedCrossRefGoogle Scholar
  102. Perrin MJ, Adler A, Green S, Al-Zoughool F, Doroshenko P, Orr N, Uppal S, Healey JS, Birnie D, Sanatani S, Gardner M, Champagne J, Simpson C, Ahmad K, van den Berg MP, Chauhan V, Backx PH, van Tintelen JP, Krahn AD, Gollob MH. Evaluation of genes encoding for the transient outward current (Ito) identifies the KCND2 gene as a cause of J-wave syndrome associated with sudden cardiac death. Circ Cardiovasc Genet. 2014;7(6):782–9.PubMedCrossRefGoogle Scholar
  103. Pfeufer A, van Noord C, Marciante KD, Arking DE, Larson MG, Smith AV, Tarasov KV, Muller M, Sotoodehnia N, Sinner MF, Verwoert GC, Li M, Kao WH, Kottgen A, Coresh J, Bis JC, Psaty BM, Rice K, Rotter JI, Rivadeneira F, Hofman A, Kors JA, Stricker BH, Uitterlinden AG, van Duijn CM, Beckmann BM, Sauter W, Gieger C, Lubitz SA, Newton-Cheh C, Wang TJ, Magnani JW, Schnabel RB, Chung MK, Barnard J, Smith JD, Van Wagoner DR, Vasan RS, Aspelund T, Eiriksdottir G, Harris TB, Launer LJ, Najjar SS, Lakatta E, Schlessinger D, Uda M, Abecasis GR, Muller-Myhsok B, Ehret GB, Boerwinkle E, Chakravarti A, Soliman EZ, Lunetta KL, Perz S, Wichmann HE, Meitinger T, Levy D, Gudnason V, Ellinor PT, Sanna S, Kaab S, Witteman JC, Alonso A, Benjamin EJ, Heckbert SR. Genome-wide association study of PR interval. Nat Genet. 2010;42(2):153–9.PubMedPubMedCentralCrossRefGoogle Scholar
  104. Postma AV, van de Meerakker JB, Mathijssen IB, Barnett P, Christoffels VM, Ilgun A, Lam J, Wilde AA, Lekanne DR, Moorman AF. A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation. Circ Res. 2008;102(11):1433–42.PubMedCrossRefGoogle Scholar
  105. Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001;103(2):196–200.PubMedCrossRefGoogle Scholar
  106. Priori SG, Pandit SV, Rivolta I, Berenfeld O, Ronchetti E, Dhamoon A, Napolitano C, Anumonwo J, di Barletta MR, Gudapakkam S, Bosi G, Stramba-Badiale M, Jalife J. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res. 2005;96(7):800–7.PubMedCrossRefGoogle Scholar
  107. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10(12):1932–63.PubMedCrossRefGoogle Scholar
  108. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekval TM, Spaulding C, Van Veldhuisen DJ. 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). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J. 2015;36(41):2793–867.CrossRefGoogle Scholar
  109. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekval TM, Spaulding C, Van Veldhuisen DJ. ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Rev Esp Cardiol (Engl Ed). 2016;69(2):176.CrossRefGoogle Scholar
  110. Riuro H, Beltran-Alvarez P, Tarradas A, Selga E, Campuzano O, Verges M, Pagans S, Iglesias A, Brugada J, Brugada P, Vazquez FM, Perez GJ, Scornik FS, Brugada R. A missense mutation in the sodium channel beta2 subunit reveals SCN2B as a new candidate gene for Brugada syndrome. Hum Mutat. 2013;34(7):961–6.PubMedCrossRefGoogle Scholar
  111. Robaei D, Ford T, Ooi SY. Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult. Heart Lung Circ. 2015;24(2):e31–4.PubMedCrossRefGoogle Scholar
  112. Rodriguez RD, Schocken DD. Update on sick sinus syndrome, a cardiac disorder of aging. Geriatrics. 1990;45(1):26–30. 33–6PubMedGoogle Scholar
  113. Roston TM, Vinocur JM, Maginot KR, Mohammed S, Salerno JC, Etheridge SP, Cohen M, Hamilton RM, Pflaumer A, Kanter RJ, Potts JE, LaPage MJ, Collins KK, Gebauer RA, Temple JD, Batra AS, Erickson C, Miszczak-Knecht M, Kubus P, Bar-Cohen Y, Kantoch M, Thomas VC, Hessling G, Anderson C, Young ML, Cabrera OM, Lau YR, Johnsrude CL, Fournier A, Kannankeril PJ, Sanatani S. Catecholaminergic polymorphic ventricular tachycardia in children: analysis of therapeutic strategies and outcomes from an international multicenter registry. Circ Arrhythm Electrophysiol. 2015;8(3):633–42.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Roston TM, Yuchi Z, Kannankeril PJ, Hathaway J, Vinocur JM, Etheridge SP, Potts JE, Maginot KR, Salerno JC, Cohen MI, Hamilton RM, Pflaumer A, Mohammed S, Kimlicka L, Kanter RJ, LaPage MJ, Collins KK, Gebauer RA, Temple JD, Batra AS, Erickson C, Miszczak-Knecht M, Kubus P, Bar-Cohen Y, Kantoch M, Thomas VC, Hessling G, Anderson C, Young ML, Choi S, Cabrera OM, Lau YR, Johnsrude CL, Fournier A, Van Petegem F, Sanatani S. The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: findings from an international multicentre registry. Europace. 2018;20(3):541–7.PubMedCrossRefGoogle Scholar
  115. Roux-Buisson N, Cacheux M, Fourest-Lieuvin A, Fauconnier J, Brocard J, Denjoy I, Durand P, Guicheney P, Kyndt F, Leenhardt A, Le Marec H, Lucet V, Mabo P, Probst V, Monnier N, Ray PF, Santoni E, Tremeaux P, Lacampagne A, Faure J, Lunardi J, Marty I. Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human. Hum Mol Genet. 2012;21(12):2759–67.PubMedPubMedCentralCrossRefGoogle Scholar
  116. Royer A, van Veen TA, Le Bouter S, Marionneau C, Griol-Charhbili V, Leoni AL, Steenman M, van Rijen HV, Demolombe S, Goddard CA, Richer C, Escoubet B, Jarry-Guichard T, Colledge WH, Gros D, de Bakker JM, Grace AA, Escande D, Charpentier F. Mouse model of SCN5A-linked hereditary Lenegre’s disease: age-related conduction slowing and myocardial fibrosis. Circulation. 2005;111(14):1738–46.PubMedCrossRefGoogle Scholar
  117. Schamroth L, Dove E. The Wenckebach phenomenon in sino-atrial block. Br Heart J. 1966;28(3):350–8.PubMedPubMedCentralCrossRefGoogle Scholar
  118. Schott JJ, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, Maron BJ, Seidman CE, Seidman JG. Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science. 1998;281(5373):108–11.PubMedPubMedCentralCrossRefGoogle Scholar
  119. Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999;23(1):20–1.PubMedPubMedCentralCrossRefGoogle Scholar
  120. Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino S, Mosca F, Nespoli L, Rimini A, Rosati E, Salice P, Spazzolini C. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120(18):1761–7.PubMedPubMedCentralCrossRefGoogle Scholar
  121. Seki A, Ishikawa T, Daumy X, Mishima H, Barc J, Sasaki R, Nishii K, Saito K, Urano M, Ohno S, Otsuki S, Kimoto H, Baruteau AE, Thollet A, Fouchard S, Bonnaud S, Parent P, Shibata Y, Perrin JP, Le Marec H, Hagiwara N, Mercier S, Horie M, Probst V, Yoshiura KI, Redon R, Schott JJ, Makita N. Progressive atrial conduction defects associated with bone malformation caused by a Connexin-45 mutation. J Am Coll Cardiol. 2017;70(3):358–70.PubMedCrossRefGoogle Scholar
  122. Shimizu W. The long QT syndrome: therapeutic implications of a genetic diagnosis. Cardiovasc Res. 2005;67(3):347–56.PubMedCrossRefGoogle Scholar
  123. Shimizu W, Horie M, Ohno S, Takenaka K, Yamaguchi M, Shimizu M, Washizuka T, Aizawa Y, Nakamura K, Ohe T, Aiba T, Miyamoto Y, Yoshimasa Y, Towbin JA, Priori SG, Kamakura S. Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: multicenter study in Japan. J Am Coll Cardiol. 2004;44(1):117–25.PubMedCrossRefGoogle Scholar
  124. Shimizu W, Moss AJ, Wilde AA, Towbin JA, Ackerman MJ, January CT, Tester DJ, Zareba W, Robinson JL, Qi M, Vincent GM, Kaufman ES, Hofman N, Noda T, Kamakura S, Miyamoto Y, Shah S, Amin V, Goldenberg I, Andrews ML, McNitt S. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol. 2009;54(22):2052–62.PubMedPubMedCentralCrossRefGoogle Scholar
  125. Shy D, Gillet L, Abriel H. Cardiac sodium channel NaV1.5 distribution in myocytes via interacting proteins: the multiple pool model. Biochim Biophys Acta. 2013;1833(4):886–94.PubMedCrossRefGoogle Scholar
  126. Sinner MF, Porthan K, Noseworthy PA, Havulinna AS, Tikkanen JT, Muller-Nurasyid M, Peloso G, Ulivi S, Beckmann BM, Brockhaus AC, Cooper RR, Gasparini P, Hengstenberg C, Hwang SJ, Iorio A, Junttila MJ, Klopp N, Kahonen M, Laaksonen MA, Lehtimaki T, Lichtner P, Lyytikainen LP, Martens E, Meisinger C, Meitinger T, Merchant FM, Nieminen MS, Peters A, Pietila A, Perz S, Oikarinen L, Raitakari O, Reinhard W, Silander K, Thorand B, Wichmann HE, Sinagra G, Viikari J, O’Donnell CJ, Ellinor PT, Huikuri HV, Kaab S, Newton-Cheh C, Salomaa V. A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern. Heart Rhythm. 2012;9(10):1627–34.PubMedPubMedCentralCrossRefGoogle Scholar
  127. Smits JP, Koopmann TT, Wilders R, Veldkamp MW, Opthof T, Bhuiyan ZA, Mannens MM, Balser JR, Tan HL, Bezzina CR, Wilde AA. A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families. J Mol Cell Cardiol. 2005;38(6):969–81.PubMedCrossRefGoogle Scholar
  128. Sun Y, Quan XQ, Fromme S, Cox RH, Zhang P, Zhang L, Guo D, Guo J, Patel C, Kowey PR, Yan GX. A novel mutation in the KCNH2 gene associated with short QT syndrome. J Mol Cell Cardiol. 2011;50(3):433–41.PubMedCrossRefGoogle Scholar
  129. Swan H, Piippo K, Viitasalo M, Heikkila P, Paavonen T, Kainulainen K, Kere J, Keto P, Kontula K, Toivonen L. Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J Am Coll Cardiol. 1999;34(7):2035–42.PubMedCrossRefGoogle Scholar
  130. Templin C, Ghadri JR, Rougier JS, Baumer A, Kaplan V, Albesa M, Sticht H, Rauch A, Puleo C, Hu D, Barajas-Martinez H, Antzelevitch C, Luscher TF, Abriel H, Duru F. Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6). Eur Heart J. 2011;32(9):1077–88.PubMedPubMedCentralCrossRefGoogle Scholar
  131. Ten SJ, Postema PG, Boekholdt SM, Tan HL, van der Heijden JF, de Groot NM, Volders PG, Zeppenfeld K, Boersma LV, Nannenberg EA, Christiaans I, Wilde AA. Detailed characterization of familial idiopathic ventricular fibrillation linked to the DPP6 locus. Heart Rhythm. 2016;13(4):905–12.CrossRefGoogle Scholar
  132. Thorsen K, Dam VS, Kjaer-Sorensen K, Pedersen LN, Skeberdis VA, Jurevicius J, Treinys R, Petersen I, Nielsen MS, Oxvig C, Morth JP, Matchkov VV, Aalkjaer C, Bundgaard H, Jensen HK. Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome. Nat Commun. 2017;8(1):1696.PubMedPubMedCentralCrossRefGoogle Scholar
  133. Ueda K, Hirano Y, Higashiuesato Y, Aizawa Y, Hayashi T, Inagaki N, Tana T, Ohya Y, Takishita S, Muratani H, Hiraoka M, Kimura A. Role of HCN4 channel in preventing ventricular arrhythmia. J Hum Genet. 2009;54(2):115–21.PubMedCrossRefGoogle Scholar
  134. Valdivia CR, Medeiros-Domingo A, Ye B, Shen WK, Algiers TJ, Ackerman MJ, Makielski JC. Loss-of-function mutation of the SCN3B-encoded sodium channel {beta}3 subunit associated with a case of idiopathic ventricular fibrillation. Cardiovasc Res. 2010;86(3):392–400.PubMedCrossRefGoogle Scholar
  135. Vatta M, Ackerman MJ, Ye B, Makielski JC, Ughanze EE, Taylor EW, Tester DJ, Balijepalli RC, Foell JD, Li Z, Kamp TJ, Towbin JA. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation. 2006;114(20):2104–12.PubMedCrossRefGoogle Scholar
  136. Wang C, Hennessey JA, Kirkton RD, Wang C, Graham V, Puranam RS, Rosenberg PB, Bursac N, Pitt GS. Fibroblast growth factor homologous factor 13 regulates Na+ channels and conduction velocity in murine hearts. Circ Res. 2011;109(7):775–82.PubMedPubMedCentralCrossRefGoogle Scholar
  137. Wang QI, Ohno S, Ding WG, Fukuyama M, Miyamoto A, Itoh H, Makiyama T, Wu J, Bai J, Hasegawa K, Shinohara T, Takahashi N, Shimizu A, Matsuura H, Horie M. Gain-of-function KCNH2 mutations in patients with Brugada syndrome. J Cardiovasc Electrophysiol. 2014;25(5):522–30.PubMedCrossRefGoogle Scholar
  138. Watanabe H, Koopmann TT, Le Scouarnec S, Yang T, Ingram CR, Schott JJ, Demolombe S, Probst V, Anselme F, Escande D, Wiesfeld AC, Pfeufer A, Kaab S, Wichmann HE, Hasdemir C, Aizawa Y, Wilde AA, Roden DM, Bezzina CR. Sodium channel beta1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. J Clin Invest. 2008;118(6):2260–8.PubMedPubMedCentralGoogle Scholar
  139. Watanabe H, Nogami A, Ohkubo K, Kawata H, Hayashi Y, Ishikawa T, Makiyama T, Nagao S, Yagihara N, Takehara N, Kawamura Y, Sato A, Okamura K, Hosaka Y, Sato M, Fukae S, Chinushi M, Oda H, Okabe M, Kimura A, Maemura K, Watanabe I, Kamakura S, Horie M, Aizawa Y, Shimizu W, Makita N. Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization. Circ Arrhythm Electrophysiol. 2011;4(6):874–81.PubMedCrossRefGoogle Scholar
  140. Whittaker DG, Ni H, El HA, Hancox JC, Zhang H. Atrial arrhythmogenicity of KCNJ2 mutations in short QT syndrome: insights from virtual human atria. PLoS Comput Biol. 2017;13(6):e1005593.PubMedPubMedCentralCrossRefGoogle Scholar
  141. Wilde A, Amin A. Channelopathies, genetic testing and risk stratification. Int J Cardiol. 2017;237:53–5.PubMedPubMedCentralCrossRefGoogle Scholar
  142. Wilde AA, Postema PG, Di Diego JM, Viskin S, Morita H, Fish JM, Antzelevitch C. The pathophysiological mechanism underlying Brugada syndrome: depolarization versus repolarization. J Mol Cell Cardiol. 2010;49(4):543–53.PubMedPubMedCentralCrossRefGoogle Scholar
  143. Wu ZJ, Huang Y, Fu YC, Zhao XJ, Zhu C, Zhang Y, Xu B, Zhu QL, Li Y. Characterization of a Chinese KCNQ1 mutation (R259H) that shortens repolarization and causes short QT syndrome 2. J Geriatr Cardiol. 2015;12(4):394–401.PubMedPubMedCentralGoogle Scholar
  144. Yang Y, Li J, Lin X, Yang Y, Hong K, Wang L, Liu J, Li L, Yan D, Liang D, Xiao J, Jin H, Wu J, Zhang Y, Chen YH. Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation. J Hum Genet. 2009;54(5):277–83.PubMedCrossRefGoogle Scholar
  145. Yang T, Yang P, Roden DM, Darbar D. Novel KCNA5 mutation implicates tyrosine kinase signaling in human atrial fibrillation. Heart Rhythm. 2010;7(9):1246–52.PubMedPubMedCentralCrossRefGoogle Scholar
  146. Yang YQ, Wang MY, Zhang XL, Tan HW, Shi HF, Jiang WF, Wang XH, Fang WY, Liu X. GATA4 loss-of-function mutations in familial atrial fibrillation. Clin Chim Acta. 2011;412(19–20):1825–30.PubMedCrossRefGoogle Scholar
  147. Yang YQ, Li L, Wang J, Zhang XL, Li RG, Xu YJ, Tan HW, Wang XH, Jiang JQ, Fang WY, Liu X. GATA6 loss-of-function mutation in atrial fibrillation. Eur J Med Genet. 2012a;55(10):520–6.PubMedCrossRefGoogle Scholar
  148. Yang YQ, Wang J, Wang XH, Wang Q, Tan HW, Zhang M, Shen FF, Jiang JQ, Fang WY, Liu X. Mutational spectrum of the GATA5 gene associated with familial atrial fibrillation. Int J Cardiol. 2012b;157(2):305–7.CrossRefGoogle Scholar
  149. Yu R, Fan XF, Chen C, Liu ZH. Whole exome sequencing identifies a novel mutation (R367G) in SCN5A to be associated with familial cardiac conduction disease. Mol Med Rep. 2017;16(1):410–4.PubMedCrossRefGoogle Scholar
  150. Zhabyeyev P, Hiess F, Wang R, Liu Y, Wayne CS, Oudit GY. S4153R is a gain-of-function mutation in the cardiac Ca(2+) release channel ryanodine receptor associated with catecholaminergic polymorphic ventricular tachycardia and paroxysmal atrial fibrillation. Can J Cardiol. 2013;29(8):993–6.PubMedCrossRefGoogle Scholar
  151. Zhao J, Yao H, Li Z, Wang L, Liu G, Wang DW, Wang DW, Liang Z. A novel nonsense mutation in LMNA gene identified by exome sequencing in an atrial fibrillation family. Eur J Med Genet. 2016;59(8):396–400.PubMedCrossRefGoogle Scholar
  152. Zumhagen S, Stallmeyer B, Friedrich C, Eckardt L, Seebohm G, Schulze-Bahr E. Inherited long QT syndrome. Herzschrittmacherther Elektrophysiol. 2012;23(3):211–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Zhenyan Xu
    • 1
    • 2
  • Qinmei Xiong
    • 1
  • Yang Shen
    • 2
    • 3
  • Jinzhu Hu
    • 1
  • Kui Hong
    • 1
    • 2
    • 3
  1. 1.Department of Cardiovascular MedicineThe Second Affiliated Hospital of Nanchang UniversityNanchang of JiangxiChina
  2. 2.Department of Genetic MedicineThe Second Affiliated Hospital of Nanchang UniversityNanchang of JiangxiChina
  3. 3.Jiangxi Key Laboratory of Molecular MedicineNanchang of JiangxiChina

Personalised recommendations