Unravelling the Mystery of Sudden Cardiac Death Through Genetic Approaches

Seok Hwee Koo, National University of Singapore, Singapore
Chee Seng Ku, National University of Singapore, Singapore
Paul Chui, Forensic Medicine Division, Singapore
Edmund Jon Deoon Lee, National University of Singapore, Singapore

Published online: July 2011

DOI: 10.1002/9780470015902.a0023214

The sudden unexplained death syndrome is a tragic and distressing event, which may arise due to an underlying fatal cardiac arrhythmia, which may be associated with a defective ion channel. These electrical abnormalities of the heart do not present with gross structural changes, rendering it a challenging task to the forensic pathologist in ascertaining the cause of death during autopsies. The attempts to identify genetic variations in the key ion channels known to cause arrhythmias have only been able to reveal the presence of putative mutations in a small percentage of the cases. It is thus imperative to look beyond the discovery of single-nucleotide polymorphisms to other forms of genetic variations (such as copy number variations and structural rearrangements), as well as alternative mechanisms that may underlie the molecular pathogenesis of arrhythmias and electrocardiographic abnormalities causing sudden death. Additionally, the various technological platforms for genetic analysis are also described in this article.

Key Concepts:

  • Sudden unexplained death syndrome is an important clinical problem.
  • Sudden death may be the result of a fatal cardiac arrhythmia.
  • Arrhythmias are associated with genetic mutations in ion channel genes.
  • Genetic mutations often exhibit incomplete penetrance.
  • Genetic mutations may have functional impact on the ion channel.
  • Single-nucleotide polymorphisms only account for a fraction of the cases.
  • Copy number variations and chromosomal aberrations may play a role in sudden death pathology.
  • The role of alternative mechanisms such as epigenetics in arrhythmias/sudden death remains to be ascertained.
  • The technology for identifying genetic variations is advancing rapidly.
  • Genome-wide sequencing is expected to become increasingly feasible.

Keywords: sudden unexplained death syndrome; arrhythmias; genetic variants; ion channels; genome-wide association studies; candidate gene sequencing; next-generation sequencing

Figure 1. Schematic diagram illustrating the diverse causes of sudden cardiac death.
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 References
    1000 Genomes Project Consortium, Durbin RM, Abecasis GR et al. (2010) A map of human genome variation from population-scale sequencing. Nature 467: 1061–1073.
    Ackerman MJ, Siu BL, Sturner WQ et al. (2001) Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. Journal of the American Medical Association 286: 2264–2269.
    Antzelevitch C, Pollevick GD, Cordeiro JM et al. (2007) 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 115: 442–449.
    Arbour L, Rezazadeh S, Eldstrom J et al. (2008) A KCNQ1 V205M missense mutation causes a high rate of long QT syndrome in a First Nations community of northern British Columbia: a community-based approach to understanding the impact. Genetics Medicine 10: 545–550.
    Arking DE, Pfeufer A, Post W et al. (2006) A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nature Genetics 38: 644–651.
    Arking DE, Reinier K, Post W et al. (2010) Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest. Public Library of Science One 5: e9879.
    Arnestad M, Crotti L, Rognum TO et al. (2007) Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation 115: 361–367.
    Arnett DK, Li N, Tang W et al. (2009) Genome-wide association study identifies single-nucleotide polymorphism in KCNB1 associated with left ventricular mass in humans: the HyperGEN Study. BioMed Central Medical Genetics 10: 43.
    Banerjee B, Peiris DN, Koo SH et al. (2008) Genomic imbalances in key ion channel genes and telomere shortening in sudden cardiac death victims. Cytogenetics and Genome Research 122: 350–355.
    Bezzina CR, Pazoki R, Bardai A et al. (2010) Genome-wide association study identifies a susceptibility locus at 21q21 for ventricular fibrillation in acute myocardial infarction. Nature Genetics 42: 688–691.
    Brkanac Z, Spencer D, Shendure J et al. (2009) IFRD1 is a candidate gene for SMNA on chromosome 7q22–q23. American Journal of Human Genetics 84: 692–697.
    Carter NP (2007) Methods and strategies for analyzing copy number variation using DNA microarrays. Nature Genetics 39: S16–21.
    Chambers JC, Zhao J, Terracciano CM et al. (2010) Genetic variation in SCN10A influences cardiac conduction. Nature Genetics 42: 149–152.
    Chen S, Zhang L, Bryant RM et al. (2003) KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death. Clinical Genetics 63: 273–282.
    Chugh SS, Senashova O, Watts A et al. (2004) Postmortem molecular screening in unexplained sudden death. Journal of the American College of Cardiology 43: 1625–1629.
    Cooper RS, Tayo B, Zhu X et al. (2008) Genome-wide association studies: implications for multiethnic samples. Human Molecular Genetics 17: R151–R155.
    Denny JC, Ritchie MD, Crawford DC et al. (2010) Identification of genomic predictors of atrioventricular conduction: using electronic medical records as a tool for genome science. Circulation 122: 2016–2021.
    Doolan A, Langlois N, Chiu C et al. (2008) Postmortem molecular analysis of KCNQ1 and SCN5A genes in sudden unexplained death in young Australians. International Journal of Cardiology 127: 138–141.
    Feuk L (2010) Inversion variants in the human genome: role in disease and genome architecture. Genome Medicine 2: 11.
    Han JW, Zheng HF, Cui Y et al. (2009) Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nature Genetics 41: 1234–1237.
    Holm H, Gudbjartsson DF, Arnar DO et al. (2010) Several common variants modulate heart rate, PR interval and QRS duration. Nature Genetics 42: 117–122.
    Huang X, Feng Q, Qian Q et al. (2009) High-throughput genotyping by whole-genome resequencing. Genome Research 19: 1068–1076.
    Koo SH, Chui P and Lee EJ (2008) Genetics of ion channels in sudden unexplained death syndrome: moving beyond idiopathic reactions to personalized risk assessment. Current Pharmacogenomics and Personalized Medicine 6: 185–200.
    Ku CS and Chia KS (2008) The success of the genome-wide association approach: a brief story of a long struggle. European Journal of Human Genetics 15: 554–564.
    Lai LP, Su YN, Hsieh FJ et al. (2005) Denaturing high-performance liquid chromatography screening of the long QT syndrome-related cardiac sodium and potassium channel genes and identification of novel mutations and single nucleotide polymorphisms. Journal of Human Genetics 50: 490–496.
    Larson MG, Atwood LD, Benjamin EJ et al. (2007) Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes. BioMed Central Medical Genetics 8(suppl. 1): S5.
    Li Y, Vinckenbosch N, Tian G et al. (2010) Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nature Genetics 42: 969–972.
    Liu W, Yang J, Hu D et al. (2002) KCNQ1 and KCNH2 mutations associated with long QT syndrome in a Chinese population. Human Mutation 20: 475–476.
    Luo Y, Wang H, Han X et al. (2009) Meta-analysis of the association between SNPs in TCF7L2 and type 2 diabetes in East Asian population. Diabetes Research and Clinical Practice 85: 139–146.
    Makiyama T, Akao M, Tsuji K et al. (2005) High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations. Journal of American College of Cardiology 46: 2100–2106.
    Manolio TA, Collins FS, Cox NJ et al. (2009) Finding the missing heritability of complex diseases. Nature 461: 747–753.
    Marroni F, Pfeufer A, Aulchenko YS et al. (2009) A genome-wide association scan of RR and QT interval duration in 3 European genetically isolated populations: the EUROSPAN project. Circulatory and Cardiovascular Genetics 2: 322–328.
    Medvedev P, Stanciu M and Brudno M (2009) Computational methods for discovering structural variation with next-generation sequencing. Nature Methods 6: S13–S20.
    Nejentsev S, Walker N, Riches D et al. (2009) Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324: 387–389.
    Newton-Cheh C, Eijgelsheim M, Rice KM et al. (2009) Common variants at ten loci influence QT interval duration in the QTGEN Study. Nature Genetics 41: 399–406.
    Newton-Cheh C, Guo CY, Wang TJ et al. (2007) Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study. BioMed Central Medical Genetics 8(suppl. 1): S7.
    Ng SB, Nickerson DA, Bamshad MJ et al. (2010) Massively parallel sequencing and rare disease. Human Molecular Genetics 19: R119–R124.
    Ng SB, Turner EH, Robertson PD et al. (2009) Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461: 272–276.
    Nishio H, Kuwahara M, Tsubone H et al. (2009) Identification of an ethnic-specific variant (V207M) of the KCNQ1 cardiac potassium channel gene in sudden unexplained death and implications from a knock-in mouse model. International Journal of Legal Medicine 123: 253–257.
    Nolte IM, Wallace C, Newhouse SJ et al. (2009) Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies. Public Library of Science One 4: e6138.
    Pfeufer A, van Noord C, Marciante KD et al. (2010) Genome-wide association study of PR interval. Nature Genetics 42: 153–159.
    Pfeufer A, Sanna S, Arking DE et al. (2009) Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nature Genetics 41: 407–414.
    Ragoussis J (2009) Genotyping technologies for genetic research. Annual Review of Genomics and Human Genetics 10: 117–133.
    Rosenberg NA, Huang L, Jewett EM et al. (2010) Genome-wide association studies in diverse populations. Nature Reviews Genetics 11: 356–366.
    Sarkozy A and Brugada P (2005) Sudden cardiac death: what is inside our genes? Canadian Journal of Cardiology 21: 1099–1110.
    Shendure J and Ji H (2008) Next-generation DNA sequencing. Nature Biotechnology 26: 1135–1145.
    Skinner JR, Crawford J, Smith W et al. (2011) Prospective, population-based long QT molecular autopsy study of postmortem negative sudden death in victims 1 to 40 years old. Heart Rhythm 8: 412–419.
    Shu XO, Long J, Cai Q et al. (2010) Identification of new genetic risk variants for type 2 diabetes. Public Library of Science Genetics 16: e1001127.
    Smith NL, Felix JF, Morrison AC et al. (2010) Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. Circulatory and Cardiovascular Genetics 3: 256–266.
    Sotoodehnia N, Isaacs A, de Bakker PI et al. (2010) Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. Nature Genetics 42: 1068–1076.
    Takata R, Akamatsu S, Kubo M et al. (2010) Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population. Nature Genetics 42: 751–754.
    Tarpey PS, Smith R, Pleasance E et al. (2009) A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nature Genetics 41: 535–543.
    Tester DJ and Ackerman MJ (2007) Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. Journal of the American College of Cardiology 49: 240–246.
    Toruner GA, Kurvathi R, Sugalski R et al. (2009) Copy number variations in three children with sudden infant death. Clinical Genetics 76: 63–68.
    Unoki H, Takahashi A, Kawaguchi T et al. (2008) SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nature Genetics 40: 1098–1102.
    Voight BF, Scott LJ, Steinthorsdottir V et al. (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nature Genetics 42: 579–589.
    Wain LV, Armour JA and Tobin MD (2009) Genomic copy number variation, human health, and disease. Lancet 374: 340–350.
    Wong CH, Koo SH, She GQ et al. (2009) Genetic variability of RyR2 and CASQ2 genes in an Asian population. Forensic Science International 192: 53–55.
    Yamauchi T, Hara K, Maeda S et al. (2010) A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A–C2CD4B. Nature Genetics 42: 864–868.
    Yasuda K, Miyake K, Horikawa Y et al. (2008) Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nature Genetics 40: 1092–1097.
 Further Reading
    Brion M, Quintela I, Sobrino B et al. (2010) New technologies in the genetic approach to sudden cardiac death in the young. Forensic Science International 203: 15–24.
    Koo SH, Ho WF and Lee EJ (2006) Genetic polymorphisms in KCNQ1, HERG, KCNE1 and KCNE2 genes in the Chinese, Malay and Indian populations of Singapore. British Journal of Clinical Pharmacology 61: 301–308.
    Koo SH, Teo WS, Ching CK et al. (2007) Mutation screening in KCNQ1, HERG, KCNE1, KCNE2 and SCN5A genes in a long QT syndrome family. Annals Academy of Medicine Singapore 36: 394–395.
    Ku CS, Loy EY, Pawitan Y et al. (2010) The pursuit of genome-wide association studies: where are we now? Journal of Human Genetics 55: 195–206.
    Ku CS, Loy EY, Salim A et al. (2010) The discovery of human genetic variations and their use as disease markers: past, present and future. Journal of Human Genetics 55: 403–415.
    Ku CS, Pawitan Y, Sim X et al. (2010) Genomic copy number variations in three Southeast Asian populations. Human Mutation 31: 851–857.
    Milan DJ, Lubitz SA, Kääb S et al. (2010) Genome-wide association studies in cardiac electrophysiology: recent discoveries and implications for clinical practice. Heart Rhythm 7: 1141–1148.

Related Sub-Topics:

Molecular Genetics of Common and Complex Disease | Gene Mapping by Disease Association | Inter-Individual Variation and Polymorphism
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Article Title: Unravelling the Mystery of Sudden Cardiac Death Through Genetic Approaches
 
How to Cite close
Koo, Seok Hwee, Ku, Chee Seng, Chui, Paul, and Lee, Edmund Jon Deoon(Jul 2011) Unravelling the Mystery of Sudden Cardiac Death Through Genetic Approaches. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023214]