Advertisement

Genetic Testing for Inheritable Cardiac Channelopathies

  • Florence Kyndt
  • Jean-Baptiste Gourraud
  • Julien Barc
Chapter
Part of the Cardiac and Vascular Biology book series (Abbreviated title: Card. vasc. biol.)

Abstract

Inheritable cardiac channelopathies (ICC) are defined as primary electrical disorders without identifiable cardiac structural abnormalities and are mostly encountered in young adults (under 40 years). Diagnosis of ICC is often established after the first symptoms such as recurrent palpitations and syncope or more dramatically after unexplained sudden cardiac death (SCD). In this context, familial clinical screening coupled with genetic testing are required to prevent additional (fatal) arrhythmia events in relatives. This review presents an update of the ICC-associated genes and proposes a screening hierarchy according to the phenotype. The impact of the new sequencing technologies on the genetic testing as well as on the patient management will be also discussed.

Notes

Compliance with Ethical Standards

Sources of Funding

Julien Barc was supported by the H2020-MSCA-IF-2014 Program of the European Commission (RISTRAD-661617).

Conflict of Interest

Florence Kyndt declares that she has no conflict of interest. Jean-Baptiste Gourraud declares that he has no conflict of interest. Julien Barc declares that he has no conflict of interest.

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. Ackerman MJ. Genetic purgatory and the cardiac channelopathies: exposing the variants of uncertain/unknown significance issue. Heart Rhythm. 2015;12:2325–31.PubMedCrossRefPubMedCentralGoogle Scholar
  2. Ackerman MJ, Priori SG, Willems S, et al. 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). Europace. 2011;13:1077–109.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Akgün M, Bayrak AO, Ozer B, Sağıroğlu MŞ. Privacy preserving processing of genomic data: a survey. J Biomed Inform. 2015;56:103–11.PubMedCrossRefPubMedCentralGoogle Scholar
  4. Altmann HM, Tester DJ, Will ML, et al. Homozygous/compound heterozygous triadin mutations associated with autosomal-recessive long-QT syndrome and pediatric sudden cardiac arrest: elucidation of the triadin knockout syndrome. Circulation. 2015;131:2051–60.PubMedCrossRefPubMedCentralGoogle Scholar
  5. Andorin A, Behr ER, Denjoy I, et al. Impact of clinical and genetic findings on the management of young patients with Brugada syndrome. Heart Rhythm. 2016;13:1274–82.PubMedCrossRefPubMedCentralGoogle Scholar
  6. Andreasen C, Nielsen JB, Refsgaard L, et al. New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. Eur J Hum Genet. 2013;21:918–28.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Anselme F, Moubarak G, Savouré A, et al. Implantable cardioverter-defibrillators in Lamin a/C mutation carriers with cardiac conduction disorders. Heart Rhythm. 2013;10:1492–8.PubMedCrossRefPubMedCentralGoogle Scholar
  8. Antzelevitch C, Pollevick GD, Cordeiro JM, 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. 2007;115:442–9.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bagnall RD, Das KJ, Duflou J, Semsarian C. Exome analysis-based molecular autopsy in cases of sudden unexplained death in the young. Heart Rhythm. 2014;11:655–62.PubMedCrossRefPubMedCentralGoogle Scholar
  10. Barc J, Briec F, Schmitt S, et al. Screening for copy number variation in genes associated with the long QT syndrome: clinical relevance. J Am Coll Cardiol. 2011;57:40–7.PubMedCrossRefGoogle Scholar
  11. Barsheshet A, Goldenberg I, O-Uchi J, et al. Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to β-blocker therapy in type 1 long-QT syndrome. Circulation. 2012;125:1988–96.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Baruteau A-EE, Probst V, Abriel H. Inherited progressive cardiac conduction disorders. Curr Opin Cardiol. 2015;30:33–9.PubMedCrossRefGoogle Scholar
  13. Basson CT, Cowley GS, Solomon SD, et al. The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). N Engl J Med. 1994;330:885–91.PubMedCrossRefGoogle Scholar
  14. Bauce B, Nava A, Beffagna G, et al. Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm. 2010;7:22–9.PubMedCrossRefPubMedCentralGoogle Scholar
  15. Behr ER, Dalageorgou C, Christiansen M, et al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J. 2008;29:1670–80.PubMedCrossRefPubMedCentralGoogle Scholar
  16. Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation. 2004;109:2394–7.PubMedCrossRefGoogle Scholar
  17. Bezzina CR, Barc J, Mizusawa Y, 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. 2013;45:1044–9.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Bhonsale A, Groeneweg JA, James CA, et al. Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers. Eur Heart J. 2015;36:847–55.PubMedCrossRefPubMedCentralGoogle Scholar
  19. Bhuiyan ZA, van den Berg MP, van Tintelen JP, et al. Expanding spectrum of human RYR2-related disease: new electrocardiographic, structural, and genetic features. Circulation. 2007;116:1569–76.PubMedCrossRefGoogle Scholar
  20. Bjerregaard P. Proposed diagnostic criteria for short QT syndrome are badly founded. J Am Coll Cardiol. 2011;58:549–50; author reply 550–1.PubMedCrossRefGoogle Scholar
  21. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol. 1992;20:1391. Available at: PM:1309182PubMedCrossRefGoogle Scholar
  22. Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation. 2004;109:30–5.PubMedCrossRefPubMedCentralGoogle Scholar
  23. Campbell MJ, Czosek RJ, Hinton RB, Miller EM. Exon 3 deletion of ryanodine receptor causes left ventricular noncompaction, worsening catecholaminergic polymorphic ventricular tachycardia, and sudden cardiac arrest. Am J Med Genet A. 2015;167A:2197–200.PubMedCrossRefGoogle Scholar
  24. Chen Q, Kirsch GE, Zhang D, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998;392:293. Available at: PM:9521325PubMedCrossRefGoogle Scholar
  25. Christiaans I, van Langen IM, Birnie E, Bonsel GJ, Wilde AA, Smets EM. Quality of life and psychological distress in hypertrophic cardiomyopathy mutation carriers: a cross-sectional cohort study. Am J Med Genet A. 2009;149A:602–12.PubMedCrossRefGoogle Scholar
  26. Christiansen SL, Hertz CL, Ferrero-Miliani L, et al. Genetic investigation of 100 heart genes in sudden unexplained death victims in a forensic setting. Eur J Hum Genet. 2016;24:1797–802.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Chugh SS, Chung K, Zheng Z-JJ, John B, Titus JL. Cardiac pathologic findings reveal a high rate of sudden cardiac death of undetermined etiology in younger women. Am Heart J. 2003;146:635–9.PubMedCrossRefGoogle Scholar
  28. Corrado D, Link MS, Calkins H. Arrhythmogenic right ventricular cardiomyopathy. N Engl J Med. 2017;376:61–72.PubMedCrossRefGoogle Scholar
  29. Crotti L, Spazzolini C, Schwartz PJ, et al. The common long-QT syndrome mutation KCNQ1/A341V causes unusually severe clinical manifestations in patients with different ethnic backgrounds: toward a mutation-specific risk stratification. Circulation. 2007;116:2366–75.PubMedCrossRefPubMedCentralGoogle Scholar
  30. Crotti L, Marcou CA, Tester DJ, et al. Spectrum and prevalence of mutations involving BrS1- through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing: implications for genetic testing. J Am Coll Cardiol. 2012;60:1410. Available at: PM:22840528PubMedPubMedCentralCrossRefGoogle Scholar
  31. Crotti L, Johnson CN, Graf E, et al. Calmodulin mutations associated with recurrent cardiac arrest in infants. Circulation. 2013;127:1009–17.PubMedCrossRefPubMedCentralGoogle Scholar
  32. Daumy X, Amarouch M-YY, Lindenbaum P, et al. Targeted resequencing identifies TRPM4 as a major gene predisposing to progressive familial heart block type I. Int J Cardiol. 2016;207:349–58.PubMedCrossRefPubMedCentralGoogle Scholar
  33. Devalla HD, Gélinas R, Aburawi EH, et al. TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT. EMBO Mol Med. 2016;8:1390–408.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Donger C, Denjoy I, Berthet M, et al. KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation. 1997;96:2778–81.PubMedCrossRefPubMedCentralGoogle Scholar
  35. Eastaugh LJ, James PA, Phelan DG, Davis AM. Brugada syndrome caused by a large deletion in SCN5A only detected by multiplex ligation-dependent probe amplification. J Cardiovasc Electrophysiol. 2011;22:1073–6.PubMedCrossRefGoogle Scholar
  36. Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: pharmacological treatment. J Am Coll Cardiol. 2004;43:1494–9.PubMedCrossRefPubMedCentralGoogle Scholar
  37. García-Molina E, Lacunza J, Ruiz-Espejo F, et al. A study of the SCN5A gene in a cohort of 76 patients with Brugada syndrome. Clin Genet. 2013;83:530–8.PubMedCrossRefGoogle Scholar
  38. Garg V, Kathiriya IS, Barnes R, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature. 2003;424:443–7.PubMedCrossRefGoogle Scholar
  39. George CH, Jundi H, Thomas NL, Fry DL, Lai FA. Ryanodine receptors and ventricular arrhythmias: emerging trends in mutations, mechanisms and therapies. J Mol Cell Cardiol. 2007;42:34–50.PubMedCrossRefGoogle Scholar
  40. Ghouse J, Have CT, Skov MW, et al. Numerous Brugada syndrome-associated genetic variants have no effect on J-point elevation, syncope susceptibility, malignant cardiac arrhythmia, and all-cause mortality. Genet Med. 2017;19:521–8.PubMedCrossRefPubMedCentralGoogle Scholar
  41. Giustetto C, Schimpf R, Mazzanti A, et al. Long-term follow-up of patients with short QT syndrome. J Am Coll Cardiol. 2011;58:587–95.PubMedCrossRefPubMedCentralGoogle Scholar
  42. Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol. 2008;51:2291–300. Available at: PM:18549912PubMedCrossRefPubMedCentralGoogle Scholar
  43. Goldenberg I, Horr S, Moss AJ, et al. 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;57:51–9.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Gollob MH, Redpath CJ, Roberts JD. The short QT syndrome: proposed diagnostic criteria. J Am Coll Cardiol. 2011;57:802–12.PubMedCrossRefPubMedCentralGoogle Scholar
  45. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15:565–74.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Gussak I, Brugada P, Brugada J, et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology. 2000;94:99–102.PubMedCrossRefPubMedCentralGoogle Scholar
  47. Hashemi SM, Hund TJ, Mohler PJ. Cardiac ankyrins in health and disease. J Mol Cell Cardiol. 2009;47:203–9.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Hayashi M, Denjoy I, Extramiana F, et al. Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia. Circulation. 2009;119:2426–34.PubMedCrossRefGoogle Scholar
  49. Hendriks KS, Hendriks MM, Birnie E, et al. Familial disease with a risk of sudden death: a longitudinal study of the psychological consequences of predictive testing for long QT syndrome. Heart Rhythm. 2008;5:719. Available at: PM:18452877PubMedCrossRefPubMedCentralGoogle Scholar
  50. Hertz CL, Christiansen SL, Ferrero-Miliani L, et al. Next-generation sequencing of 34 genes in sudden unexplained death victims in forensics and in patients with channelopathic cardiac diseases. Int J Legal Med. 2015;129:793–800.PubMedCrossRefPubMedCentralGoogle Scholar
  51. Imboden M, Swan H, Denjoy I, et al. Female predominance and transmission distortion in the long-QT syndrome. N Engl J Med. 2006;355:2744. Available at: PM:17192539PubMedCrossRefPubMedCentralGoogle Scholar
  52. Imbrici P, Liantonio A, Camerino GM, et al. Therapeutic approaches to genetic ion channelopathies and perspectives in drug discovery. Front Pharmacol. 2016;7:121.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J. 1957;54:59–68.PubMedCrossRefPubMedCentralGoogle Scholar
  54. Kalia SS, Adelman K, Bale SJ, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017;19(2):249–55.PubMedCrossRefPubMedCentralGoogle Scholar
  55. Kapplinger JD, Tester DJ, Salisbury BA, et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009;6:1297. Available at: PM:19716085PubMedPubMedCentralCrossRefGoogle Scholar
  56. Kapplinger JD, Tester DJ, Alders M, et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm. 2010;7:33–46.PubMedCrossRefPubMedCentralGoogle Scholar
  57. Kingsmore SF, Saunders CJ. Deep sequencing of patient genomes for disease diagnosis: when will it become routine? Sci Transl Med. 2011;3:87ps23.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Kokunai Y, Nakata T, Furuta M, et al. A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1. Neurology. 2014;82:1058–64.PubMedCrossRefPubMedCentralGoogle Scholar
  59. Konigstein M, Rosso R, Topaz G, et al. Drug-induced Brugada syndrome: clinical characteristics and risk factors. Heart Rhythm. 2016;13:1083–7.PubMedCrossRefPubMedCentralGoogle Scholar
  60. Koopmann TT, Beekman L, Alders M, et al. Exclusion of multiple candidate genes and large genomic rearrangements in SCN5A in a Dutch Brugada syndrome cohort. Heart Rhythm. 2007;4:752–5.PubMedCrossRefPubMedCentralGoogle Scholar
  61. Larsen MK, Berge KE, Leren TP, et al. Postmortem genetic testing of the ryanodine receptor 2 (RYR2) gene in a cohort of sudden unexplained death cases. Int J Legal Med. 2013;127:139–44.PubMedCrossRefPubMedCentralGoogle Scholar
  62. Le SS, Bhasin N, Vieyres C, et al. Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease. Proc Natl Acad Sci U S A. 2008;105:15617. Available at: PM:18832177CrossRefGoogle Scholar
  63. Le Scouarnec S, Karakachoff M, J-BB G, et al. Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome. Hum Mol Genet. 2015;24:2757–63.PubMedCrossRefPubMedCentralGoogle Scholar
  64. Lenegre J. Etiology and pathology of bilateral bundle branch block in relation to complete heart block. Prog Cardiovasc Dis. 1964;6:409–44.PubMedCrossRefPubMedCentralGoogle Scholar
  65. Lev M. The pathology of complete atrioventricular block. Prog Cardiovasc Dis. 1964;6:317–26.PubMedCrossRefPubMedCentralGoogle Scholar
  66. Li Mura IE, Bauce B, Nava A, et al. Identification of a PKP2 gene deletion in a family with arrhythmogenic right ventricular cardiomyopathy. Eur J Hum Genet. 2013;21:1226–31.PubMedPubMedCentralCrossRefGoogle Scholar
  67. Liu N, Ruan Y, Priori SG. Catecholaminergic polymorphic ventricular tachycardia. Prog Cardiovasc Dis. 2008;51:23–30.PubMedCrossRefPubMedCentralGoogle Scholar
  68. Liu H, El Zein L, Kruse M, et al. Gain-of-function mutations in TRPM4 cause autosomal dominant isolated cardiac conduction disease. Circ Cardiovasc Genet. 2010;3:374–85.PubMedCrossRefPubMedCentralGoogle Scholar
  69. Makita N. Phenotypic overlap of cardiac sodium channelopathies. individual-specific or mutation-specific? Circ J. 2009;73:810–7.PubMedPubMedCentralGoogle Scholar
  70. Makita N, Seki A, Sumitomo N, et al. A connexin40 mutation associated with a malignant variant of progressive familial heart block type I. Circ Arrhythm Electrophysiol. 2012;5:163–72.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Eur Heart J. 2010;31:806–14.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Marsman RF, Bardai A, Postma AV, et al. A complex double deletion in LMNA underlies progressive cardiac conduction disease, atrial arrhythmias, and sudden death. Circ Cardiovasc Genet. 2011;4:280–7.PubMedCrossRefPubMedCentralGoogle Scholar
  73. Marsman RF, Barc J, Beekman L, et al. A mutation in CALM1 encoding calmodulin in familial idiopathic ventricular fibrillation in childhood and adolescence. J Am Coll Cardiol. 2014;63:259–66.PubMedCrossRefGoogle Scholar
  74. Mayosi BM, Fish M, Shaboodien G, et al. Identification of cadherin 2 (CDH2) mutations in arrhythmogenic right ventricular cardiomyopathy. Circ Cardiovasc Genet. 2017;10Google Scholar
  75. Medeiros-Domingo A, Bhuiyan ZA, Tester DJ, et al. The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutational analysis. J Am Coll Cardiol. 2009;54:2065–74.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Migdalovich D, Moss AJ, Lopes CM, et al. Mutation and gender-specific risk in type 2 long QT syndrome: implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome. Heart Rhythm. 2011;8:1537–43.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Mohler PJ, Splawski I, Napolitano C, et al. A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc Natl Acad Sci U S A. 2004;101:9137–42.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Morita H, Wu J, Zipes DP. The QT syndromes: long and short. Lancet. 2008;372:750. Available at: PM:18761222PubMedCrossRefGoogle Scholar
  79. Moss AJ, Zareba W, Kaufman ES, et al. 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;105:794–9.PubMedCrossRefGoogle Scholar
  80. Novelli V, Gambelli P, Memmi M, Napolitano C. Challenges in molecular diagnostics of channelopathies in the next-generation sequencing era: less is more? Front Cardiovasc Med. 2016;3:29.PubMedPubMedCentralCrossRefGoogle Scholar
  81. Nyegaard M, Overgaard MT, Sondergaard MT, et al. Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death. Am J HumGenet. 2012;91:703. Available at: PM:23040497PubMedCrossRefPubMedCentralGoogle Scholar
  82. Ohno S. The genetic background of arrhythmogenic right ventricular cardiomyopathy. J Arrhythm. 2016;32:398–403.PubMedPubMedCentralCrossRefGoogle Scholar
  83. Orgeron GM, Calkins H. Advances in the diagnosis and management of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Curr Cardiol Rep. 2016;18:53.PubMedCrossRefGoogle Scholar
  84. Pagon RA, Adam MP, Ardinger HH, et al. GeneReviews(®). Seattle: University of Washington; 1993.Google Scholar
  85. Paludan-Müller C, Ahlberg G, Ghouse J, et al. Integration of 60,000 exomes and ACMG guidelines question the role of Catecholaminergic polymorphic ventricular tachycardia-associated variants. Clin Genet. 2017;91:63–72.PubMedCrossRefPubMedCentralGoogle Scholar
  86. Patel C, Yan G-XX, Antzelevitch C. Short QT syndrome: from bench to bedside. Circ Arrhythm Electrophysiol. 2010;3:401–8.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Pipilas DC, Johnson CN, Webster G, et al. Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes. Heart Rhythm. 2016;13:2012–9.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Postema PG, Wolpert C, Amin AS, et al. Drugs and Brugada syndrome patients: review of the literature, recommendations, and an up-to-date website (www.brugadadrugs.org). Heart Rhythm. 2009;6:1335–41.
  89. Priori SG, Napolitano C. Cardiac and skeletal muscle disorders caused by mutations in the intracellular Ca2+ release channels. J Clin Invest. 2005;115(8):2033.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348:1866–74.PubMedCrossRefGoogle Scholar
  91. Priori SG, Napolitano C, Schwartz PJ, et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA. 2004;292:1341–4.PubMedCrossRefGoogle Scholar
  92. Priori SG, Pandit SV, Rivolta I, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res. 2005;96(7):800.PubMedCrossRefGoogle Scholar
  93. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and Management of Patients with inherited primary arrhythmia syndromes expert consensus statement on 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;19:e75. Available at: PM:24011539Google Scholar
  94. Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 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). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J. 2015;36:2793–867.PubMedCrossRefPubMedCentralGoogle Scholar
  95. Probst V, Kyndt F, Potet F, et al. Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lenègre disease. J Am Coll Cardiol. 2003;41:643–52.PubMedCrossRefPubMedCentralGoogle Scholar
  96. Probst V, Wilde AA, Barc J, et al. SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome. Circ Cardiovasc Genet. 2009;2:552. Available at: PM:20031634PubMedCrossRefGoogle Scholar
  97. Probst V, Veltmann C, Eckardt L, et al. Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada syndrome registry. Circulation. 2010;121:635. Available at: PM:20100972PubMedCrossRefGoogle Scholar
  98. Pua CJ, Bhalshankar J, Miao K, et al. Development of a comprehensive sequencing assay for inherited cardiac condition genes. J Cardiovasc Transl Res. 2016;9:3–11.PubMedPubMedCentralCrossRefGoogle Scholar
  99. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Rigato I, Bauce B, Rampazzo A, et al. Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy. Circ Cardiovasc Genet. 2013;6:533–42.PubMedCrossRefGoogle Scholar
  101. Risgaard B, Jabbari R, Refsgaard L, et al. High prevalence of genetic variants previously associated with Brugada syndrome in new exome data. Clin Genet. 2013;84:489–95.PubMedCrossRefGoogle Scholar
  102. Roberts JD, Herkert JC, Rutberg J, et al. Detection of genomic deletions of PKP2 in arrhythmogenic right ventricular cardiomyopathy. Clin Genet. 2013;83:452–6.PubMedCrossRefGoogle Scholar
  103. Roden DM. Clinical practice. Long-QT syndrome. N Engl J Med. 2008;358:169–76.PubMedCrossRefGoogle Scholar
  104. Romano C, Gemme G, Pongiglione R. Rare cardiac arrythmias of the pediatric age. II. Syncopal attacks due to paroxysmal ventricular fibrillation (presentation of 1st case in Italian pediatric literature). Clin Pediatr (Bologna). 1963;45:656–83.Google Scholar
  105. Rooryck C, Kyndt F, Bozon D, et al. New family with catecholaminergic polymorphic ventricular tachycardia linked to the triadin gene. J Cardiovasc Electrophysiol. 2015;26:1146–50.PubMedCrossRefGoogle Scholar
  106. Roux-Buisson N, Cacheux M, Fourest-Lieuvin A, et al. Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human. Hum Mol Genet. 2012;21:2759–67.PubMedPubMedCentralCrossRefGoogle Scholar
  107. Schott JJ, Charpentier F, Peltier S, et al. Mapping of a gene for long QT syndrome to chromosome 4q25-27. Am J Hum Genet. 1995;57:1114–22.PubMedPubMedCentralGoogle Scholar
  108. Schott JJ, Benson DW, Basson CT, et al. Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science. 1998;281:108–11.PubMedCrossRefPubMedCentralGoogle Scholar
  109. Schott JJ, Alshinawi C, Kyndt F, et al. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999;23:20–1.PubMedCrossRefPubMedCentralGoogle Scholar
  110. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation. 1993;88:782–4.PubMedCrossRefPubMedCentralGoogle Scholar
  111. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. 2001;103:89–95.PubMedCrossRefPubMedCentralGoogle Scholar
  112. Schwartz PJ, Stramba-Badiale M, Crotti L, et al. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120:1761–7.PubMedPubMedCentralCrossRefGoogle Scholar
  113. Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management. Circ Arrhythm Electrophysiol. 2012;5:868–77.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Selga E, Campuzano O, Pinsach-Abuin ML, et al. Comprehensive genetic characterization of a Spanish Brugada syndrome cohort. PLoS One. 2015;10:e0132888.PubMedPubMedCentralCrossRefGoogle Scholar
  115. Sen-Chowdhry S, Syrris P, Ward D, Asimaki A, Sevdalis E, McKenna WJ. Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression. Circulation. 2007;115:1710–20.PubMedCrossRefPubMedCentralGoogle Scholar
  116. Shimizu W, Moss AJ, Wilde AA, et al. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol. 2009;54:2052–62.PubMedPubMedCentralCrossRefGoogle Scholar
  117. Sisakian H. Cardiomyopathies: evolution of pathogenesis concepts and potential for new therapies. World J Cardiol. 2014;6:478–94.PubMedPubMedCentralCrossRefGoogle Scholar
  118. Skinner JR, Crawford J, Smith W, et al. Prospective, population-based long QT molecular autopsy study of postmortem negative sudden death in 1 to 40 year olds. Heart Rhythm. 2011;8:412–9.PubMedCrossRefGoogle Scholar
  119. Spazzolini C, Mullally J, Moss AJ, et al. Clinical implications for patients with long QT syndrome who experience a cardiac event during infancy. J Am Coll Cardiol. 2009;54:832–7.PubMedPubMedCentralCrossRefGoogle Scholar
  120. Spjuth O, Bongcam-Rudloff E, Dahlberg J, et al. Recommendations on e-infrastructures for next-generation sequencing. Gigascience. 2016;5:26.PubMedPubMedCentralCrossRefGoogle Scholar
  121. Spoonamore KG, Ware SM. Genetic testing and genetic counseling in patients with sudden death risk due to heritable arrhythmias. Heart Rhythm. 2016;13:789–97.PubMedCrossRefPubMedCentralGoogle Scholar
  122. Stallmeyer B, Koopmann M, Schulze-Bahr E. Identification of novel mutations in LMNA associated with familial forms of dilated cardiomyopathy. Genet Test Mol Biomarkers. 2012;16:543–9.PubMedCrossRefGoogle Scholar
  123. Steffensen AB, Refaat MM, J-PP D, et al. High incidence of functional ion-channel abnormalities in a consecutive long QT cohort with novel missense genetic variants of unknown significance. Sci Rep. 2015;5:10009.PubMedPubMedCentralCrossRefGoogle Scholar
  124. Sudmant PH, Rausch T, Gardner EJ, et al. An integrated map of structural variation in 2,504 human genomes. Nature. 2015;526:75–81.PubMedPubMedCentralCrossRefGoogle Scholar
  125. Tan HL, Bezzina CR, Smits JP, Verkerk AO, Wilde AA. Genetic control of sodium channel function. Cardiovasc Res. 2003;57:961. Available at: PM:12650874PubMedPubMedCentralCrossRefGoogle Scholar
  126. Tan HL, Hofman N, van Langen IM, van der Wal AC, Wilde AA. Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives. Circulation. 2005;112:207–13.PubMedCrossRefPubMedCentralGoogle Scholar
  127. Te Riele AS, Agullo-Pascual E, James CA, et al. Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis. Cardiovasc Res. 2017;113:102–11.CrossRefGoogle Scholar
  128. Tennessen JA, Bigham AW, O’Connor TD, et al. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science. 2012;337:64–9.PubMedPubMedCentralCrossRefGoogle Scholar
  129. Tester DJ, Ackerman MJ. Novel gene and mutation discovery in congenital long QT syndrome: let’s keep looking where the street lamp standeth. Heart Rhythm. 2008;5:1282–4.PubMedPubMedCentralCrossRefGoogle Scholar
  130. Tester DJ, Ackerman MJ. Genetics of long QT syndrome. Methodist Debakey Cardiovasc J. 2014;10:29–33.PubMedPubMedCentralCrossRefGoogle Scholar
  131. Tester DJ, Medeiros-Domingo A, Will ML, Haglund CM, Ackerman MJ. Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing. Mayo Clin Proc. 2012;87:524–39.PubMedPubMedCentralCrossRefGoogle Scholar
  132. Tomaselli GF, Barth AS. Ion channel diseases: an update for 2016. Curr Treat Options Cardiovasc Med. 2016;18:21.PubMedCrossRefPubMedCentralGoogle Scholar
  133. Tully I, Atherton J, Hunt L, Ingles J, Semsarian C, McGaughran J. Rarity and phenotypic heterogeneity provide challenges in the diagnosis of Andersen-Tawil syndrome: two cases presenting with ECGs mimicking catecholaminergic polymorphic ventricular tachycardia (CPVT). Int J Cardiol. 2015;201:473–5.PubMedCrossRefPubMedCentralGoogle Scholar
  134. Van der Werf C, Wilde AA. Catecholaminergic polymorphic ventricular tachycardia: from bench to bedside. Heart. 2013;99:497–504.PubMedCrossRefPubMedCentralGoogle Scholar
  135. Veltmann C, Borggrefe M. Arrhythmias: a “Schwartz score” for short QT syndrome. Nat Rev Cardiol. 2011;8:251–2.PubMedCrossRefPubMedCentralGoogle Scholar
  136. Ward OC. A new familial cardiac syndrome in children. J Irish Med Assoc. 1964;54:103–6.Google Scholar
  137. Watanabe H, Koopmann TT, Le Scouarnec S, et al. Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. J Clin Invest. 2008;118:2260–8.PubMedPubMedCentralGoogle Scholar
  138. Wijeyeratne YD, Behr ER. Sudden death and cardiac arrest without phenotype: the utility of genetic testing. Trends Cardiovasc Med. 2017;27(3):207–13.PubMedCrossRefPubMedCentralGoogle Scholar
  139. Wilde AA, Behr ER. Genetic testing for inherited cardiac disease. Nat Rev Cardiol. 2013;10:571–83.PubMedCrossRefPubMedCentralGoogle Scholar
  140. Wilde AA, Bhuiyan ZA, Crotti L, et al. Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia. N Engl J Med. 2008;358:2024–9.PubMedCrossRefPubMedCentralGoogle Scholar
  141. Winkel BG, Holst AG, Theilade J, et al. Nationwide study of sudden cardiac death in persons aged 1-35 years. Eur Heart J. 2011;32:983–90.PubMedCrossRefPubMedCentralGoogle Scholar
  142. Winkel BG, Larsen MK, Berge KE, et al. The prevalence of mutations in KCNQ1, KCNH2, and SCN5A in an unselected national cohort of young sudden unexplained death cases. J Cardiovasc Electrophysiol. 2012;23:1092–8.PubMedCrossRefPubMedCentralGoogle Scholar
  143. Wolf CM, Berul CI. Inherited conduction system abnormalities--one group of diseases, many genes. J Cardiovasc Electrophysiol. 2006;17:446–55.PubMedCrossRefGoogle Scholar
  144. Wolf CM, Wang L, Alcalai R, et al. Lamin a/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease. J Mol Cell Cardiol. 2008;44:293–303.PubMedCrossRefPubMedCentralGoogle Scholar
  145. Zawistowski M, Reppell M, Wegmann D, et al. Analysis of rare variant population structure in Europeans explains differential stratification of gene-based tests. Eur J Hum Genet. 2014;22:1137–44.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Florence Kyndt
    • 1
    • 2
  • Jean-Baptiste Gourraud
    • 1
    • 3
  • Julien Barc
    • 1
  1. 1.l’institut du thorax, INSERM, CNRS, UNIV NantesNantesFrance
  2. 2.CHU Nantes, Service de Génétique MédicaleNantesFrance
  3. 3.L’institut du thorax, CHU Nantes, Service de CardiologieNantesFrance

Personalised recommendations