Abstract
Sequence variants in the ion channel genes KCNH2 and SCN5A may cause the cardiac disorder long QT syndrome (LQTS). This disorder is associated with incomplete penetrance and variable expression in KCNH2- or SCN5A-mutation carriers. Common genetic variants, if associated with a mutation, may affect the severity of this cardiac disorder. This study identified rare mutations in the cardiac ion channel genes KCNH2 and SCN5A in a SCD case, as well as in a LQTS-affected family with a history of SCD. Moreover, common variants were found to occur together within the same genes. These findings support the concept that common single-nucleotide polymorphisms (SNPs) in genes encoding cardiac ion channels can directly modulate the functional effect of mutations and therefore enhance or weaken the risk of cardiac events.
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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 (2009) Prevalence of the congenital long-QT syndrome. Circulation 120(18):1761–1767. https://doi.org/10.1161/CIRCULATIONAHA.109.863209
Schwartz PJ, Moss AJ, Vincent GM, Crampton RS (1993) Diagnostic criteria for the long QT syndrome. An update. Circulation 88(2):782–784. https://doi.org/10.1161/01.CIR.88.2.782
Mizusawa Y, Horie M, Am WA (2014) Genetic and clinical advances in congenital long QT syndrome. Circ J 78(12):2827–2833. https://doi.org/10.1253/circj.CJ-14-0905
Splawski I, Shen J, Timothy KW, Vincent GM, Lehmann MH, Keating MT (1998) Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1. Genomics 51(1):86–97. https://doi.org/10.1006/geno.1998.5361
Curran ME, Splawski I, Timothy KW, Vincen G, Green ED, Keating MTA (1995) Molecular basis for cardiac arrhythmia. HERG mutations cause long QT syndrome. Cell 80(5):795–803. https://doi.org/10.1016/0092-8674(95)90358-5
Wang Q, Zhizhong L, Jiaxiang S, Keating MT (1996) Genomic organization of the human SCN5A gene encoding the cardiac sodium channel. Genomics 34(1):9–16. https://doi.org/10.1006/geno.1996.0236
Sanguinetti MC, Jiang C, Curran ME, Keating MTA (1995) Mechanistic link between an inherited and an acquired cardiac arrhythmia. HERG encodes the IKr potassium channel. Cell 81(2):299–307. https://doi.org/10.1016/0092-8674(95)90340-2
Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA, Keating MT (1995) SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80(5):805–811. https://doi.org/10.1016/0092-8674(95)90359-3
Giudicessi JR, Ackerman MJ (2013) Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes. Transl Res 161(1):1–14. https://doi.org/10.1016/j.trsl.2012.08.005
Locati EH, Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Lehmann MH, Towbin JA, Priori SG, Napolitano C, Robinson JL, Andrews M, Timothy K, Hall WJ (1998) Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome. Findings from the International LQTS Registry. Circulation 97(22):2237–2244. https://doi.org/10.1161/01.CIR.97.22.2237
Sakaguchi T, Shimizu W, Itoh H, Noda T, Miyamoto Y, Nagaoka I et al (2008) Age- and genotype-specific triggers for life-threatening arrhythmia in the genotyped long QT syndrome. J Cardiovasc Electrophysiol 19(8):794–799. https://doi.org/10.1111/j.1540-8167.2008.01138.x
Amin AS, Pinto YM, Wilde AAM (2013) Long QT syndrome: beyond the causal mutation. J Physiol Lond 591(17):4125–4139. https://doi.org/10.1113/jphysiol.2013.254920
Bezzina CA (2003) Common polymorphism in KCNH2 (HERG) hastens cardiac repolarization. Cardiovasc Res 59(1):27–36. https://doi.org/10.1016/S0008-6363(03)00342-0
Pfeufer A (2005) Common variants in myocardial ion channel genes modify the QT interval in the general population: results from the KORA study. Circ Res 96(6):693–701. https://doi.org/10.1161/01.RES.0000161077.53751.e6
Crotti L, Lundquist AL, Insolia R, Pedrazzini M, Ferrandi C, de Ferrari GM et al (2005) KCNH2-K897T is a genetic modifier of latent congenital long-QT syndrome. Circulation 112(9):1251–1258. https://doi.org/10.1161/CIRCULATIONAHA.105.549071
Gouas L, Nicaud V, Berthet M, Forhan A, Tiret L, Balkau B et al (2005) Association of KCNQ1, KCNE1, KCNH2 and SCN5A polymorphisms with QTc interval length in a healthy population. Eur J Hum Genet 13(11):1213–1222. https://doi.org/10.1038/sj.ejhg.5201489
Amin AS, Giudicessi JR, Tijsen AJ, Spanjaart AM, Reckman YJ, Klemens CA, Tanck MW, Kapplinger JD, Hofman N, Sinner MF, Müller M, Wijnen WJ, Tan HL, Bezzina CR, Creemers EE, Wilde AAM, Ackerman MJ, Pinto YM (2012) Variants in the 3′ untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner. Eur Heart J 33(6):714–723. https://doi.org/10.1093/eurheartj/ehr473
Jenewein T, Beckmann BM, Rose S, Osterhues HH, Schmidt U, Wolpert C, Miny P, Marschall C, Alders M, Bezzina CR, Wilde AAM, Kääb S, Kauferstein S (2017) Genotype-phenotype dilemma in a case of sudden cardiac death with the E1053K mutation and a deletion in the SCN5A gene. Forensic Sci Int 275:187–194. https://doi.org/10.1016/j.forsciint.2017.02.038
Kauferstein S, Herz N, Scheiper S, Biel S, Jenewein T, Kunis M, Erkapic D, Beckmann BM, Neumann T (2017) Relevance of molecular testing in patients with a family history of sudden death. Forensic Sci Int 276:18–23. https://doi.org/10.1016/j.forsciint.2017.04.001
Kauferstein S, Kiehne N, Jenewein T, Biel S, Kopp M, König R, Erkapic D, Rothschild M, Neumann T (2013) Genetic analysis of sudden unexplained death: a multidisciplinary approach. Forensic Sci Int 229(1-3):122–127. https://doi.org/10.1016/j.forsciint.2013.03.050
Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT (2000) Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 102(10):1178–1185. https://doi.org/10.1161/01.CIR.102.10.1178
Tiso N, Stephan DA, Nava A, Bagattin A, Devaney JM, Stanchi F, Larderet G, Brahmbhatt B, Brown K, Bauce B, Muriago M, Basso C, Thiene G, Danieli GA, Rampazzo A (2001) Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet 10(3):189–194. https://doi.org/10.1093/hmg/10.3.189
C-W L, Lin J-H, Rajawat YS, Jerng H, Rami TG, Sanchez X et al (2006) Functional and clinical characterization of a mutation in KCNJ2 associated with Andersen-Tawil syndrome. J Med Genet 43:653–659
Tester DJ, Valdivia C, Harris-Kerr C, Alders M, Salisbury BA, Wilde AA et al (2010) Epidemiologic, molecular, and functional evidence suggest A572D-SCN5A should not be considered an independent LQT3-susceptibility mutation. Heart Rhythm 7(7):912–919. https://doi.org/10.1016/j.hrthm.2010.04.014
Schwartz PJ, Moss AJ, Vincent GM, Crampton RS (1993) Diagnostic criteria for the long QT syndrome. An update. Circulation 88(2):782–784. https://doi.org/10.1161/01.CIR.88.2.782
Sy RW, van der Werf C, Chattha IS, Chockalingam P, Adler A, Healey JS, Perrin M, Gollob MH, Skanes AC, Yee R, Gula LJ, Leong-Sit P, Viskin S, Klein GJ, Wilde AA, Krahn AD (2011) Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands. Circulation 124(20):2187–2194. https://doi.org/10.1161/CIRCULATIONAHA.111.028258
Ortiz-Bonnin B, Rinne S, Moss R, Streit AK, Scharf M, Richter K et al (2016) Electrophysiological characterization of a large set of novel variants in the SCN5A-gene: identification of novel LQTS3 and BrS mutations. Pflugers Arch 468(8):1375–1387. https://doi.org/10.1007/s00424-016-1844-3
Paulussen A, Matthijs G, Gewillig M, Verhasselt P, Cohen N, Aerssens J (2003) Mutation analysis in congenital long QT syndrome—a case with missense mutations in KCNQ1 and SCN5A. Genet Test 7(1):57–61. https://doi.org/10.1089/109065703321560958
Tester DJ, Will ML, Haglund CM, Ackerman MJ (2005) Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm 2(5):507–517. https://doi.org/10.1016/j.hrthm.2005.01.020
Shinlapawittayatorn K, XX D, Liu H, Ficker E, Kaufman ES, Deschênes IA (2011) Common SCN5A polymorphism modulates the biophysical defects of SCN5A mutations. Heart Rhythm 8(3):455–462. https://doi.org/10.1016/j.hrthm.2010.11.034
Kauferstein S, Kiehne N, Peigneur S, Tytgat J, Bratzke H (2013) Cardiac channelopathy causing sudden death as revealed by molecular autopsy. Int J Legal Med 127(1):145–151. https://doi.org/10.1007/s00414-012-0679-5
Teng S, Ma L, Dong Y, Lin C, Ye J, Bahring R et al (2004) Clinical and electrophysiological characterization of a novel mutation R863X in HERG C-terminus associated with long QT syndrome. J Mol Med (Berl) 82(3):189–196. https://doi.org/10.1007/s00109-003-0504-1
Newton-Cheh C, Guo C-Y, Larson MG, Musone SL, Surti A, Camargo AL, Drake JA, Benjamin EJ, Levy D, D'Agostino RB, Hirschhorn JN, O'Donnell CJ (2007) Common genetic variation in KCNH2 is associated with QT interval duration: the Framingham Heart Study. Circulation 116(10):1128–1136. https://doi.org/10.1161/CIRCULATIONAHA.107.710780
Pietila E, Fodstad H, Niskasaari E, Laitinen PPJ, Swan H, Savolainen M et al (2002) Association between HERG K897T polymorphism and QT interval in middle-aged Finnish women. J Am Coll Cardiol 40(3):511–514. https://doi.org/10.1016/S0735-1097(02)01979-4
Koskela J, Laiho J, KaHonen M, Rontu R, Lehtinen R, Viik J et al (2008) Potassium channel KCNH2 K897T polymorphism and cardiac repolarization during exercise test: the Finnish Cardiovascular Study. Scand J Clin Lab Invest 68(1):31–38. https://doi.org/10.1080/00365510701496488
Zhang X, Chen S, Zhang L, Liu M, Redfearn S, Bryant RM, Oberti C, Vincent GM, Wang QK (2008) Protective effect of KCNH2 single nucleotide polymorphism K897T in LQTS families and identification of novel KCNQ1 and KCNH2 mutations. BMC Med Genet 9(1):87. https://doi.org/10.1186/1471-2350-9-87
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We thank the Foundation Forensisches Forum and the Feith Foundation for supporting this work.
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Jenewein, T., Neumann, T., Erkapic, D. et al. Influence of genetic modifiers on sudden cardiac death cases. Int J Legal Med 132, 379–385 (2018). https://doi.org/10.1007/s00414-017-1739-7
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DOI: https://doi.org/10.1007/s00414-017-1739-7