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Targeted molecular genetic testing in young sudden cardiac death victims from Western Denmark

  • Maiken Kudahl Larsen
  • Sofie Lindgren ChristiansenEmail author
  • Christin Løth Hertz
  • Rune Frank-Hansen
  • Henrik Kjærulf Jensen
  • Jytte Banner
  • Niels Morling
Original Article

Abstract

Sudden unexpected death in the young continues to be an important unsolved challenge. A significant proportion of the deaths are suspected to be caused by inherited cardiac diseases and are referred to as sudden cardiac deaths (SCD). We performed targeted molecular testing of 70 deceased individuals under 40 years of age that after forensic autopsy were suspected to have died of SCD. The individuals were previously genetically investigated using smaller numbers of genes associated with specific cardiac diseases. In our previous studies, seven (10%) individuals had pathogenic or likely pathogenic variants according to the 2015 ACMG guidelines. In order to investigate the value of expanding the panel to 100 genes associated with cardiac diseases, we histopathologically re-examined the 70 suspected SCD cases and grouped them according to phenotypes into suspected cardiomyopathy (the cardiomyopathy group), left ventricular hypertrophy (the hypertrophy group) and structural normal hearts (the SUD group). DNA was captured with the Haloplex target enrichment system and sequenced using an Illumina MiSeq. We found that 11 (16%) individuals harboured pathogenic or likely pathogenic variants. In the cardiomyopathy, hypertrophy and SUD groups, 22%, 6% and 17% of the individuals, respectively, harboured pathogenic or likely pathogenic variants. Our findings show that testing of a broad panel of genes associated with cardiac diseases identify potential pathogenic variants of cardiac diseases in a significant proportion of SCD cases, and this may have important implications in family screening to prevent future deaths.

Keywords

Cardiomyopathy Channelopathy DNA sequencing Genetics Molecular autopsy Sudden cardiac death (SCD) 

Notes

Acknowledgements

We thank the staff members of the Department of Forensic Medicine, University of Aarhus, and Department of Forensic Medicine, University of Copenhagen for excellent help and assistance during the project. We also thank Jeppe Dyrberg Andersen for help with the bioinformatic sorting of variants according to the ACMG guidelines. This work was supported by Ellen and Aage Andersen’s Foundation.

Funding information

This work was supported by Ellen and Aage Andersen’s Foundation. Henrik Kjærulf Jensen is supported by a research grant from the Novo Nordisk Foundation (NNF18OC0031258).

Compliance with ethical standards

This study was approved by The National Committee on Health Research Ethics (1402655) and the Danish Data Protection Agency (2011-54-1262). The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments and comparable ethical standards.

Conflict of interest

The authors declare that they have no conflict of interest. HKJ is supported by a research grant from The Novo Nordisk Foundation (NNF18OC0031258).

Informed consent

According to The National Committee on Health Research Ethics (1402655), informed consent is not necessary for the samples used in this study.

References

  1. 1.
    Chugh SS, Jui J, Gunson K, Stecker EC, John BT, Thompson B, Ilias N, Vickers C, Dogra V, Daya M, Kron J, Zheng ZJ, Mensah G, McAnulty J (2004) Current burden of sudden cardiac death: multiple source surveillance versus retrospective death certificate-based review in a large U.S. community. J Am Coll Cardiol 44(6):1268–1275PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    de Vreede-Swagemakers JJ, Gorgels AP, Dubois-Arbouw WI, van Ree JW, Daemen MJ, Houben LG, Wellens HJ (1997) Out-of-hospital cardiac arrest in the 1990's: a population-based study in the Maastricht area on incidence, characteristics and survival. J Am Coll Cardiol 30(6):1500–1505PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Roberts WC (1990) Sudden cardiac death: a diversity of causes with focus on atherosclerotic coronary artery disease. Am J Cardiol 65(4):13B–19BPubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Zheng ZJ, Croft JB, Giles WH, Mensah GA (2001) Sudden cardiac death in the United States, 1989 to 1998. Circulation 104(18):2158–2163PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Papadakis M, Sharma S, Cox S, Sheppard MN, Panoulas VF, Behr ER (2009) The magnitude of sudden cardiac death in the young: a death certificate-based review in England and Wales. Europace 11(10):1353–1358PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Vaartjes I, Hendrix A, Hertogh EM, Grobbee DE, Doevendans PA, Mosterd A, Bots ML (2009) Sudden death in persons younger than 40 years of age: incidence and causes. Eur J Cardiovasc Prev Rehabil 16(5):592–596PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Winkel BG, Holst AG, Theilade J, Kristensen IB, Thomsen JL, Ottesen GL, Bundgaard H, Svendsen JH, Haunso S, Tfelt-Hansen J (2011) Nationwide study of sudden cardiac death in persons aged 1-35 years. Eur Heart J 32(8):983–990PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Chugh SS, Senashova O, Watts A, Tran PT, Zhou Z, Gong Q, Titus JL, Hayflick SJ (2004) Postmortem molecular screening in unexplained sudden death. J Am Coll Cardiol 43(9):1625–1629PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Skinner JR, Crawford J, Smith W, Aitken A, Heaven D, Evans CA, Hayes I, Neas KR, Stables S, Koelmeyer T, Denmark L, Vuletic J, Maxwell F, White K, Yang T, Roden DM, Leren TP, Shelling A, Love DR, Cardiac Inherited Disease Group New Z (2011) Prospective, population-based long QT molecular autopsy study of postmortem negative sudden death in 1 to 40 year olds. Heart Rhythm 8(3):412–419PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Tester DJ, Medeiros-Domingo A, Will ML, Haglund CM, Ackerman MJ (2012) Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing. Mayo Clin Proc 87(6):524–539PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Kauferstein S, Kiehne N, Jenewein T, Biel S, Kopp M, Konig R, Erkapic D, Rothschild M, Neumann T (2013) Genetic analysis of sudden unexplained death: a multidisciplinary approach. Forensic Sci Int 229(1-3):122–127PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Hertz CL, Christiansen SL, Ferrero-Miliani L, Fordyce SL, Dahl M, Holst AG, Ottesen GL, Frank-Hansen R, Bundgaard H, Morling N (2015) Next-generation sequencing of 34 genes in sudden unexplained death victims in forensics and in patients with channelopathic cardiac diseases. Int J Legal Med 129(4):793–800PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Winkel BG, Larsen MK, Berge KE, Leren TP, Nissen PH, Olesen MS, Hollegaard MV, Jespersen T, Yuan L, Nielsen N, Haunso S, Svendsen JH, Wang Y, Kristensen IB, Jensen HK, Tfelt-Hansen J, Banner J (2012) The prevalence of mutations in KCNQ1, KCNH2, and SCN5A in an unselected national cohort of young sudden unexplained death cases. J Cardiovasc Electrophysiol 23(10):1092–1098PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Larsen MK, Berge KE, Leren TP, Nissen PH, Hansen J, Kristensen IB, Banner J, Jensen HK (2013) Postmortem genetic testing of the ryanodine receptor 2 (RYR2) gene in a cohort of sudden unexplained death cases. Int J Legal Med 127(1):139–144PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Larsen MK, Nissen PH, Berge KE, Leren TP, Kristensen IB, Jensen HK, Banner J (2012) Molecular autopsy in young sudden cardiac death victims with suspected cardiomyopathy. Forensic Sci Int 219(1-3):33–38PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Cann F, Corbett M, O'Sullivan D, Tennant S, Hailey H, Grieve JH, Broadhurst P, Rankin R, Dean JC (2017) Phenotype-driven molecular autopsy for sudden cardiac death. Clinical genetics 91(1):22–29PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Alcalde M, Campuzano O, Allegue C, Torres M, Arbelo E, Partemi S, Iglesias A, Brugada J, Oliva A, Carracedo A, Brugada R (2015) Sequenom MassARRAY approach in the arrhythmogenic right ventricular cardiomyopathy post-mortem setting: clinical and forensic implications. Int J Legal Med 129(1):1–10PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Zhang M, Tavora F, Oliveira JB, Li L, Franco M, Fowler D, Zhao Z, Burke A (2012) PKP2 mutations in sudden death from arrhythmogenic right ventricular cardiomyopathy (ARVC) and sudden unexpected death with negative autopsy (SUDNA). Circ J 76(1):189–194PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Allegue C, Gil R, Blanco-Verea A, Santori M, Rodriguez-Calvo M, Concheiro L, Carracedo A, Brion M (2011) Prevalence of HCM and long QT syndrome mutations in young sudden cardiac death-related cases. Int J Legal Med 125(4):565–572PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Hertz CL, Christiansen SL, Ferrero-Miliani L, Dahl M, Weeke PE, LuCamp OGL, Frank-Hansen R, Bundgaard H, Morling N (2016) 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 130(1):91–102PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Neubauer J, Haas C, Bartsch C, Medeiros-Domingo A, Berger W (2016) 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 130(4):1011–1021PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Nunn LM, Lopes LR, Syrris P, Murphy C, Plagnol V, Firman E, Dalageorgou C, Zorio E, Domingo D, Murday V, Findlay I, Duncan A, Carr-White G, Robert L, Bueser T, Langman C, Fynn SP, Goddard M, White A, Bundgaard H, Ferrero-Miliani L, Wheeldon N, Suvarna SK, O'Beirne A, Lowe MD, McKenna WJ, Elliott PM, Lambiase PD (2016) Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing. Europace 18(6):888–896PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Bagnall RD, Weintraub RG, Ingles J, Duflou J, Yeates L, Lam L, Davis AM, Thompson T, Connell V, Wallace J, Naylor C, Crawford J, Love DR, Hallam L, White J, Lawrence C, Lynch M, Morgan N, James P, du Sart D, Puranik R, Langlois N, Vohra J, Winship I, Atherton J, McGaughran J, Skinner JR, Semsarian C (2016) A Prospective Study of Sudden Cardiac Death among Children and Young Adults. N Engl J Med 374(25):2441–2452PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Bagnall RD, Das KJ, Duflou J, Semsarian C (2014) Exome analysis-based molecular autopsy in cases of sudden unexplained death in the young. Heart Rhythm 11(4):655–662PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Narula N, Tester DJ, Paulmichl A, Maleszewski JJ, Ackerman MJ (2015) Post-mortem Whole exome sequencing with gene-specific analysis for autopsy-negative sudden unexplained death in the young: a case series. Pediatr Cardiol 36(4):768–778PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Christiansen SL, Hertz CL, Ferrero-Miliani L, Dahl M, Weeke PE, LuCamp OGL, Frank-Hansen R, Bundgaard H, Morling N (2016) Genetic investigation of 100 heart genes in sudden unexplained death victims in a forensic setting. Eur J Hum Genet 24(12):1797–1802PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Hata Y, Kinoshita K, Mizumaki K, Yamaguchi Y, Hirono K, Ichida F, Takasaki A, Mori H, Nishida N (2016) Postmortem genetic analysis of sudden unexplained death syndrome under 50 years of age: A next-generation sequencing study. Heart Rhythm 13(7):1544–1551PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Lahrouchi N, Raju H, Lodder EM, Papatheodorou E, Ware JS, Papadakis M, Tadros R, Cole D, Skinner JR, Crawford J, Love DR, Pua CJ, Soh BY, Bhalshankar JD, Govind R, Tfelt-Hansen J, Winkel BG, van der Werf C, Wijeyeratne YD, Mellor G, Till J, Cohen MC, Tome-Esteban M, Sharma S, Wilde AAM, Cook SA, Bezzina CR, Sheppard MN, Behr ER (2017) Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome. J Am Coll Cardiol 69(17):2134–2145PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Shanks GW, Tester DJ, Nishtala S, Evans JM, and Ackerman MJ (2017) Genomic Triangulation and Coverage Analysis in Whole-Exome Sequencing-Based Molecular Autopsies. Circ Cardiovasc Genet 10(5).Google Scholar
  30. 30.
    Hellenthal N, Gaertner-Rommel A, Klauke B, Paluszkiewicz L, Stuhr M, Kerner T, Farr M, Puschel K, Milting H (2017) Molecular autopsy of sudden unexplained deaths reveals genetic predispositions for cardiac diseases among young forensic cases. Europace 19(11):1881–1890PubMedPubMedCentralGoogle Scholar
  31. 31.
    Neubauer J, Lecca MR, Russo G, Bartsch C, Medeiros-Domingo A, Berger W, Haas C (2018) Exome analysis in 34 sudden unexplained death (SUD) victims mainly identified variants in channelopathy-associated genes. Int J Legal Med 132(4):1057–1065PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Basso C, Aguilera B, Banner J, Cohle S, d'Amati G, de Gouveia RH, di Gioia C, Fabre A, Gallagher PJ, Leone O, Lucena J, Mitrofanova L, Molina P, Parsons S, Rizzo S, Sheppard MN, MPS M, Kim Suvarna S, Thiene G, van der Wal A, Vink A, Michaud K, Association for European Cardiovascular P (2017) Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the Association for European Cardiovascular Pathology. Virchows Arch 471(6):691–705PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Hughes SE (2004) The pathology of hypertrophic cardiomyopathy. Histopathology 44(5):412–427PubMedCrossRefGoogle Scholar
  34. 34.
    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA (2015) 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 17(5):405–424PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, Strom CM, Keiles SB, Higgins JJ (2016) A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. Hum Mutat 37(1):127–134PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    R Core Team (2014), R: A language and environment for statistical computing.Google Scholar
  37. 37.
    Grantham R (1974) Amino acid difference formula to help explain protein evolution. Science 185(4154):862–864PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Mathe E, Olivier M, Kato S, Ishioka C, Hainaut P, Tavtigian SV (2006) Computational approaches for predicting the biological effect of p53 missense mutations: a comparison of three sequence analysis based methods. Nucleic Acids Res 34(5):1317–1325PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Henikoff S, Henikoff JG (1992) Amino acid substitution matrices from protein blocks. Proc Natl Acad Sci U S A 89(22):10915–10919PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
  41. 41.
    Stone EA, Sidow A (2005) Physicochemical constraint violation by missense substitutions mediates impairment of protein function and disease severity. Genome Res 15(7):978–986PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Ng PC, Henikoff S (2001) Predicting deleterious amino acid substitutions. Genome Res 11(5):863–874PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Schwarz JM, Rodelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7(8):575–576PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29(1):308–311PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Karczewski KJ, Weisburd B, Thomas B, Solomonson M, Ruderfer DM, Kavanagh D, Hamamsy T, Lek M, Samocha KE, Cummings BB, Birnbaum D, The Exome Aggregation C, Daly MJ, MacArthur DG (2017) The ExAC browser: displaying reference data information from over 60 000 exomes. Nucleic Acids Res 45(D1):D840–D845PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, Abeysinghe S, Krawczak M, Cooper DN (2003) Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat 21(6):577–581PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR (2014) ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res 42(Database issue):D980–D985CrossRefGoogle Scholar
  48. 48.
    Ng D, Johnston JJ, Teer JK, Singh LN, Peller LC, Wynter JS, Lewis KL, Cooper DN, Stenson PD, Mullikin JC, Biesecker LG, Program NIHISCCS (2013) Interpreting secondary cardiac disease variants in an exome cohort. Circ Cardiovasc Genet 6(4):337–346PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Dorschner MO, Amendola LM, Turner EH, Robertson PD, Shirts BH, Gallego CJ, Bennett RL, Jones KL, Tokita MJ, Bennett JT, Kim JH, Rosenthal EA, Kim DS, National Heart L, Blood Institute Grand Opportunity Exome Sequencing P, Tabor HK, Bamshad MJ, Motulsky AG, Scott CR, Pritchard CC, Walsh T, Burke W, Raskind WH, Byers P, Hisama FM, Nickerson DA, Jarvik GP (2013) Actionable, pathogenic incidental findings in 1,000 participants' exomes. Am J Hum Genet 93(4):631–640PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Silver MM, Freedom RM (1991) Gross examination and structure of the heart. In: Silver MD (ed) Cardiovascular pathology, 2nd edn. Churchill Livingstone, New York, pp 1–42Google Scholar
  51. 51.
    Kitzman DW, Scholz DG, Hagen PT, Ilstrup DM, Edwards WD (1988) Age-related changes in normal human hearts during the first 10 decades of life. Part II (Maturity): A quantitative anatomic study of 765 specimens from subjects 20 to 99 years old. Mayo Clin Proc 63(2):137–146PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Tfelt-Hansen J, Winkel BG, Grunnet M, Jespersen T (2010) Inherited cardiac diseases caused by mutations in the Nav1.5 sodium channel. J Cardiovasc Electrophysiol 21(1):107–115PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Calloe K, Broendberg AK, Christensen AH, Pedersen LN, Olesen MS, de Los Angeles Tejada M, Friis S, Thomsen MB, Bundgaard H, Jensen HK (2018) Multifocal atrial and ventricular premature contractions with an increased risk of dilated cardiomyopathy caused by a Nav1.5 gain-of-function mutation (G213D). Int J Cardiol 257:160–167PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Kanters JK, Skibsbye L, Hedley PL, Dembic M, Liang B, Hagen CM, Eschen O, Grunnet M, Christiansen M, Jespersen T (2015) Combined gating and trafficking defect in Kv11.1 manifests as a malignant long QT syndrome phenotype in a large Danish p.F29L founder family. Scand J Clin Lab Invest 75(8):699–709PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Cerrone M, Delmar M (2014) Desmosomes and the sodium channel complex: implications for arrhythmogenic cardiomyopathy and Brugada syndrome. Trends Cardiovasc Med 24(5):184–190PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Cerrone M, Lin X, Zhang M, Agullo-Pascual E, Pfenniger A, Chkourko Gusky H, Novelli V, Kim C, Tirasawadichai T, Judge DP, Rothenberg E, Chen HS, Napolitano C, Priori SG, Delmar M (2014) Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype. Circulation 129(10):1092–1103PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Zhang Q, Deng C, Rao F, Modi RM, Zhu J, Liu X, Mai L, Tan H, Yu X, Lin Q, Xiao D, Kuang S, Wu S (2013) Silencing of desmoplakin decreases connexin43/Nav1.5 expression and sodium current in HL1 cardiomyocytes. Mol Med Rep 8(3):780–786PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Rizzo S, Lodder EM, Verkerk AO, Wolswinkel R, Beekman L, Pilichou K, Basso C, Remme CA, Thiene G, Bezzina CR (2012) Intercalated disc abnormalities, reduced Na(+) current density, and conduction slowing in desmoglein-2 mutant mice prior to cardiomyopathic changes. Cardiovasc Res 95(4):409–418PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Brion M, Allegue C, Santori M, Gil R, Blanco-Verea A, Haas C, Bartsch C, Poster S, Madea B, Campuzano O, Brugada R, Carracedo A (2012) Sarcomeric gene mutations in sudden infant death syndrome (SIDS). Forensic Sci Int 219(1-3):278–281PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Zaklyazminskaya E, Dzemeshkevich S (2016) The role of mutations in the SCN5A gene in cardiomyopathies. Biochim Biophys Acta 1863(7 Pt B):1799–1805PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Baruteau AE, Behr ER (2017) Investigation of the family of sudden cardiac death victims. Prog Pediatr Cardiol 45:25–29CrossRefGoogle Scholar
  62. 62.
    Behr ER, Dalageorgou C, Christiansen M, Syrris P, Hughes S, Tome Esteban MT, Rowland E, Jeffery S, McKenna WJ (2008) Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J 29(13):1670–1680PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Ranthe MF, Winkel BG, Andersen EW, Risgaard B, Wohlfahrt J, Bundgaard H, Haunso S, Melbye M, Tfelt-Hansen J, Boyd HA (2013) Risk of cardiovascular disease in family members of young sudden cardiac death victims. Eur Heart J 34(7):503–511PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Tan HL, Hofman N, van Langen IM, van der Wal AC, Wilde AA (2005) Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives. Circulation 112(2):207–213PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Mullally J, Goldenberg I, Moss AJ, Lopes CM, Ackerman MJ, Zareba W, McNitt S, Robinson JL, Benhorin J, Kaufman ES, Towbin JA, Barsheshet A (2013) Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations. Heart Rhythm 10(3):378–382PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    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):1178–1185PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Nastoli J, Bottelli G, Cerrone M, Leonardi S (2005) Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA 294(23):2975–2980PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Palmer RE, Amartino HM, Niizawa G, Blanco M, Pomponio RJ, Chamoles NA (2007) Pompe disease (glycogen storage disease type II) in Argentineans: clinical manifestations and identification of 9 novel mutations. Neuromuscul Disord 17(1):16–22PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Kamisago M, Schmitt JP, McNamara D, Seidman C, Seidman JG (2006) Sarcomere protein gene mutations and inherited heart disease: a beta-cardiac myosin heavy chain mutation causing endocardial fibroelastosis and heart failure. Novartis Foundation symposium 274:176-189; discussion 189-195, 272-176Google Scholar
  70. 70.
    Taylor M, Graw S, Sinagra G, Barnes C, Slavov D, Brun F, Pinamonti B, Salcedo EE, Sauer W, Pyxaras S, Anderson B, Simon B, Bogomolovas J, Labeit S, Granzier H, Mestroni L (2011) Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. Circulation 124(8):876–885PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Potet F, Mabo P, Le Coq G, Probst V, Schott JJ, Airaud F, Guihard G, Daubert JC, Escande D, Le Marec H (2003) Novel brugada SCN5A mutation leading to ST segment elevation in the inferior or the right precordial leads. J Cardiovasc Electrophysiol 14(2):200–203PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB, Markowitz SM, Ellinor PT, MacRae CA, Peters S, Grossmann KS, Drenckhahn J, Michely B, Sasse-Klaassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr E, Thierfelder L (2004) Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 36(11):1162–1164PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Olivotto I, Girolami F, Ackerman MJ, Nistri S, Bos JM, Zachara E, Ommen SR, Theis JL, Vaubel RA, Re F, Armentano C, Poggesi C, Torricelli F, Cecchi F (2008) Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc 83(6):630–638PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Astejada MN, Goto K, Nagano A, Ura S, Noguchi S, Nonaka I, Nishino I, Hayashi YK (2007) Emerinopathy and laminopathy clinical, pathological and molecular features of muscular dystrophy with nuclear envelopathy in Japan. Acta Myol 26(3):159–164Google Scholar
  75. 75.
    Carniel E, Taylor MR, Sinagra G, Di Lenarda A, Ku L, Fain PR, Boucek MM, Cavanaugh J, Miocic S, Slavov D, Graw SL, Feiger J, Zhu XZ, Dao D, Ferguson DA, Bristow MR, Mestroni L (2005) Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy. Circulation 112(1):54–59PubMedCrossRefPubMedCentralGoogle Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Forensic Medicine, Faculty of Health SciencesUniversity of AarhusAarhusDenmark
  2. 2.Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  3. 3.Novo Nordisk A/SSøborgDenmark
  4. 4.Chr. Hansen A/SHørsholmDenmark
  5. 5.Department of CardiologyAarhus University HospitalAarhusDenmark
  6. 6.Department of Clinical Medicine, HealthAarhus UniversityAarhusDenmark
  7. 7.Section of Forensic Pathology, Department of Forensic Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark

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