Advertisement

The role of genetic testing in unexplained sudden death

  • Chris J. Miles
    Affiliations
    Division of Clinical Sciences, Cardiovascular Sciences Research Centre, St George's University of London, London, UK
    Search for articles by this author
  • Elijah R. Behr
    Correspondence
    Reprint requests: Elijah R. Behr, Division of Clinical Sciences, Cardiovascular Sciences Research Centre, St George's University of London, Cranmer Terrace, London SW17 0RE, UK
    Affiliations
    Division of Clinical Sciences, Cardiovascular Sciences Research Centre, St George's University of London, London, UK
    Search for articles by this author
      Most sudden deaths are because of a cardiac etiology and are termed sudden cardiac death (SCD). In younger individuals coronary artery disease is less prevalent and cardiac genetic disorders are more common. If sudden death is unexplained despite an appropriate autopsy and toxicologic assessment the term sudden arrhythmic death syndrome (SADS) may be used. This is an umbrella term and common underlying etiologies are primary arrhythmia syndromes with a familial basis such as Brugada syndrome, long QT syndrome, and subtle forms of cardiomyopathy. The first clinical presentation of these conditions is often SCD, which makes identification, screening, and risk stratification crucial to avert further deaths. This review will focus on genetic testing in the context of family screening. It will address the role of the “molecular autopsy” alongside current postmortem practices in the evaluation of SADS deaths. We describe the current data underlying genetic testing in these conditions, explore the potential for next-generation sequencing, and discuss the inherent diagnostic problems in determination of pathogenicity.

      Abbreviations:

      AHA (American Heart Association), ARVC (arrhythmogenic right ventricular cardiomyopathy), BrS (Brugada syndrome), ChIP (channel interacting protein), CPVT (catecholaminergic polymorphic ventricular tachycardia), DCM (dilated cardiomyopathy), EHRA (European Heart Rhythm Association), ERS (early repolarization syndrome), HCM (hypertrophic cardiomyopathy), HRS (Heart Rhythm Society), IVF (idiopathic ventricular fibrillation), LQTS (long QT syndrome), PCCD (premature cardiac conduction disease), SADS (sudden arrhythmic death syndrome), SCD (sudden cardiac death), SNR (signal-to-noise ratio), SQTS (short QT syndrome), SUDS (sudden unexpected death syndrome), VUS (variant of unknown significance)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Nichol G.
        • Thomas E.
        • Callaway C.W.
        • et al.
        Regional variation in out-of-hospital cardiac arrest incidence and outcome.
        JAMA. 2008; 300: 1423-1431
        • Chugh S.S.
        • Jui J.
        • Gunson K.
        • et al.
        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. 2004; 44: 1268-1275
        • Byrne R.
        • Constant O.
        • Smyth Y.
        • et al.
        Multiple source surveillance incidence and aetiology of out-of-hospital sudden cardiac death in a rural population in the west of Ireland.
        Eur Heart J. 2008; 29: 1418-1423
        • Engelstein E.D.
        • Zipes D.P.
        Sudden cardiac death.
        in: Alexander R.W. Schlant R.C. Fuster V. The heart, arteries and veins. McGraw-Hill, New York, NY1998: 1081-1112
        • Myerburg R.J.
        Cardiac arrest and sudden cardiac death' in heart disease: a textbook of cardiovascular medicine.
        7th ed. WB Saunders, Philadelphia2005
      1. NICE Technology Appraisal—implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure. 2014. Available at: http://www.nice.org.uk/guidance/ta314/chapter/2-clinical-need-and-practice. Accessed September 2014.

        • Winkel B.G.
        Sudden cardiac death in young Danes.
        Dan Med J. 2012; 59: B4403
        • Eckart R.E.
        • Scoville S.L.
        • Campbell C.L.
        • et al.
        Sudden death in young adults: a 25-year review of autopsies in military recruits.
        Ann Intern Med. 2004; 141: 829-834
        • Puranik R.
        • Chow C.K.
        • Duflou J.A.
        • Kilborn M.J.
        • McGuire M.A.
        Sudden death in the young.
        Heart Rhythm. 2005; 2: 1277-1282
        • Risgaard B.
        • Winkel B.G.
        • Jabbari R.
        • et al.
        Burden of sudden cardiac death in persons aged 1 to 49 years: nationwide study in Denmark.
        Circ Arrhythm Electrophysiol. 2014; 7: 205-211
        • Corrado D.
        • Basso C.
        • Thiene G.
        Sudden cardiac death in young people with apparently normal heart.
        Cardiovasc Res. 2001; 50: 399-408
        • Corrado D.
        • Fontaine G.
        • Marcus F.I.
        • et al.
        Arrhythmogenic right ventricular dysplasia/cardiomyopathy: need for an international registry. Study Group on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy of the Working Groups on Myocardial and Pericardial Disease and Arrhythmias of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the World Heart Federation.
        Circulation. 2000; 101: E101-E106
        • Maron B.J.
        • Doerer J.J.
        • Haas T.S.
        • Tierney D.M.
        • Mueller F.O.
        Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006.
        Circulation. 2009; 119: 1085-1092
        • Papadakis M.
        • Sharma S.
        • Cox C.
        • Sheppard M.N.
        • Panoulas V.F.
        • Behr E.R.
        The magnitude of sudden cardiac death in the young: a death certificate-based review in England and Wales.
        Europace. 2009; 11: 1353-1358
        • Tester D.J.
        • Medeiros-Domingo A.
        • Will M.L.
        • Ackerman M.J.
        Unexplained drownings and the cardiac channelopathies: a molecular autopsy series.
        Mayo Clin Proc. 2011; 86: 941-947
        • Raji H.
        • Behr E.R.
        Unexplained sudden death, focussing on genetics and family phenotyping.
        Curr Opin Cardiol. 2013; 28: 19-25
        • Sandorfi G.
        • Clemens B.
        • Csanadi Z.
        Electrical storm in the brain and in the heart: epilepsy and Brugada syndrome.
        Mayo Clin Proc. 2013; 88: 1167-1173
        • Priori S.G.
        • Wilde A.A.
        • Horie M.
        • 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: 1932-1963
        • Papadakis M.
        • Hariharan R.
        • Behr E.R.
        • et al.
        Sudden cardiac death with autopsy findings of uncertain significance.
        Circ Arrhythm Electrophysiol. 2013; 6: 588-596
        • de Noronha S.V.
        • Behr E.R.
        • Papadakis M.
        • et al.
        The importance of specialist cardiac histopathological examination in the investigation of young sudden cardiac deaths.
        Europace. 2014; 16: 899-907
      2. Trans-Tasman Response Against Sudden Death in the Young (TRAGADY). Post-mortem in sudden unexpected death in the young: guidelines on autopsy practice. 2008. Available at: https://www.cidg.org/webcontent/LinkClick.aspx?fileticket=DO9YIQWqegI%3D&tabid=161. Accessed June 5, 2015.

      3. Office of the Chief Coroner for Ontario. Guidelines for the investigation of sudden cardiac death. Memo #08–01. Available at: http://nsgc.org/d/do/978. Accessed June 5, 2015.

      4. Sudden Death in the Young Case Registry. University of Michigan. National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Neurological Disorders and Stroke (NINDS), and the Centers for Disease Control and Prevention (CDC). Available at: http://www.nhlbi.nih.gov/news/spotlight/fact-sheet/frequently-asked-questions-about-sudden-death-young-case-registry. Accessed June 5, 2015.

        • Coronary Heart Disease National Service Framework
        Chapter 8. Arrhythmias and sudden cardiac death.
        Department of Health, London2005
        • Wilde A.A.
        • Behr E.R.
        Genetic testing for inherited cardiac disease.
        Nat Rev Cardiol. 2013; 10: 571-583
        • Landstrom A.P.
        • Ackerman M.J.
        The Achilles' heel of cardiovascular genetic testing: distinguishing pathogenic mutations from background genetic noise.
        Clin Pharmacol Ther. 2011; 90: 496-499
        • Ackermann M.J.
        • Priori S.G.
        • Willems S.
        • et al.
        HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies.
        Europace. 2011; 13: 1077-1109
        • Willerson J.
        • Cohn J.
        • Wellens H.
        • Holmes D.
        Cardiovascular medicine.
        3rd ed. Springer, New York2007 (ISBN-10: 1846281881. P2592)
        • Tester D.J.
        • Ackerman M.J.
        Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice.
        Circulation. 2011; 123: 1021-1037
      5. Exome Aggregation Consortium (ExAC), Cambridge, MA. Available at: http://exac.broadinstitute.org. Accessed June 3, 2015.

        • Tfelt-Hansen J.
        • Jespersen T.
        • Hofman-Bang J.
        • et al.
        Ventricular tachycardia in a Brugada syndrome patient caused by a novel deletion in SCN5A.
        Can J Cardiol. 2009; 25: 156-160
        • Herman D.S.
        • Lam L.
        • Taylor M.R.
        • et al.
        Truncations of titin causing dilated cardiomyopathy.
        N Engl J Med. 2012; 366: 619-628
        • Roberts A.M.
        • Ware J.S.
        • Herman D.S.
        • et al.
        Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.
        Sci Transl Med. 2015; 7: 270ra6
        • Jabbari J.
        • Jabbari R.
        • Nielsen M.W.
        • et al.
        New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia.
        Circ Cardiovasc Genet. 2013; 6: 481-489
        • Refsgaard L.
        • Holst A.G.
        • Sadjadieh G.
        • Haunsø S.
        • Nielsen J.B.
        • Olesen M.S.
        High prevalence of genetic variants previously associated with LQT syndrome in new exome data.
        Eur J Hum Genet. 2012; 20: 905-908
        • Norton N.
        • Robertson P.D.
        • Rieder M.J.
        • et al.
        Evaluating pathogenicity of rare variants from dilated cardiomyopathy in the exome era.
        Circ Cardiovasc Genet. 2012; 5: 167-174
        • Bell C.J.
        • Dinwiddie D.L.
        • Miller N.A.
        • et al.
        Carrier testing for severe childhood recessive diseases by next-generation sequencing.
        Sci Transl Med. 2011; 3: 65ra4
        • Grantham R.
        Amino acid difference formula to help explain protein evolution.
        Science. 1974; 185: 862-864
        • Giudicessi J.R.
        • Kapplinger J.D.
        • Tester D.J.
        • 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: 519-528
        • Kapplinger J.D.
        • Giudicessi J.R.
        • Ye D.
        • et al.
        Enhanced classification of Brugada syndrome- and long QT syndrome-associated genetic variants in the SCN5A-encoded Nav1.5 cardiac sodium channel.
        Circ Cardiovasc Genet. 2015; ([Epub ahead of print])
        • Campuzano O.
        • Allegue C.
        • Fernandez A.
        • Iglesias A.
        • Brugada R.
        Determining the pathogenicity of genetic variants associated with cardiac channelopathies.
        Sci Rep. 2015; 5: 7953
        • Itoh H.
        • Shimizu W.
        • Hayashi K.
        • et al.
        Long QT syndrome with compound mutations is associated with a more severe phenotype: a Japanese multicenter study.
        Heart Rhythm. 2010; 7: 1411-1418
        • Crotti L.
        • Marcou C.A.
        • Tester D.J.
        • et al.
        Spectrum and prevalence of mutations involving BrS1-12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing: implications for genetic testing.
        J Am Coll Cardiol. 2012; 60: 1410-1418
        • Burashnikov E.
        • Pfeiffer R.
        • Barajas-Martinez H.
        • et al.
        Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death.
        Heart Rhythm. 2010; 7: 1872-1882
        • Antzelevitch C.
        • Pollevick G.D.
        • Cordeiro J.M.
        • 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: 442-449
        • Ueda K.
        • Hirano Y.
        • Higashiuesato Y.
        • et al.
        Role of HCN4 channel in preventing ventricular arrhythmia.
        J Hum Genet. 2009; 54: 115-121
        • Ishikawa T.
        • Sato A.
        • Marcou C.A.
        • et al.
        A novel disease gene for Brugada syndrome: sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5.
        Circ Arrhythm Electrophysiol. 2012; 5: 1098-1107
        • Hedley P.L.
        • Jørgensen P.
        • Schlamowitz S.
        • Wangari R.
        • Moolman-Smook J.
        • Brink P.A.
        The genetic basis of long QT and short QT syndromes: a mutation update.
        Hum Mutat. 2009; 30: 1486-1511
        • Yang Y.
        • Liang B.
        • Liu J.
        • et al.
        Identification of a Kir3.4 mutation in congenital long QT syndrome.
        Am J Hum Genet. 2010; 86: 872-880
        • Crotti L.
        • Johnson C.N.
        • Graf E.
        • et al.
        Calmodulin mutations associated with recurrent cardiac arrest in infants.
        Circulation. 2013; 127: 1009-1017
        • Priori S.G.
        • Napolitano C.
        • Memmi M.
        • et al.
        Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.
        Circulation. 2002; 106: 69-74
        • Lahat H.
        • Pras E.
        • Olender T.
        • 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: 1378-1384
        • 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: 2759-2767
        • Nyegaard M.
        • Overgaard M.T.
        • Søndergaard M.T.
        • et al.
        Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death.
        Am J Hum Genet. 2012; 91: 703-712
        • Bellocq C.
        • van Ginneken A.C.
        • Bezzina C.R.
        • et al.
        Mutation in the KCNQ1 gene leading to the short QT-interval syndrome.
        Circulation. 2004; 109: 2394-2397
        • Bartos D.C.
        • Anderson J.B.
        • Bastiaenen R.
        • et al.
        A KCNQ1 mutation causes a high penetrance for familial atrial fibrillation.
        J Cardiovasc Electrophysiol. 2013; 24: 562-569
        • Priori S.G.
        • Pandit S.V.
        • 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: 800-807
        • Yang Y.
        • Xia M.
        • Jin Q.
        • et al.
        Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation.
        Am J Hum Genet. 2004; 75: 899-905
        • Xia M.
        • Jin Q.
        • Bendahhou S.
        • et al.
        A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation.
        Biochem Biophys Res Commun. 2005; 332: 1012-1019
        • Medeiros-Domingo A.
        • Tan B.H.
        • Crotti L.
        • et al.
        Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes.
        Heart Rhythm. 2010; 7: 1466-1471
        • Haïssaguerre M.
        • Chatel S.
        • Sacher F.
        • et al.
        Ventricular fibrillation with prominent early repolarization associated with a rare variant of KCNJ8/KATP channel.
        J Cardiovasc Electrophysiol. 2009; 20: 93-98
        • Alders M.
        • Koopmann T.T.
        • Christiaans I.
        • et al.
        Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation.
        Am J Hum Genet. 2009; 84: 468-476
        • Schulze-Bahr E.
        • Neu A.
        • Friederich P.
        • et al.
        Pacemaker channel dysfunction in a patient with sinus node disease.
        J Clin Invest. 2003; 111: 1537-1545
        • Schott J.J.
        • Alshinawi C.
        • Kyndt F.
        • et al.
        Cardiac conduction defects associate with mutations in SCN5A.
        Nat Genet. 1999; 23: 20-21
        • Watanabe H.
        • Nogami A.
        • Ohkubo K.
        • et al.
        Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization.
        Circ Arrhythm Electrophysiol. 2011; 4: 874-881
        • Benson D.W.
        • Wang D.W.
        • Dyment M.
        • et al.
        Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).
        J Clin Invest. 2003; 112: 1019-1028
        • Makita N.
        • Behr E.
        • Shimizu W.
        • et al.
        The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome.
        J Clin Invest. 2008; 118: 2219-2229
        • Bezzina C.
        • Veldkamp M.W.
        • van Den Berg M.P.
        • et al.
        A single Na(+) channel mutation causing both long-QT and Brugada syndromes.
        Circ Res. 1999; 85: 1206-1213
        • Laurent G.
        • Saal S.
        • Amarouch M.Y.
        • et al.
        Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy.
        J Am Coll Cardiol. 2012; 60: 144-156
        • Behr E.R.
        • 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: 1670-1680
        • Schwartz P.J.
        • Stramba-Badiale M.
        • Crotti L.
        • et al.
        Prevalence of the congenital long-QT syndrome.
        Circulation. 2009; 120: 1761-1767
        • Mizusawa Y.
        • Horie M.
        • Wilde A.A.
        Genetic and clinical advances in congenital long QT syndrome.
        Circ J. 2014; 78: 2827-2833
        • Hedley P.L.
        • Kanters J.K.
        • Dembic M.
        • et al.
        The role of CAV3 in long-QT syndrome: clinical and functional assessment of a caveolin-3/Kv11.1 double heterozygote versus caveolin-3 single heterozygote.
        Circ Cardiovasc Genet. 2013; 6: 452-461
        • Wilde A.
        • Antzelevitch C.
        • Borggrefe M.
        • et al.
        Proposed diagnostic criteria for the Brugada syndrome.
        Eur Heart J. 2002; 23: 1648-1654
        • Matsuo K.
        • Kurita T.
        • Inagaki M.
        • et al.
        The circadian pattern of the development of ventricular fibrillation in patients with Brugada syndrome.
        Eur Heart J. 1999; 20: 465-470
        • Amin A.S.
        • Klemens C.A.
        • Verkerk A.O.
        • et al.
        Fever-triggered ventricular arrhythmias in Brugada syndrome and type 2 long-QT syndrome.
        Neth Heart J. 2010; 18: 165-169
        • Wolpert C.
        • Echternach C.
        • Veltmann C.
        • et al.
        Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome.
        Heart Rhythm. 2005; 2: 254-260
        • Raju H.
        • Papadakis M.
        • Govindan M.
        • et al.
        Low prevalence of risk markers in cases of sudden death due to Brugada syndrome: relevance to risk stratification in Brugada syndrome.
        J Am Coll Cardiol. 2011; 57: 2340-2345
        • Kamakura S.
        Epidemiology of Brugada syndrome in Japan and the rest of the world.
        J Arrhythmia. 2013; 29: 52-55
        • Gray B.
        • Semsarian C.
        • Sy R.W.
        Brugada syndrome: a heterogeneous disease with a common ECG phenotype?.
        J Cardiovasc Electrophysiol. 2014; 25: 450-456
        • Schulze-Bahr E.
        • Eckardt L.
        • Breithardt G.
        • et al.
        Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: different incidences in familial and sporadic disease.
        Hum Mutat. 2005; 26: 61
        • Bezzina C.R.
        • 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: 1044-1049
        • Antzelevitch C.
        • Brugada P.
        • Borggrefe M.
        • et al.
        Brugada syndrome: report of the Second Consensus Conference Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association.
        Circulation. 2005; 111: 659-670
        • Kapplinger D.
        • Tester D.J.
        • 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
        • Bezzina C.R.
        • Rook M.B.
        • Wilde A.A.
        Cardiac sodium channel and inherited arrhythmia syndromes.
        Cardiovasc Res. 2001; 49: 257-271
        • Probst V.
        • Wilde A.A.
        • Barc J.
        • et al.
        SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome.
        Circ Cardiovasc Genet. 2009; 2: 552-557
        • Hu D.
        • Barajas-Martínez H.
        • Pfeiffer R.
        • et al.
        Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome.
        J Am Coll Cardiol. 2014; 64: 66-79
        • Reid D.S.
        • Tynan M.
        • Braidwood L.
        • Fitzgerald G.R.
        Bidirectional tachycardia in a child: a study using His bundle electrography.
        Br Heart J. 1975; 37: 339-344
        • Napolitano C.
        • Bloise R.
        • Memmi M.
        • Priori S.
        Clinical utility gene card for: catecholaminergic polymorphic ventricular tachycardia (CPVT).
        Eur J Hum Genet. 2014; 22 (published online April 3, 2013)https://doi.org/10.1038/ejhg.2013.55
        • Kumar D.
        • Elliot P.
        Principles and practice of clinical cardiovascular genetics.
        Oxford University Press, US2010: P257 (ISBN 978-0-19-536895-6)
        • Bastiaenen R.
        • Behr E.
        Sudden death and ion channel disease: pathophysiology and implications for management.
        Heart. 2011; 97: 1365-1372
        • Napolitano C.
        • Priori S.G.
        • Bloise R.
        Catecholaminergic polymorphic ventricular tachycardia.
        in: Pagon R.A. Adam M.P. Ardinger H.H. GeneReviews® [Internet]. University of Washington, Seattle, Seattle, WA2004: 1993-2014 (Available at:) (Accessed March 6, 2014)
        • George C.H.
        • Jundi H.
        • Thomas N.L.
        • Fry D.L.
        • Lai F.A.
        Ryanodine receptors and ventricular arrhythmias: emerging trends in mutations, mechanisms and therapies.
        J Mol Cell Cardiol. 2007; 42: 34-50
        • Medeiros-Domingo A.
        • Bhuiyan Z.A.
        • Tester D.J.
        • 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: 2065-2074
        • Van der Werf C.
        • Nederend I.
        • Hofman N.
        • 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: 748-756
        • Maron B.J.
        • Towbin J.A.
        • Thiene G.
        • et al.
        Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
        Circulation. 2006; 113: 1807-1816
        • Roma-Rodrigues C.
        • Fernandes A.
        Genetics of hypertrophic cardiomyopathy: advances and pitfalls in molecular diagnosis and therapy.
        Appl Clin Genet. 2014; 7: 195-208
        • Sheppard M.
        Practical cardiovascular pathology.
        2nd ed. CRC Press, US2011 (ISBN-10: 0340981938)
        • van Spaendonck-Zwarts K.Y.
        • van Rijsingen I.A.
        • van den Berg M.P.
        • et al.
        Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: overview of 10 years' experience.
        Eur J Heart Fail. 2013; 15: 628-636
        • Mestroni L.
        • Taylor M.
        Genetics and genetic testing of dilated cardiomyopathy: a new perspective.
        Discov Med. 2013; 15: 43-49
        • Sen-Chowdhry S.
        • Morgan R.D.
        • Chambers J.C.
        • McKenna W.J.
        Arrhythmogenic cardiomyopathy: etiology, diagnosis, and treatment.
        Annu Rev Med. 2010; 61: 233-253
        • Marcus F.I.
        • McKenna W.J.
        • Sherrill D.
        • et al.
        Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia.
        Circulation. 2010; 121: 1533-1541
        • Behr E.
        • Wood D.A.
        • Wright M.
        • et al.
        Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome.
        Lancet. 2003; 362: 1457-1459
        • Van der Werf C.
        • Hofman N.
        • Tan H.L.
        • et al.
        Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The Netherlands.
        Heart Rhythm. 2010; 7: 1383-1389
        • Tan H.L.
        • Hofman N.
        • van Langen I.M.
        • van der Wal A.C.
        • Wilde A.A.
        Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives.
        Circulation. 2005; 112: 207-213
        • McGorrian C.
        • Constant O.
        • Harper N.
        • et al.
        Family-based cardiac screening in relatives of victims of sudden arrhythmic death syndrome.
        Europace. 2013; 15: 1050-1058
        • Kumar S.
        • Peters S.
        • Thompson T.
        • et al.
        Familial cardiological and targeted genetic evaluation: low yield in sudden unexplained death and high yield in unexplained cardiac arrest syndromes.
        Heart Rhythm. 2013; 10: 1653-1660
        • Mellor G.
        • Raju H.
        • de Noronha S.V.
        • et al.
        Clinical characteristics and circumstances of death in the sudden arrhythmic death syndrome.
        Circ Arrhythm Electrophysiol. 2014; 7: 1078-1083
        • Kauferstein S.
        • Kiehne N.
        • Jenewein T.
        • et al.
        Genetic analysis of sudden unexplained death: a multidisciplinary approach.
        Forensic Sci Int. 2013; 229: 122-127
        • van der Werf C.
        • Stiekema L.
        • Tan H.L.
        • et al.
        Low rate of cardiac events in first-degree relatives of diagnosis-negative young sudden unexplained death syndrome victims during follow-up.
        Heart Rhythm. 2014; 11: 1728-1732
        • Garratt C.J.
        • Elliott P.
        • Behr E.R.
        • et al.
        Clinical indications for genetic testing in familial sudden cardiac death syndromes: an HRUK position statement.
        Heart. 2008; 94: 502-507
        • Erskine K.E.
        • Hidayatallah N.Z.
        • Walsh C.A.
        • et al.
        Motivation to pursue genetic testing in individuals with a personal or family history of cardiac events or sudden cardiac death.
        J Genet Couns. 2014; 23: 849-859
      6. UK Department of Health. National Service Framework for Coronary Heart Disease—Chapter 8: arrhythmias and sudden cardiac death. 2005. Available at: http://webarchive.nationalarchives.gov.uk/20130107105354/http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_4105280.pdf. Accessed June 4, 2016.

        • Pilmer C.M.
        • Porter B.
        • Kirsh J.A.
        • et al.
        Scope and nature of sudden cardiac death before age 40 in Ontario: a report from the cardiac death advisory committee of the office of the chief coroner.
        Heart Rhythm. 2013; 10: 517-523
        • Skinner J.R.
        • Duflou J.A.
        • Semsarian C.
        Reducing sudden death in young people in Australia and New Zealand: the TRAGADY initiative.
        Med J Aust. 2008; 189: 539-540
        • Carturan E.
        • Tester D.J.
        • Brost B.C.
        • Basso C.
        • Thiene G.
        • Ackerman M.J.
        Postmortem genetic testing for conventional autopsy-negative sudden unexplained death: an evaluation of different DNA extraction protocols and the feasibility of mutational analysis from archival paraffin-embedded heart tissue.
        Am J Clin Pathol. 2008; 129: 391-397
        • Middleton O.
        • Baxter S.
        • Demo E.
        • et al.
        National Association of Medical Examiners Position Paper: retaining postmortem samples for genetic testing.
        Acad Forensic Pathol. 2013; 3: 191-194
        • Ackerman M.J.
        • Tester D.J.
        • Coburn J.P.
        • Edwards W.D.
        Molecular diagnosis of the inherited long-QT syndrome in a woman who died after near-drowning.
        N Engl J Med. 1999; 341: 1121-1125
        • Tester D.J.
        • Ackerman M.J.
        Postmortem long QT syndrome genetic testing for sudden unexplained death in the young.
        J Am Coll Cardiol. 2007; 49: 240-246
        • Tester D.J.
        • Spoon D.B.
        • Valdivia H.H.
        • Makielski J.C.
        • Ackerman M.J.
        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: 1380-1384
        • Skinner J.R.
        • 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: 412-419
        • Winkel B.
        • Larsen M.
        • Olesen M.
        • Tfelt-Hansen J.
        • Banner J.
        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: 1092-1098
        • Dean J.
        • Cann F.
        • Corbett M.
        • et al.
        Molecular autopsy for sudden cardiac death—outcome of a practical approach.
        Heart Lung Circ. 2014; 23: e3
        • Tester D.J.
        • Medeiros-Domingo A.
        • Will M.L.
        • Haglund C.M.
        • Ackerman M.J.
        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: 524-539
        • Bagnall R.
        • Das K.J.
        • Duflou J.
        • Semsarian C.
        Exome analysis-based molecular autopsy in cases of sudden unexplained death in the young.
        Heart Rhythm. 2014; 11: 655-662
        • Larsen M.K.
        • Berge K.E.
        • Leren T.P.
        • 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: 139-144
        • Churko J.
        • Mantalas G.
        • Synder M.
        • Wu J.
        Overview of high throughput sequencing technologies to elucidate molecular pathways in cardiovascular diseases.
        Circ Res. 2013; 112: 1613-1623
        • Chugh S.S.
        • Huertas-Vazquez A.
        Inherited arrhythmia syndromes: exome sequencing opens a new door to diagnosis.
        J Am Coll Cardiol. 2014; 63: 267-268
        • Laish-Farkash A.
        • Nof E.
        • Luria D.
        • et al.
        Incessant bidirectional ventricular tachycardia as the presenting arrhythmia of Andersen-Tawil syndrome in two families.
        J Interv Card Electrophysiol. 2009; 24 (Special Abstract Issue of ECAS): 213-217
        • Wong L.C.
        • Behr E.R.
        Sudden unexplained death in infants and children: the role of undiagnosed inherited cardiac conditions.
        Europace. 2014; 16: 1706-1713