Next-Generation Sequencing in Post-mortem Genetic Testing of Young Sudden Cardiac Death Cases

Frontiers in Cardiovascular Medicine

Volumn 3, Issue , 2016, Pages

  Lahrouchi, Najim ^a   Behr, Elijah R ^b   Bezzina, Connie R ^a  

^a ACADEMIC MEDICAL CENTER   (Netherlands)

^b ST GEORGE'S UNIVERSITY OF LONDON   (United Kingdom)

Author keywords

cardiomyopathy; channelopathy; molecular autopsy; next generation sequencing; post mortem genetic testing; sudden cardiac death

Indexed keywords

EID: 85015107058     PISSN: None     EISSN: 2297055X     Source Type: Journal    
DOI: 10.3389/fcvm.2016.00013     Document Type: Review

References (83)

1. Meyer L, Stubbs B, Fahrenbruch C, Maeda C, Harmon K, Eisenberg M, et al. Incidence, causes, and survival trends from cardiovascular-related sudden cardiac arrest in children and young adults 0 to 35 years of age: a 30-year review. Circulation (2012) 126:1363–72.10.1161/CIRCULATIONAHA.111.07681022887927
2. Bezzina CR, Lahrouchi N, Priori SG. Genetics of sudden cardiac death. Circ Res (2015) 116:1919–36.10.1161/CIRCRESAHA.116.30403026044248
3. Semsarian C, Ingles J, Wilde AAM. Sudden cardiac death in the young: the molecular autopsy and a practical approach to surviving relatives. Eur Heart J (2015) 36:1290–6.10.1093/eurheartj/ehv06325765769
4. Behr ER, Casey A, Sheppard M, Wright M, Bowker TJ, Davies MJ, et al. Sudden arrhythmic death syndrome: a national survey of sudden unexplained cardiac death. Heart (2007) 93:601–5.10.1136/hrt.2006.09959817237131
5. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, et al. 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) 10:1932–63.10.1016/j.hrthm.2013.05.014
6. Miles CJ, Behr ER. The role of genetic testing in unexplained sudden death. Transl Res (2016) 168:59–73.10.1016/j.trsl.2015.06.00726143861
7. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, 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). Heart Rhythm (2011) 8:1308–39.10.1016/j.hrthm.2011.05.020
8. Lubitz SA, Ellinor PT. Next generation sequencing for the diagnosis of cardiac arrhythmia syndromes. Heart Rhythm (2015) 12(5):1062–70.10.1016/j.hrthm.2015.01.011
9. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation (1993) 88:782–4.10.1161/01.CIR.88.2.782
10. Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, et al. Prevalence of the congenital long-QT syndrome. Circulation (2009) 120:1761–7.10.1161/CIRCULATIONAHA.109.86320919841298
11. Mizusawa Y, Horie M, Wilde AA. Genetic and clinical advances in congenital long QT syndrome. Circ J (2014) 78(12):2827–33.10.1253/circj.CJ-14-0905
12. Hedley PL, Jørgensen P, Schlamowitz S, Wangari R, Moolman-Smook J, Brink PA, et al. The genetic basis of long QT and short QT syndromes: a mutation update. Hum Mutat (2009) 30:1486–511.10.1002/humu.2110619862833
13. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation (2001) 103:89–95.10.1161/01.CIR.103.1.8911136691
14. Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, Barhanin J, et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet (1997) 15:186–9.10.1038/ng0297-1869020846
15. Schulze-Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun Y, et al. KCNE1 mutations cause Jervell and Lange-Nielsen syndrome. Nat Genet (1997) 17:267–8.10.1038/ng1197-267
16. Plaster NM, Tawil R, Tristani-Firouzi M, Canún S, Bendahhou S, Tsunoda A, et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell (2001) 105:511–9.10.1016/S0092-8674(01)00342-7
17. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell (2004) 119:19–31.10.1016/j.cell.2004.09.01115454078
18. Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation (1995) 91:1512–9.10.1161/01.CIR.91.5.15127867192
19. Priori SG, Napolitano C, Memmi M, Colombi B, Drago F, Gasparini M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation (2002) 106:69–74.10.1161/01.CIR.0000020013.73106.D812093772
20. Hayashi M, Denjoy I, Extramiana F, Maltret A, Buisson NR, Lupoglazoff JM, et al. Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia. Circulation (2009) 119:2426–34.10.1161/CIRCULATIONAHA.108.82926719398665
21. Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation (2001) 103:196–200.10.1161/01.CIR.103.2.19611208676
22. Lahat H, Pras E, Olender T, Avidan N, Ben-Asher E, Man O, et al. A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. Am J Hum Genet (2001) 69:1378–84.10.1086/324565
23. Laitinen PJ, Brown KM, Piippo K, Swan H, Devaney JM, Brahmbhatt B, et al. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation (2001) 103:485–90.10.1161/01.CIR.103.4.48511157710
24. Medeiros-Domingo A, Bhuiyan ZA, Tester DJ, Hofman N, Bikker H, van Tintelen JP, 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) 54:2065–74.10.1016/j.jacc.2009.08.022
25. van der Werf C, Nederend I, Hofman N, van Geloven N, Ebink C, Frohn-Mulder IM, et al. Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives. Circ Arrhythm Electrophysiol (2012) 5:748–56.10.1161/CIRCEP.112.97051722787013
26. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, et al. Brugada syndrome: report of the second consensus conference. Heart Rhythm (2005) 2:429–40.10.1016/j.hrthm.2005.01.00515898165
27. Crotti L, Marcou CA, Tester DJ, Castelletti S, Giudicessi JR, Torchio M, 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) 60:1410–8.10.1016/j.jacc.2012.04.03722840528
28. Probst V, Wilde AA, Barc J, Sacher F, Babuty D, Mabo P, et al. SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome. Circ Cardiovasc Genet (2009) 2:552–7.10.1161/CIRCGENETICS.109.85337420031634
29. Bezzina CR, Barc J, Mizusawa Y, Remme CA, Gourraud JB, Simonet F, et al. Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nat Genet (2013) 45:1044–9.10.1038/ng.271223872634
30. Gussak I, Brugada P, Brugada J, Wright RS, Kopecky SL, Chaitman BR, et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology (2000) 94:99–102.10.1159/00004729911173780
31. Gaita F, Giustetto C, Bianchi F, Wolpert C, Schimpf R, Riccardi R, et al. Short QT syndrome: a familial cause of sudden death. Circulation (2003) 108:965–70.10.1161/01.CIR.0000085071.28695.C412925462
32. Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation (2004) 109:30–5.10.1161/01.CIR.0000109482.92774.3A14676148
33. Bellocq C, van Ginneken AC, Bezzina CR, Alders M, Escande D, Mannens MM, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation (2004) 109:2394–7.10.1161/01.CIR.0000130409.72142.FE15159330
34. Priori SG, Pandit SV, Rivolta I, Berenfeld O, Ronchetti E, Dhamoon A, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res (2005) 96:800–7.10.1161/01.RES.0000162101.76263.8c15761194
35. Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation (2007) 115:442–9.10.1161/CIRCULATIONAHA.106.66839217224476
36. Mazzanti A, Kanthan A, Monteforte N, Memmi M, Bloise R, Novelli V, et al. Novel insight into the natural history of short QT syndrome. J Am Coll Cardiol (2014) 63:1300–8.10.1016/j.jacc.2013.09.07824291113
37. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, et al. Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on myocardial and pericardial diseases. Eur Heart J (2008) 29:270–6.10.1093/eurheartj/ehm34217916581
38. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet (2013) 381:242–55.10.1016/S0140-6736(12)60397-322874472
39. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation (2003) 107:2227–32.10.1161/01.CIR.0000066323.15244.5412707239
40. Li Q, Gruner C, Chan RH, Care M, Siminovitch K, Williams L, et al. Genotype-positive status in patients with hypertrophic cardiomyopathy is associated with higher rates of heart failure events. Circ Cardiovasc Genet (2014) 7:416–22.10.1161/CIRCGENETICS.113.00033124909666
41. Jefferies JL, Towbin JA. Dilated cardiomyopathy. Lancet (2010) 375:752–62.10.1016/S0140-6736(09)62023-720189027
42. Petretta M, Pirozzi F, Sasso L, Paglia A, Bonaduce D. Review and metaanalysis of the frequency of familial dilated cardiomyopathy. Am J Cardiol (2011) 108:1171–6.10.1016/j.amjcard.2011.06.02221798502
43. Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol (2013) 10:531–47.10.1038/nrcardio.2013.10523900355
44. Towbin JA. Inherited cardiomyopathies. Circ J (2014) 78:2347–56.10.1253/circj.CJ-14-089325186923
45. van Rijsingen IA, Arbustini E, Elliott PM, Mogensen J, Hermans-van Ast JF, van der Kooi AJ, et al. Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study. J Am Coll Cardiol (2012) 59:493–500.10.1016/j.jacc.2011.08.07822281253
46. Basso C, Bauce B, Corrado D, Thiene G. Pathophysiology of arrhythmogenic cardiomyopathy. Nat Rev Cardiol (2012) 9:223–33.10.1038/nrcardio.2011.173
47. Marcus FI, Edson S, Towbin JA. Genetics of arrhythmogenic right ventricular cardiomyopathy: a practical guide for physicians. J Am Coll Cardiol (2013) 61:1945–8.10.1016/j.jacc.2013.01.07323500315
48. Lodder EM, Bezzina CR. Arrhythmogenic right ventricular cardiomyopathy: growing evidence for complex inheritance. Circ Cardiovasc Genet (2013) 6:525–7.10.1161/CIRCGENETICS.113.000367
49. Ackerman MJ, Tester DJ, Porter CJ, Edwards WD. Molecular diagnosis of the inherited long-QT syndrome in a woman who died after near-drowning. N Engl J Med (1999) 341:1121–5.10.1056/NEJM199910073411504
50. Chugh SS, Senashova O, Watts A, Tran PT, Zhou Z, Gong Q, et al. Postmortem molecular screening in unexplained sudden death. J Am Coll Cardiol (2004) 43:1625–9.10.1016/j.jacc.2003.11.05215120823
51. Di Paolo M, Luchini D, Bloise R, Priori SG. Postmortem molecular analysis in victims of sudden unexplained death. Am J Forensic Med Pathol (2004) 25:182–4.10.1097/01.paf.0000127406.20447.8a15166777
52. Creighton W, Virmani R, Kutys R, Burke A. Identification of novel missense mutations of cardiac ryanodine receptor gene in exercise-induced sudden death at autopsy. J Mol Diagn (2006) 8:62–7.10.2353/jmoldx.2006.05008116436635
53. Nishio H, Iwata M, Suzuki K. Postmortem molecular screening for cardiac ryanodine receptor type 2 mutations in sudden unexplained death: R420W mutated case with characteristics of status thymico-lymphatics. Circ J (2006) 70:1402–6.10.1253/circj.70.140217062961
54. Gladding PA, Evans CA, Crawford J, Chung SK, Vaughan A, Webster D, et al. Posthumous diagnosis of long QT syndrome from neonatal screening cards. Heart Rhythm (2010) 7:481–6.10.1016/j.hrthm.2009.12.02320167303
55. Winkel BG, Larsen MK, Berge KE, Leren TP, Nissen PH, Olesen MS, 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) 23:1092–8.10.1111/j.1540-8167.2012.02371.x22882672
56. Larsen MK, Berge KE, Leren TP, Nissen PH, Hansen J, Kristensen IB, 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) 127:139–44.10.1007/s00414-011-0658-222222782
57. Dean J, Cann F, Corbett M, O’Sullivan D, Tennant S, Hailey H, et al. Molecular autopsy for sudden cardiac death – outcome of a practical approach. Heart Lung Circ (2014) 23:e3.10.1016/j.hlc.2014.07.007
58. Stattin EL, Westin IM, Cederquist K, Jonasson J, Jonsson BA, Mörner S, et al. Genetic screening in sudden cardiac death in the young can save future lives. Int J Legal Med (2016) 130:59–66.10.1007/s00414-015-1237-826228265
59. Skinner JR, Crawford J, Smith W, Aitken A, Heaven D, Evans CA, et al. Prospective, population-based long QT molecular autopsy study of postmortem negative sudden death in 1 to 40 year olds. Heart Rhythm (2011) 8:412–9.10.1016/j.hrthm.2010.11.01621070882
60. Tester DJ, Spoon DB, Valdivia HH, Makielski JC, Ackerman MJ. Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: a molecular autopsy of 49 medical examiner/coroner’s cases. Mayo Clin Proc (2004) 79:1380–4.10.4065/79.11.1380
61. Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. J Am Coll Cardiol (2007) 49:240–6.10.1016/j.jacc.2006.10.01017222736
62. 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) 87:524–39.10.1016/j.mayocp.2012.02.01722677073
63. 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) 11:655–62.10.1016/j.hrthm.2014.01.01724440382
64. Nunn LM, Lopes LR, Syrris P, Murphy C, Plagnol V, Firman E, et al. Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing. Europace (2015).10.1093/europace/euv28526498160
65. Hertz CL, Christiansen SL, Ferrero-Miliani L, Dahl M, Weeke PE, LuCamp et al. Next-generation sequencing of 100 candidate genes in young victims of suspected sudden cardiac death with structural abnormalities of the heart. Int J Legal Med (2016) 130:91–102.10.1007/s00414-015-1261-826383259
66. Narula N, Tester DJ, Paulmichl A, Maleszewski JJ, Ackerman MJ. Post-mortem whole exome sequencing with gene-specific analysis for autopsy-negative sudden unexplained death in the young: a case series. Pediatr Cardiol (2015) 36:768–78.10.1007/s00246-014-1082-425500949
67. Anderson JH, Tester DJ, Will ML, Ackerman MJ. Whole exome molecular autopsy following exertion-related sudden unexplained death in the young. Circ Cardiovasc Genet (2016).10.1161/CIRCGENETICS.115.001370
68. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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) 17:405–24.10.1038/gim.2015.3025741868
69. Farrugia A, Keyser C, Hollard C, Raul JS, Muller J, Ludes B. Targeted next generation sequencing application in cardiac channelopathies: analysis of a cohort of autopsy-negative sudden unexplained deaths. Forensic Sci Int (2015) 254:5–11.10.1016/j.forsciint.2015.06.02326164358
70. Hertz CL, Christiansen SL, Ferrero-Miliani L, Fordyce SL, Dahl M, Holst AG, 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) 129:793–800.10.1007/s00414-014-1105-y25467552
71. Neubauer J, Haas C, Bartsch C, Domingo-Medeiros A, Berger W. Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases. Int J Legal Med (2016).10.1007/s00414-016-1317-426846766
72. Buscemi L, Alessandrini F, Perna G, Tagliabracci A. Next-generation sequencing of 68 genes in sudden unexplained death of young individuals in forensics. Forensic Sci Int Genet Suppl Ser (2015) 5:e138–40.10.1016/j.fsigss.2015.09.056
73. Ackerman MJ. Genetic purgatory and the cardiac channelopathies: exposing the variants of uncertain/unknown significance issue. Heart Rhythm (2015) 12:2325–31.10.1016/j.hrthm.2015.07.00226144349
74. MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, et al. Guidelines for investigating causality of sequence variants in human disease. Nature (2014) 508:469–76.10.1038/nature1312724759409
75. Exome Aggregation Consortium (ExAC). Cambridge, MA (2016). Available from: http://exac.broadinstitute.org; http://exac.broadinstitute.org/about
76. Etheridge SP, Bowles NE, Arrington CB, Pilcher T, Rope A, Wilde AA, et al. Somatic mosaicism contributes to phenotypic variation in Timothy syndrome. Am J Med Genet A (2011) 155A:2578–83.10.1002/ajmg.a.3422321910241
77. Refsgaard L, Holst AG, Sadjadieh G, Haunsø S, Nielsen JB, Olesen MS. High prevalence of genetic variants previously associated with LQT syndrome in new exome data. Eur J Hum Genet (2012) 20:905–8.10.1038/ejhg.2012.2322378279
78. Risgaard B, Jabbari R, Refsgaard L, Holst AG, Haunsø S, Sadjadieh A, et al. High prevalence of genetic variants previously associated with Brugada syndrome in new exome data. Clin Genet (2013) 84:489–95.10.1111/cge.1212623414114
79. Jabbari J, Jabbari R, Nielsen MW, Holst AG, Nielsen JB, Haunsø S, et al. New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia. Circ Cardiovasc Genet (2013) 6:481–9.10.1161/CIRCGENETICS.113.00011824025405
80. Ware JS, Walsh R, Cunningham F, Birney E, Cook SA. Paralogous annotation of disease-causing variants in long QT syndrome genes. Hum Mutat (2012) 33:1188–91.10.1002/humu.2211422581653
81. Grantham R. Amino acid difference formula to help explain protein evolution. Science (1974) 185:862–4.10.1126/science.185.4154.8624843792
82. Giudicessi JR, Kapplinger JD, Tester DJ, Alders M, Salisbury BA, Wilde AA, et al. Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome. Circ Cardiovasc Genet (2012) 5:519–28.10.1161/CIRCGENETICS.112.96378522949429
83. Kapplinger JD, Giudicessi JR, Ye D, Tester DJ, Callis TE, Valdivia CR, et al. Enhanced classification of Brugada syndrome-associated and long-QT syndrome-associated genetic variants in the SCN5A-encoded Na(v)1.5 cardiac sodium channel. Circ Cardiovasc Genet (2015) 8:582–95.10.1161/CIRCGENETICS.114.00083125904541