Recommendations for the Use of Genetic Testing in the Clinical Evaluation of Inherited Cardiac Arrhythmias Associated With Sudden Cardiac Death_ Canadian Cardiovascular Society_Canadian

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doi:10.1016/j.cjca.2010.12.078

Canadian Journal of CardiologyVolume 27, Issue 2, March–April 2011, Pages 232–245Society position statementRecommendations for the Use of Genetic Testing in the ClinicalRecommendations for the Use of Genetic Testing in the ClinicalRecommendations for the Use of Genetic Testing in the ClinicalRecommendations for the Use of Genetic Testing in the ClinicalEvaluation of Inherited Cardiac Arrhythmias Associated with SuddenEvaluation of Inherited Cardiac Arrhythmias Associated with SuddenEvaluation of Inherited Cardiac Arrhythmias Associated with SuddenEvaluation of Inherited Cardiac Arrhythmias Associated with SuddenCardiac Death: Canadian Cardiovascular Society/Canadian HeartCardiac Death: Canadian Cardiovascular Society/Canadian HeartCardiac Death: Canadian Cardiovascular Society/Canadian HeartCardiac Death: Canadian Cardiovascular Society/Canadian HeartRhythm Society Joint Position PaperRhythm Society Joint Position PaperRhythm Society Joint Position PaperRhythm Society Joint Position PaperMichael H. Gollob, MDa, , (Chair), Louis Blier, MDb, Ramon Brugada, MDc, Jean Champagne, MDb,Vijay Chauhan, MDd, Sean Connors, MDe, Martin Gardner, MDf, Martin S. Green, MDa, Robert Gow,MB, BSg, Robert Hamilton, MDh, Louise Harris, MBd, Jeff S. Healey, MDi, Kathleen Hodgkinson, PhDj,Christina Honeywell, MScg, Michael Kantoch, MDk, Joel Kirsh, MDh, Andrew Krahn, MDn, MichelleMullen, PhDo, Ratika Parkash, MDf, Damian Redfearn, MBl, Julie Rutberg, MSca, Shubhayan Sanatani,MDm, Anna Woo, MDdShow moreShow moreShow moreShow moreAbstractThe era of gene discovery and molecular medicine has had a significant impact on clinical practice.Knowledge of specific genetic findings causative for or associated with human disease may enhancediagnostic accuracy and influence treatment decisions. In cardiovascular disease, gene discovery forinherited arrhythmia syndromes has advanced most rapidly. The arrhythmia specialist is often confrontedwith the challenge of diagnosing and managing genetic arrhythmia syndromes. There is now a clear needfor guidelines on the appropriate use of genetic testing for the most common genetic conditions associatedwith a risk of sudden cardiac death. This document represents the first ever published recommendationsoutlining the role of genetic testing in various clinical scenarios, the specific genes to be considered fortesting, and the utility of test results in the management of patients and their families.RésuméL'ère de la découverte génétique et de la médecine moléculaire a eu un impact significatif dans la pratiqueclinique. La connaissance des découvertes génétiques spécifiques causales ou reliées à la maladiehumaine peut améliorer la précision diagnostique et influencer les décisions de traitement. Dans lamaladie cardiovasculaire, la découverte génétique dans les syndromes d'arythmie héréditaire a progresséplus rapidement. Le spécialiste de l'arythmie est souvent confronté au défi du diagnostic et de la gestiondes syndromes d'arythmie génétique. Il y a maintenant un besoin évident de lignes directrices surl'utilisation appropriée de tests génétiques pour les conditions génétiques les plus communes associées àun risque de mort cardiaque subite. Ce document est le tout premier à publier les recommandationsdécrivant le rôle des tests génétiques dans des scénarios cliniques variés, les gènes spécifiques àconsidérer dans les tests, et l'utilité des résultats de tests dans la gestion des patients et de leur famille.IntroductionThe evolution of knowledge in cardiovascular genetics over the past 15 years has refined our mechanisticunderstanding of inherited cardiac syndromes associated with sudden cardiac death (SCD) and has led tochanges in our approach to clinical diagnosis and management of patients and their families.Clinical training does not routinely emphasize the appropriate use of genetic testing as a clinical tool. Yet,with the advent of commercial, for-profit genetic testing facilities, the availability of this option is well knownto physicians. This novel testing has been embraced with marked enthusiasm, often with little regard forthe utility of genetic testing or the role of patient counseling and education.This paper presents the consensus of a panel of Canadian arrhythmia specialists, geneticists, geneticcounsellors, and a medical ethicist. The mandate of the panel was to formulate disease-specific

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recommendations for the use of genetic testing in the care of patients and families with documented orsuspected genetic conditions associated with SCD. In the context of contemporary knowledge, the paneldeliberated on the clinical value of genetic testing with reference to the potential yield of positive andinterpretable genetic findings.In formulating recommendations, the committee recognized that there exists a paucity of double-blind,randomized trials that form the basis for most guideline documents. Thus, the panel endeavored to reachconsensus based on their collective experience. Not all regions of Canada have available the resources toprovide care according to all the recommendations of this document. In such circumstances, physiciansare encouraged to consult with expert colleagues elsewhere while attempting to develop the necessaryresources locally.Decision making for genetic testingDecisions regarding the need to proceed with genetic testing should be based primarily on the clinicalvalue the genetic information may provide in the care of patients or their families. For many diseases,genetic testing is not necessary in establishing a diagnosis, but serves as a tool to screen family membersto reconcile concerns of subclinical disease and the need for medical surveillance. In other instances,genetic testing may help to establish a diagnosis in equivocal clinical presentations, understanding that thegenetic information may require cautious interpretation, similar to other clinical tests (eg, cardiac magneticresonance imaging) that provide helpful but often inconclusive diagnostic results.In light of the low prevalence of inherited arrhythmia syndromes, clinical evaluation and decisionsregarding the utility of genetic testing should be made by physicians with a dedicated practice. Thephysician expert should have knowledge in the interpretation of genetic data. Specialized arrhythmiaclinics with the involvement of trained genetic counsellors focused on inherited arrhythmias are stronglyencouraged. Inherited arrhythmia syndromes are often challenging to diagnose and are potentially lethal,and the implications of a wrong diagnosis may be fatal or have lifelong consequences. Discordance indiagnostic accuracy between nonspecialty clinics and specialized clinics exists. For the long QT syndrome(LQTS), 40% of patients labelled with LQTS were considered inappropriately diagnosed after evaluation ina dedicated inherited arrhythmia clinic.1 Specialized clinics also serve to improve cost-effectiveness andyield from genetic testing.2RecommendationRecommendationRecommendationRecommendationDiagnostic evaluation for a potential inherited arrhythmia syndrome should be performed by aphysician expert well versed in the clinical and genetic aspects of these conditions.Decisions regarding the utility of genetic testing should be made by a physician expert in collaborationwith a dedicated genetic counsellor.Prior to genetic testing, patients should receive counseling to ensure all relevant psychological, social,and ethical considerations have been addressed.Genetic testing should not be ordered on asymptomatic family members in the absence of parallelclinical assessment and discussion with a physician expert.Ethical issues in genetic testingGenetic testing for SCD susceptibility raises issues such as stigma, privacy, and insurance andemployment discrimination. Novel issues include possible child protection obligations under provincialstatutes and the possibility of public protection or “duty to warn” scenarios. Whereas genetic testing forsusceptibility for later-onset conditions (eg, breast cancer) has typically been deferred until patients attaincapacity to make their own decisions, the availability of effective prophylaxis treatment in geneticarrhythmia syndromes may mandate the testing of at-risk children. When a first-degree relative, if affected,might imperil public safety (eg, an airline pilot), duty-to-warn obligations may exist when assessment isrefused. These emerging issues are now being explored, and the ethical, legal, and social contexts arecomplex. A thorough discussion of these issues is available in the on-line supplement (see SupplementaryMaterial).Disease-Specific Recommendations for Clinical Genetic TestingThe role of genetic testing in LQTSLQTS (incidence, 1 per 3000)3 is characterized by electrocardiographic prolongation of the QT interval,syncope, and sudden death. LQTS causes 3000 to 4000 sudden deaths per year in the United States.4 Therisk of cardiac arrhythmias is directly proportional to the duration of the corrected QT interval (QTc)duration.5, 6 and 7DiagnosisDiagnosisDiagnosisDiagnosis. Most patients with LQTS have a QTc > 460 milliseconds, but up to 40% of gene carriers willhave a normal QTc, reflecting variable disease penetrance.8 and 9 The Schwartz diagnostic criteria havebeen established to facilitate the diagnosis of LQTS.10 and 11 In the normal population, the QTc is longer in

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adult women than in men.12 and 13 There may be considerable temporal variation in QTc as repolarization isaffected by factors such as autonomic tone, electrolyte balance, and pharmacologic agents. Numerousdiagnostic tests have been proposed to facilitate the diagnosis of LQTS, including exercise testing andpharmacologic provocation.14, 15, 16 and 17Management.Management.Management.Management. Risk stratification in LQTS classifies patients as low, intermediate, and high risk, based ontheir gender, QT interval, and genotype.5 Female gender, LQT2 genotype, and QTc prolongation > 500milliseconds are factors that increase risk of cardiac arrest.Two types of LQTS, LQT1 and LQT2, account for close to 90% of clinical cases. In these forms of LQTS,β-blockers are the mainstay of treatment. The role for β-blockade is less clear in LQT3 patients, who oftenhave events that occur at rest or during sleep, and proceeding with an implantable cardioverter-defibrillator(ICD) as first-line treatment warrants discussion. A paucity of genetic data exists for more rare geneticforms of LQTS (LQT4-13) to assist in management. LQTS patients should avoid exposure toQT-prolonging drugs, a list of which is kept current at www.qtdrugs.org. Exercise “prescriptions” tominimize event risk have been provided by both European and American bodies.18 and 19 In LQT3 and otherrare forms of LQTS, the value of exercise restriction in avoiding cardiac events is uncertain.Genetics.Genetics.Genetics.Genetics. LQTS is caused by genetic defects in genes that encode proteins responsible for regulating thecardiac action potential duration. Impaired function of these proteins results in prolongation of the actionpotential duration, which manifests as QT prolongation on the electrocardiogram (ECG). Genetic testingmay identify responsible genotypes in approximately 35% to 70% of suspected LQTS probands,1 and 20 thewide range likely reflecting differences in the clinical expertise of ordering physicians. The majority ofgenetically confirmed cases are the result of mutations in 3 genes. In 90% of cases, defects in the KCNQ1and KCNH2 genes, which encode for cardiac potassium channels, are identified in LQT1 and LQT2,respectively. 21 and 22 LQT3 is caused by mutations in the SCN5A cardiac sodium channel gene, accountingfor approximately 5% to 10% of cases. More rare genetic causes for LQTS collectively account for <5% ofcases.Recommendations for genetic testing in LQTS (Table 1)Genetic testing should include analysis of the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes.Routine clinical genetic testing of rare genes (<1% detection rate) associated with LQTS is notrecommended. Given the small number of variants described in these genes, results are more likely to beof unknown significance and of limited clinical value if a clear familial pattern of disease is not recognized.In patients with negative genetic testing but clinically robust phenotype, consideration may be given toassessing rare genes on a case-by-case basis.Table 1.Summary recommendations for genetic testing in long QT syndromeSymptom Testing CommentCardiac arrest survivor§ with QTprolongation on resting ECGs ++ Exception is the patient with transient QT prolongation that is commonlyseen with anoxic brain injury immediately after cardiac arrestSyncope QTc abnormal⁎ ++ Not necessary for diagnostic purposes but plays a role in riskstratification, family screening, and therapeutic decisions QTc borderline† +/− Not recommended unless characteristic abnormal T wave morphology ispresent and/or a concerning family history exists QTc normal‡ − Genetic testing is not recommendedAsymptomatic§ QTc abnormal⁎ ++ May be useful for diagnosis, risk stratification, choice of therapy, andfamily screening QTc borderline† − Not recommended unless abnormal T wave morphology is presentand/or a concerning family history existsFirst-degree relative Proband genotype positive ++ Useful for diagnostic and therapeutic purposes Proband genotype negative − In rare circumstances, if QTc is consistently borderline or prolonged,genetic testing may be consideredRecommendations: ++ (strongly recommended), + (recommended), − (not recommended).QTc > 480 milliseconds in women, > 460 milliseconds in men.QTc 460 to 480 milliseconds in women, 450 to 460 milliseconds in men.QTc < 460 milliseconds in women, <450 milliseconds in men.Secondary causes of QT prolongation ruled out (structural heart disease, electrolyte abnormalities, provoking drugs). Table options

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RecommendationRecommendationRecommendationRecommendationCardiac Arrest Survivor: Genetic testing is recommended in the cardiac arrest survivor with LQTS forthe primary purpose of screening first-degree relatives.Survived SCD may be the first presentation of patients with LQTS. Genetic testing should be performed inpatients in whom the event is attributed to LQTS only if first-degree relatives will be assessed, as theproband will invariably receive an ICD and β-blocker therapy regardless of genetic results. Diagnosis ofLQTS immediately post–cardiac arrest may be challenging because myocardial and cerebral anoxia aswell as electrolyte abnormalities may produce transient QT prolongation.All first-degree relatives of a genetically confirmed case of LQTS should be offered genetic testingregardless of symptom status or baseline ECG to determine whether they are gene carriers.RecommendationRecommendationRecommendationRecommendationSyncope with QTc prolongation: Genetic testing is recommended in the patient with syncope and QTcprolongation that is attributed to LQTS.Patients with syncope and QTc prolongation (>480 milliseconds) with characteristic T-wave abnormalitiesdo not need genetic testing for a diagnosis of LQTS. However, genetic testing plays a role in assessing riskof sudden death in combination with the corrected QT interval,5 as well as predicting efficacy of betablockade, and is therefore recommended. In patients with a borderline QTc interval (450-460milliseconds), genetic testing is not recommended unless there are characteristic T-wave morphologiesconsistent with LQTS and/or a family history of premature SCD (age < 40 years). Asymptomatic individualswith borderline QTc prolongation (460-480 milliseconds) warrant evaluation by a clinical expert prior toreceiving genetic testing.RecommendationRecommendationRecommendationRecommendationAsymptomatic patient with QTc prolongation: Genetic testing is recommended in the asymptomaticpatient with consistent QTc prolongation that is clinically suspected to represent LQTS.Genetic testing is recommended in asymptomatic individuals with a consistent QTc > 480 milliseconds(Schwartz score ≥ 3), in the absence of provoking medications, metabolic abnormalities, or structural heartdisease. The role of genetic testing to confirm the diagnosis of LQTS in these patients is unclear, althoughgenetic confirmation may be helpful for risk stratification and family screening. Given the low yield ofgenetic testing in asymptomatic patients with borderline QTc prolongation (450-460 milliseconds), routinegenetic testing is not recommended. Genetic testing for asymptomatic individuals with QTc intervals in the460- to 480-millisecond range should be considered only in the setting of a specialized inherited arrhythmiaclinic.The role of genetic testing in Brugada syndromeBrugada syndrome is characterized by anterior precordial ST elevation on ECG and risk of ventricularfibrillation, most commonly at rest or during sleep.23 ECG findings without cardiac events is termed“Brugada pattern.” The Brugada ECG pattern is present in 1 per 4000 to 1/10,000 patients, influenced byethnicity.24, 25, 26, 27 and 28Diagnosis.Diagnosis.Diagnosis.Diagnosis. The diagnosis of Brugada syndrome follows an index event of syncope or cardiac arrest andECG recognition of ST elevation of a coved-shaped pattern (type 1 ECG pattern) in leads V1 and V2. Type2 and type 3 Brugada ECG patterns are characterized by a saddleback pattern in V1 and V2, with or withoutST elevation, respectively. These additional ECG patterns are not considered diagnostic of the Brugadasyndrome.28 The various Brugada ECG patterns may be intermittent. Patients with a type 2 or 3 patternwith unheralded syncope should undergo evaluation for Brugada syndrome. Intravenous administration ofa sodium channel blocker may convert a type 2 or 3 ECG pattern into a type I pattern, raising the suspicionof Brugada syndrome. The type 1 Brugada ECG pattern may be provoked by fever or medications withsodium channel blocking properties.28 In some patients, conduction system disease coincides with theBrugada ECG pattern or may be the only ECG abnormality observed in family members.29 and 30Management.Management.Management.Management. Patients with resuscitated cardiac arrest are managed with an ICD, which is alsorecommended for those with a history of syncope suspicious for arrhythmia.30 Drug therapy withβ-blockers or amiodarone has not been useful. Quinidine has shown promise in one series, althoughefficacy based on data from randomized controls does not exist.31 Patients should avoid drugs with sodiumchannel blocking effects, comprehensively listed at www.brugadadrugs.org. Aggressive temperaturelowering during febrile illnesses is necessary. There is considerable controversy regarding SCD risk inasymptomatic patients with type I Brugada ECG pattern. Data from a large cohort of patients suggest thatasymptomatic individuals have a low event rate (<1%/y).32 The value of electrophysiological testing for riskstratification is not clearly established.32, 33, 34 and 35 A positive family history of Brugada syndrome–related


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SCD does not appear to confer a worse prognosis.36, 37 and 38Genetics.Genetics.Genetics.Genetics. The most commonly identified genetic defects are in the SCN5A gene, accounting forapproximately 20% of cases. However, sporadic cases without evident family history have a much loweryield. 39 Five additional genes (SCNB1, SCNB3, KCNE3, CACNA1C, and CACNB2b) encoding subunits ofsodium, potassium, and calcium channels have been implicated in Brugada syndrome but collectivelyaccount for a small proportion of cases (<3%). 40 and 41 In a single family of Italian descent, a mutation in theglycerol-3-phosphate dehydrogenase 1–like gene (GPD1L) was identified and found to segregate withaffected members. 42Recommendations for genetic testing in Brugada syndrome (Table 2)Since genetic testing identifies responsible genotypes in only 20% of patients, a negative genotype shouldnot reassure physicians that symptoms are on the basis of a benign condition when a Brugada ECGpattern exists. Presently, genetic testing should be limited to analysis of the SCN5A gene. Testing formutations in SCNB1, SCNB3, KCNE3, CACNA1C, CACNB2b, CACNA1C, and GPD1L are not clinicallyindicated, because of their rarity, and should be considered only under special circumstances.Table 2.Summary recommendations for genetic testing in Brugada syndromeSymptom Testing CommentCardiac arrest survivor Persistent or provocable type 1 BrugadaECG pattern ++ Not for diagnostic or therapeutic purposes but plays a role in familyscreening Apparent type 2 or 3 ECG pattern⁎ withnonprovocable type 1 ECG pattern − Genetic testing is not recommended as the diagnosis of Brugadasyndrome requires evidence of the type 1 ECG patternSyncope Persistent or provocable type 1 BrugadaECG pattern ++ Principally for the purpose of family screening Apparent type 2 or 3 ECG pattern withnonprovocable type 1 ECG pattern − Not recommended in the absence of observed type 1 ECG patternAsymptomatic Persistent type 1 Brugada ECG patter ++ Not useful for risk stratification; principally for the purpose of familyscreening Apparent type 2 or 3 ECG pattern withnonprovocable type 1 ECG pattern − Genetic testing is not recommendedFirst-degree relative Proband genotype positive ++ Clinical implications of an isolated positive genotype in theabsence of a phenotype are unknown Proband genotype negative − Not recommendedRecommendations: ++ (strongly recommended), − (not recommended).Type 2 or 3 ECG patterns may resemble early repolarization or variations of normal ST segments.RecommendationRecommendationRecommendationRecommendationCardiac arrest survivor: Genetic testing in the cardiac arrest survivor with a persistent or provocabletype 1 Brugada ECG pattern is recommended for the primary purpose of screening of family members.Cardiac arrest is often the first presentation of patients with Brugada syndrome. The purpose of testing inthis scenario is to develop a screening tool for family members. While the clinical implications of a positivegenotype in the absence of a phenotypic correlate in a family member is unknown, knowledge ofgene-carrier status provides the opportunity to counsel family members on issues related to fever andmedication use. In cardiac arrest patients with an apparent type 2 or 3 ECG pattern but no provocable type1 pattern, genetic testing is not recommended as the diagnosis of Brugada syndrome requires evidence ofthe characteristic type 1 ECG pattern.RecommendationRecommendationRecommendationRecommendationSyncope and Brugada ECG pattern: Genetic testing in the patient with syncope and a permanent orprovocable type 1 Brugada ECG pattern is recommended for the primary purpose of screening offamily members.The diagnosis of Brugada syndrome should be based on clinical grounds, with genetic testing used only as

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a family screening tool.RecommendationRecommendationRecommendationRecommendationAsymptomatic persistent or provocable type 1 Brugada ECG pattern: Genetic testing in theasymptomatic patient with persistent or provocable type 1 Brugada ECG pattern is recommended forthe primary purpose of screening family members.In asymptomatic patients, genetic testing should not be performed with the intent of risk stratification. Atpresent, there is no genotype that reliably determines prognosis in Brugada syndrome.RecommendationRecommendationRecommendationRecommendationType 2 or type 3 Brugada ECG pattern in symptomatic or asymptomatic individuals without evidencefor intermittent or provocable type 1 ECG pattern: Genetic testing is not recommended.Genetic testing is not useful in patients with nonspecific ECG features suggestive of type 2 or 3 BrugadaECG pattern but without provocable type 1 pattern.The role of genetic testing in arrhythmogenic right ventricular cardiomyopathyArrhythmogenic right ventricular cardiomyopathy (ARVC), with an estimated prevalence of ARVC 1 per5000, is characterized by fibrofatty replacement of myocardium. It affects the right ventricle predominantlybut may have left ventricular involvement.43 ARVC can result in ventricular arrhythmias, SCD, and right orbiventricular dysfunction. Often sporadic, the condition is familial in up to 50% of index cases.43 and 44Diagnosis.Diagnosis.Diagnosis.Diagnosis. Task Force criteria for the diagnosis were originally proposed in 1994 and updated in2010.45 and 46 Criteria are grouped into those involving right ventricular function, tissue characteristics of themyocardium, ECG repolarization abnormalities, ECG depolarization abnormalities, arrhythmias, familyhistory, and genetic testing. The Task Force criteria are considered to be specific but relatively insensitive.Other rare conditions, such as cardiac sarcoidosis, may affect right ventricular myocardium and mimic theclinical and imaging features of ARVC.47 and 48 As ARVC may be a progressive disease, patients suspectedof having ARVC who have initial equivocal diagnostic test results should undergo reevaluation at leastannually.Management.Management.Management.Management. Patients with proven or suspected ARVC are discouraged from participation in competitivesports or endurance training, and activity should be modified according to American Heart Associationrecommendations.19 Patients with documented ventricular arrhythmias should receive an ICD as first-linetherapy. It is not known whether an ICD or pharmacologic treatment will affect outcome in asymptomatic orgene-positive patients without overt disease. However, close medical surveillance for diseasedevelopment is necessary.Genetics.Genetics.Genetics.Genetics. A pathogenetic theme for ARVC is the presence of mutations in genes encoding desmosomalproteins.49 Desmosomes are a primary component of cell adhesion junctions, ensuring the structural andfunctional integrity of cardiomyocytes. Mutations have been identified in genes encoding for desmosomalproteins plakophilin-2 (PKP2), desmoplakin (DSP), plakoglobin (JUP), desmocollin (DSC2), anddesmoglein (DSG2). 49, 50, 51, 52, 53 and 54 A mutation in the gene encoding a nondesmosomal protein(TMEM43) has been identified as the cause in a large cohort of related patients in Newfoundland, Canada.55 The cellular function of the TMEM43 protein is unknown.Plakophilin-2 (PKP2) mutations occur in up to 45% of cases meeting ARVC Task Force criteria. 56 and 57The yield of PKP2 testing may approach 70% when familial ARVC is confirmed, in contrast to a lower yieldin sporadic cases. Variable disease penetrance and expression in PKP2 mutation carriers is common.Desmoplakin (DSP) mutations occur in 6% to 16% of ARVC cases. 51 and 58 A rare autosomal recessivesyndrome related to desmoplakin mutations is Carvajal syndrome, characterized by dilatedcardiomyopathy, wooly hair, and plantar keratoderma. 59 In patients with negative genetic findings of PKP2and DSP, 5% to 10% of cases have mutations in the DSG2 and DSC2 genes. 53 and 60 A specificplakoglobin (JUP) mutation causes a rare form of autosomal recessive ARVC known as Naxos disease. 50Recommendations for genetic testing in ARVC (Table 3)In view of the differing yields for the known causative genes, stepwise or tiered genetic testing should beperformed. Genetic testing of the PKP2 and DSP genes should be performed first, which may yield apositive test in up to 50% of Task Force positive cases. If negative, additional testing of the DSG2 andDSC2 may identify a mutation in an additional 5% to 10% of cases. In patients with ancestry linked toNewfoundland, genetic testing of TMEM43 should be considered. Lastly, it should be emphasized thatgiven the relatively recent history of gene discovery in ARVC and the natural genetic variability that occursin culprit genes in apparently healthy controls, interpretation of genetic testing results for this condition iscomplex, necessitating the involvement of a specialized clinic.Table 3.


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Summary recommendations for genetic testing in arrhythmogenic right ventricular cardiomyopathyClinical scenario Testing CommentClinical ARVC in accordance with TaskForce criteria ++ Genetic testing plays a role in the screening of identified familymembersClinical ARVC in accordance with TaskForce criteria in the absence of identifiedat-risk family members − ARVC is often sporadic, and genetic results do not provide riskstratification assistanceClinically suspected ARVC not meetingTask Force criteria ++ Current diagnostic criteria are specific but insensitive. Genetictesting may be useful in establishing a diagnosis of ARVC andsubsequent screening of at-risk family membersFirst-degree relative of genotype-positiveproband ++ Useful for decisions of medical surveillance and lifestylemodificationFirst-degree relative of genotype-negativeproband − Genetic testing not indicatedRecommendations: ++ (strongly recommended), − (not recommended).ARVC, arrhythmogenic right ventricular cardiomyopathy.RecommendationRecommendationRecommendationRecommendationClinical ARVC in accordance with Task Force criteria: Genetic testing is recommended for the primarypurpose of screening family members.Timely genetic diagnosis may lead to prevention of morbidity or mortality in family members by increasingmedical surveillance and recommending exercise restriction. Reassurance may be provided to genotype-negative family members and eliminate the need for periodic clinical testing. Genetic testing should first beperformed in the proband to limit the uncertainty of the genetic variations identified in asymptomatic familymembers without overt clinical disease. Genetic testing should not be performed in a diagnosed probandsolely for the intent of risk stratification as data for this purpose do not exist.RecommendationRecommendationRecommendationRecommendationClinically suspected ARVC not meeting Task Force criteria: Genetic testing is recommended for thepurpose of assisting in the diagnosis of ARVC.Satisfying Task Force criteria for ARVC may be challenging because of variations in clinical expression ofthe disease. Addition of genetic testing in the 2010 Task Force criteria indicates the utility of includinggenetic testing results in arriving at a diagnosis. Although the genetic test result may not provide thedefinitive answer for diagnosis, the information gained can be weighed in the context of other clinical testsin diagnostic decision making and potentially confirm a diagnosis if a known disease-causing mutation isidentified.The role of genetic testing in catecholaminergic polymorphic ventricular tachycardiaCatecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by emotion- or exercise-induced syncope or cardiac arrest in structurally normal hearts.61Diagnosis.Diagnosis.Diagnosis.Diagnosis. The rhythm disturbance of CPVT is polymorphic ventricular tachycardia (VT) that is inducedduring high adrenaline states. Clinical presentation is most common in prepubertal or adolescentyears.61 and 62 In contrast to other channelopathies, baseline ECGs are usually normal. Bidirectional VTwith exercise is a diagnostic hallmark of CPVT, although Andersen-Tawil syndrome (LQTS type 7) causedby KCNJ2 mutations may also demonstrate bidirectional VT, usually with a resting ECG showingprominent U waves. CPVT should be considered in the differential diagnosis of all adrenergic-mediatedsyncopal or cardiac arrest events, particularly in young individuals (aged < 20 years). Diagnosis issupported by reproducing the typical bidirectional VT or polymorphic VT induced by exercise or infusion ofan adrenergic agonist, while confirming no evidence of structural heart disease. 63 However, manyarrhythmogenic cardiac conditions may manifest exercise-induced polymorphic VT (eg. ischemia, ARVC),and therefore careful diagnostic workup is required before diagnosing CPVT.Management.Management.Management.Management. β-Blockers are highly effective in suppressing adrenergic-mediated arrhythmias in CPVT.Treadmill testing should be performed to titrate β-blocker dosage to ensure adequate suppression ofexercise-induced ventricular arrhythmias. Typically, high-dose β-blockers are required (eg, atenolol ≥ 2mg/kg), although complete absence of premature ventricular contractions on exercise is rare. In addition,affected patients should be advised to refrain from intense physical exercise. In patients with recurrentsyncope despite high-dose β-blockers, flecainide, cardiac sympathectomy, or ICD placement should be

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considered.64 and 65Genetics.Genetics.Genetics.Genetics. Two genetic forms of CPVT have been described: an autosomal dominant form, due tomutations in the cardiac ryanodine receptor gene (RYR2), and a rare autosomal recessive form withmutations in calsequestrin (CASQ2). 66 and 67 These genes encode proteins critical in intracellular calciumhandling. Their dysfunction leads to inappropriate levels of cytosolic calcium during cardiac diastole,causing afterdepolarizations and ventricular arrhythmias. Adrenergic stimulation enhances cellularcalcium load, increasing the susceptibility to arrhythmias.Genetic defects in the RYR2 gene are detected in up to 50% of cases. 63 Traditionally, genetic screening ofthis gene has been limited to so-called hotspot exons, regions of the gene presumed to most likely harbourdisease-causing mutations. Because of the very large size of the RYR2 gene, such limited screening hasbeen considered cost-effective. However, disease-causing mutations have been identified outside hotspotregions. 68Recommendations for genetic testing in CPVT (Table 4)The large size of the RYR2 gene, as well as the clustering of disease-causing mutations to hotspot exons,justifies an initial targeted genetic screening approach for this gene. When genetic screening of targetedexons is negative and clinical suspicion remains high, screening of the remaining RYR2 exons isrecommended. In RYR2-negative cases, or when autosomal recessive inheritance is noted, screening ofthe CASQ2 gene is warranted. Patients demonstrating prominent U waves and negative RYR2 testingshould be considered for testing of the KCNJ2 gene. Overall yield of genetic testing for clinical CPVT is inthe range of 50% to 60%.Table 4.Summary recommendations for genetic testing in catecholaminergic polymorphic ventricular tachycardiaClinical scenario Testing CommentClinically suspected CPVT ++ Genetic testing useful for the primary purpose of identifying at-risk family membersFirst-degree relative Proband genotype positive ++ Useful for decisions of medical surveillance and lifestyle modificationRecommendations: ++ (strongly recommended).CPVT, catecholaminergic polymorphic ventricular tachycardia.RecommendationRecommendationRecommendationRecommendationClinically suspected CPVT: Genetic testing is recommended for the primary purpose of screeningfamily members.Genetic diagnosis may lead to preventive therapy and exercise restriction in family members.Reassurance may be provided to genotype-negative family members.The role of genetic testing in hypertrophic cardiomyopathyHypertrophic cardiomyopathy (HCM) is characterized by cardiac hypertrophy in the absence of anothercardiac or systemic disease. HCM is relatively common, estimated to have a prevalence of 1 per 500, andis the most common cause of SCD in the young.69Diagnosis.Diagnosis.Diagnosis.Diagnosis. The evaluation of patients with suspected HCM includes a history and physical examination,ECG, and 2-dimensional echocardiography. The diagnosis is generally established by echocardiography.ECG abnormalities may occasionally precede the onset of left ventricular hypertrophy on theechocardiogram.70 and 71 In children, ECG and echocardiographic abnormalities may not develop until lateadolescence or adulthood, requiring routine medical surveillance in offspring of affected adults.It is important to distinguish patients with HCM from patients with physiological causes of hypertrophy (eg,athlete's heart) or infiltrative disorders.72, 73 and 74Management.Management.Management.Management. Risk stratification of patients is recommended to determine the risk for SCD.69 and 75 Majorrisk factors are a family history of premature SCD, unexplained syncope, nonsustained VT, an abnormalblood pressure response to exercise, and massive left ventricular hypertrophy (maximum left ventricularwall thickness ≥30 mm).69 and 75 In patients considered high risk for SCD, an ICD is indicated. Exerciserestriction is recommended to minimize arrhythmia provocation in high-risk individuals.Genetics.Genetics.Genetics.Genetics. HCM arises from genetic defects in close to 20 different genes, although the most commonforms of HCM result from mutations in genes encoding proteins of the cardiac sarcomeric apparatus (Table5).76 Genetic testing may detect a gene defect in 40% to 60% of patients.76 and 77 Mutations of the MYH7and MYBPC3 genes account for the majority of cases. 76 Approximately 3% of patients with HCM may

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have more than once pathogenic mutation, which may be associated with a more severe phenotype. 76Table 5.Genes associated with hypertrophic cardiomyopathyGene Protein FrequencyMYH7 β-Myosin heavy chain 15%-30%MYBPC Myosin-binding protein C 15%-30%TNNT2 Troponin T 5%-10%TNNI3 Troponin I 2%-5%TPM1 α-Tropomyosin 2%-5%TTN Titin <1%MYH6 α-Myosin heavy chain <1%MYL2 Ventricular regulatory myosin light chain <1%MYL3 Ventricular essential myosin light chain <1%ACTC α-Cardiac actin <1%TNNC1 Troponin C <1%LBD3 Limb binding domain 3 <1%CSRP3 Muscle LIM protein <1%TCAP Telethonin <1%VCL Vinculin <1%ACTN2 α-Actinin 2 <1%MYOZ2 Myozenin 2 <1%JPH2 Junctophilin-2 <1%PLN Phospholamban <1%Infiltrative or storage diseases may show similar findings on cardiac imaging and incorrectly lead to adiagnosis of HCM. Fabry's disease (caused by genetic defects in the GLA gene) was detected in 6% ofmale patients diagnosed with presumed HCM at age ≥40 years. 78 The identification of patients with thiscondition is important since enzyme replacement therapy is effective. 79 and 80 Other inherited storagediseases showing features of HCM commonly have the ECG finding of ventricular preexcitation. Theseconditions include the glycogen storage conditions of Danon's disease (LAMP2 gene), and the PRKAG2cardiac syndrome (PRKAG2 gene). 73, 81 and 82Recommendations for genetic testing in HCM (Table 6)Since HCM is diagnosed by imaging studies, the principal role of genetic testing is not to confirm adiagnosis but rather to provide a clinical tool for screening family members at risk of developing thedisease. In light of the large number of genes associated with HCM and their respective yields of mutationdetection, a tiered genetic testing approach is recommended. Initial testing for the 2 most common geneticcauses, MYH7 and MYBPC3, yields a positive result in 30% to 50% of cases. A second tiered approachwith testing of TNNT2, TNNI3, and TMP1 may be considered if results are negative and succeeds indetecting 10% to 15% of cases. Genetic testing of rare genes (<1% detection rate) associated with HCM isnot likely to be clinically useful or cost-effective. Given the small number of variants described in thesegenes, results are more likely to be of unknown significance if a clear familial pattern of disease is notrecognized. Lastly, in apparent HCM in which ventricular preexcitation is evident, genetic testing forcardiac storage diseases should be considered as first tier, including the genes PRKAG2, LAMP2, andGLA.Table 6.Summary recommendations for genetic testing in hypertrophic cardiomyopathyClinical scenario Testing CommentClinically diagnosed HCM ++ Genetic testing is recommended for the primary purpose of screening familymembers Tier 1 gene testing MYH7, MYBPC Tier II gene testing TNNT2, TNNI3, TPM1Clinically diagnosed HCM withECG features of ventricularpreexcitation ++ Genetic testing is recommended for the primary purpose of screening familymembers Tier I gene testing PRKAG2, LAMP2, GLA Tier II gene testing MYH7, MYBPC, TNNT2, TNNI3, TPM1

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Clinical scenario Testing CommentClinically diagnosed HCM − Genetic testing is NOT recommended for the purpose of diagnosticconfirmationClinically diagnosed HCM − Genetic testing is NOT recommended for the purpose of risk stratification andtreatment decisionsClinically suspected HCM − Genetic testing is NOT recommended for the purpose of differentiating HCMfrom other causes of cardiac hypertrophy, including athletes heart,hypertensive heart disease, and cardiac amyloidosisRecommendations: ++ (strongly recommended), − (not recommended).HCM, hypertrophic cardiomyopathy.RecommendationRecommendationRecommendationRecommendationClinically diagnosed HCM: Genetic testing is recommended for the primary purpose of screening familymembers.Although imaging studies represent a reasonable tool to screen for disease, incomplete diseasepenetrance of familial HCM warrants genetic testing. The identification of a disease-causing mutation mayencourage appropriate medical surveillance of family members or, conversely, may avoid unnecessarylong-term clinical testing in family members, particularly children, without the genotype.RecommendationRecommendationRecommendationRecommendationClinically diagnosed HCM: Genetic testing is not recommended for the purpose of diagnosticconfirmation.In the absence of known at-risk family members who may benefit from genetic screening, there exists noclinical utility in identifying the culprit genotype. In addition, genetic testing may not exclude the possibilitythat the patient has HCM, since genetic testing is not 100% sensitive.RecommendationRecommendationRecommendationRecommendationClinically diagnosed HCM: Genetic testing is not recommended for the purpose of risk stratification andtreatment decisions.The use of genetic information to predict clinical progression of disease or risk of fatal arrhythmia is notcurrently supported by the medical literature. Prediction of event risk should be guided by clinical testing.RecommendationRecommendationRecommendationRecommendationClinically suspected HCM: Genetic testing is not recommended for the purpose of differentiating HCMfrom other causes of cardiac hypertrophy, including athlete's heart, hypertensive heart disease, andcardiac amyloidosis.HCM can usually be differentiated from other causes of increased wall thickness on the basis of standardclinical history and objective tests.The role of genetic testing in dilated cardiomyopathyDilated cardiomyopathy (DCM) has a prevalence of 1 per 2500 and is characterized by dilation anddysfunction of the left or both ventricles.83 Often, the etiology remains unknown. The potential causes arevast and include myocardial destruction by toxic, infectious, or metabolic causes, such as alcoholism,viruses, or endocrine or nutritional deficiencies. Other causes may include infiltrative and inflammatorydiseases, such as hemochromatosis, amyloidosis, or sarcoidosis. Familial DCM is estimated to occur in20% to 35% of cases and most commonly involves genes encoding components of the myocyte sarcomereor cytoskeleton.84 and 85Diagnosis.Diagnosis.Diagnosis.Diagnosis. The diagnosis may be readily made by cardiac imaging studies and the exclusion of significantcoronary disease. Cardiac biopsy may be considered as a diagnostic tool.85Management.Management.Management.Management. Medical therapy includes the use of angiotensin-converting enzyme inhibitors, β-blockers,and spironolactone to minimize disease progression, control symptoms, and decrease arrhythmic risk.85Electrophysiological testing is not recommended for risk stratification. For a left ventricular ejection fraction<35% and impaired New York Heart Association functional class, consideration of an ICD for theprophylaxis of SCD should be considered. In patients with a significantly widened QRS duration (>150

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milliseconds) and impaired New York Heart Association functional class, biventricular pacing may improveheart failure symptoms.86Genetics.Genetics.Genetics.Genetics. Over 30 genes have been reported to cause DCM.87 The yield of genetic testing is significantlyenhanced when a family history is evident.85 and 88 In familial disease, the most common causes includegenetic defects in the MYBPC3, MYH7, TNNT2, LMNA, and SCN5A genes, which collectively account for15% to 30% of familial DCM. 85, 88 and 89Familial DCM with atrial arrhythmias and high-grade conduction disease is most commonly due tomutations of the LMNA gene. 85 Familial DCM demonstrating an X-linked pattern of inheritance andskeletal muscle weakness raises the suspicion of dystrophin (DMD) gene mutations. 85Recommendations for genetic testing in DCM (Table 7)Genetic determinants of sporadic DCM have not been routinely described. Thus, in the absence of a familyhistory determined either by history or by clinical evaluation of relatives, genetic testing is likely of limitedvalue.Table 7.Summary recommendations for genetic testing in dilated cardiomyopathyClinical scenario Testing CommentClinically diagnosed DCM − Genetic testing is NOT recommended in the absence of establishedor probable familial disease as determined by family history orclinical testing of first-degree relativesClinically diagnosed DCM with evidence ofprobable familial DCM ++ Genetic testing is recommended for the primary purpose ofscreening family members Genetic testing MYH7, MYPBC, TNNT2, LMNA, SCN5AClinically diagnosed familial DCM withevidence of atrial arrhythmias andhigh-grade conduction disease ++ Genetic testing is recommended for the primary purpose ofscreening family members Genetic testing LMNA, SCN5AClinically diagnosed familial DCM withevidence of X-linked inheritance ++ Genetic testing is recommended for the primary purpose ofscreening family members Genetic testing DMDRecommendations: ++ (strongly recommended), − (not recommended).DCM, dilated cardiomyopathy.Probands should be questioned about family members with cardiac devices, unexpected SCD (at age < 50years), skeletal muscle disorders, or heart failure. The presence of family members with any of thesecharacteristics increases the probability of familial disease. Since familial DCM has an autosomaldominant pattern of inheritance and is associated with incomplete penetrance and variable age of onset,genetic testing remains valuable in screening family members despite the absence of clinical features.A comprehensive testing approach for all reported DCM genes is not cost-effective. Targeting of the geneswith the most likely chance for a positive finding or interpretable test result in familial DCM is mostreasonable and includes the following genes: MYH7, TNNT2, MYBPC, TNNT, LMNA, and SCN5A. Shouldevaluation of these genes be negative, consideration may be given to genetic testing of phospholamban(PLN) and alpha-myosin heavy chain (MYH6) genes. When atrial arrhythmia or conduction disease ispresent, testing of LMNA or SCN5A should be prioritized. In X-linked inheritance, the dystrophin gene(DMD) should be targeted.RecommendationRecommendationRecommendationRecommendationClinically diagnosed DCM: Genetic testing is not recommended in the absence of established orprobable familial disease as determined by family history and clinical testing of first-degree relatives.Genetic testing in DCM in the absence of any family history is not recommended, as reports of interpretablegenetic findings in isolated cases are scarce, and unique patient results will most often fall under thecategory of “variant of unknown significance.”RecommendationRecommendationRecommendationRecommendationClinically diagnosed DCM with evidence of probable familial disease: Genetic testing is recommendedfor the primary purpose of screening family members.

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The clinical penetrance of disease and age of onset may be variable in familial DCM, warranting genetictesting as a potential tool for screening family members.The role of genetic testing in unexplained SCD, sudden cardiac arrest, and the sudden infantdeath syndromeSCD is defined as unexpected cardiac death within 1 hour of the onset of symptoms in individuals without aprior known condition that would appear to be fatal.90 and 91 Despite a complete investigation, autopsy mayfail to establish a diagnosis, and the event remains unexplained. The prevalence of these “autopsynegative” cases of SCD has been reported in between 3% of a general young population and 35% in youngmilitary recruits.92, 93 and 94 When SCD occurs in infancy without predisposing or precipitating clinicalconditions and with a negative autopsy, the diagnosis of sudden infant death syndrome (SIDS) is applied.95Similarly, in the survivor of a sudden cardiac arrest (SCA), evaluation may determine that there is astructurally normal heart. This is the clinical equivalent of a negative autopsy and is found in about 5% ofcases.This section describes the background for considering genetic testing in (1) the autopsy negativeunexpected SCD victim, (2) the individual with resuscitated SCA, and (3) the infant who experiences SIDS.Clinical and molecular considerations in unexplained SCD (Table 8)Recommendations describing the appropriate investigations that are required to establish that an autopsyis negative have been published.96 A thorough assessment to rule out a structural cause of SCD shouldinclude a rigourous cardiac autopsy, including comprehensive evaluation of the right ventricle to assess forARVC. Previous symptoms or the circumstances of death, such as syncope with exertion (CPVT),drowning (LQT1 or CPVT), auditory stimuli (LQT2), and SCD during sleep (Brugada or LQT3), may guidetargeted genetic testing.97, 98 and 99 Genetic analysis of postmortem tissue has been applied in autopsy-negative SCD. Gene defects of the cardiac ryanodine receptor gene (RYR2) have been identified in 14% ofcases, and mutations of LQTS-associated genes have been identified in 16% to 20% of cases. 100,101 and 102 Overall, 35% of unexpected SCD victims with a negative autopsy were diagnosed with eitherLQTS or CPVT by postmortem genetic testing in a specialized research setting. 100 and 102 From currentevidence, collection and storage of tissue and/or DNA for possible future molecular analysis is warranted.Table 8.The role of genetic testing in unexplained sudden cardiac death, resuscitated sudden cardiac death, and sudden infant deathsyndromeClinical scenario Testing CommentUnexplained sudden death(negative autopsy) ++ Targeted gene screening of retained tissue of the deceased based on evidence ofspecific genetic syndrome from medical history or evaluation of first- degreerelatives− In the absence of guiding clinical information, empirical gene screening for multiplepossible conditions is not recommendedResuscitated suddencardiac death ++ Targeted gene screening based on results of clinical evaluation of patient or first-degree relatives− Comprehensive empirical gene screening in the absence of guiding clinicalinformation is not recommendedSudden infant deathsyndrome ++ Targeted gene screening based on previous history or clinical evaluation of first-degree relatives+ Gene screening of KCNQ1, KCNH2, and SCN5A may be considered at thediscretion of a clinical expert− Comprehensive empirical gene screening for all possible genetic arrhythmiasyndromes is not recommendedFirst-degree relative Proband genotype positive ++ Useful for diagnostic and therapeutic purposesRecommendations: ++ (strongly recommended), + (recommended), − (not recommended).Clinical evaluation of the individual with a first-degree relative with unexplained SCDPrior to clinical assessment, background details of the deceased and family history may assist in focusingthe cardiac investigation. Relevant medical history includes events of near drowning or drowning, a familymember with seizures and a diagnosis of epilepsy, or a history of SIDS in the family. Initial cardiac testingincludes a resting and signal-averaged ECG; an exercise test; Holter monitoring; an echocardiogram; andprovocative drug testing for LQT1, Brugada syndrome, or CPVT. The value of provocative drug testing hasbeen demonstrated, unmasking either CPVT or Brugada syndrome in 16% of relatives of SCA survivors,Table options


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when patients with obvious LQTS were excluded.63 and 103 Similarly, Behr et al found evidence of aninherited arrhythmia syndrome in 16% of first-degree relatives following clinical assessment.104 Tan et alidentified a channelopathy in a total of 28% of surviving relatives of SCD victims.105Clinical evaluation in the patient with resuscitated SCAClinical workup includes resting and signal-averaged ECG, exercise testing, telemetry or Holtermonitoring, echocardiography, and magnetic resonance imaging. Coronary angiography is usuallyperformed in adults, with discretionary use of electrophysiological testing including endocardial voltagemapping, cardiac biopsy, and left and right ventricular angiography. Provocative adrenaline and sodiumchannel blocker infusion should be considered for the potential unmasking of LQTS, CPVT, and Brugadasyndrome.63 and 103Clinical and molecular considerations in SIDSSIDS is a multifactorial disorder that causes between 65 and 100 deaths per 100,000 live births.Environmental associations include parental smoking, cosleeping, and the prone sleeping position.106International standards define the process and information required to classify an infant death as SIDS.107Routine biochemical analysis of SIDS victims is performed to diagnose metabolic abnormalities that areresponsible for about 5% of cases.108 Mutations associated with LQTS can be found in 2% to 9.5% ofvictims of SIDS.109 and 110In the absence of a pathologic diagnosis, referral of siblings and parents to a physician expert for clinicalassessment is warranted and may provide information leading to targeted genetic testing of the deceasedand family members.RecommendationRecommendationRecommendationRecommendationAutopsy-negative, unexpected SCD: Genetic testing of retained tissue is recommended only whenthere is evidence of a clinical phenotype in family members.In the absence of guiding clinical information, comprehensive screening of all possible genes responsiblefor inherited arrhythmias is not recommended. Proceeding with genetic testing in the absence of anycorrelating clinical phenotype may raise significant issues in the management of family members whengenetic results of “unknown significance” are identified. When clinical history or family evaluation providesevidence for a specific genetic condition, screening of the appropriate genes should be undertaken in boththe proband and the identified affected family member to corroborate clinical suspicion.RecommendationRecommendationRecommendationRecommendationSurvivor of SCA: Genetic testing of the survivor should be directed by the results of the survivor'smedical evaluation or that of his or her first-degree relatives.Comprehensive molecular screening for all possible genetic arrhythmias as part of the medical evaluationis not recommended. Genetic testing should be performed only on the basis of clinical evidence supportinga specific diagnosis.RecommendationRecommendationRecommendationRecommendationSIDS: Genetic testing of retained tissue should be directed by history and clinical investigation of anyfirst-degree relatives.Consideration may be given to screening KCNH2, KCNQ1, and SCN5A under the direction of a clinicalexpert.ConclusionThe clinical care of patients and families with suspected genetic arrhythmia syndromes may warrant theuse of genetic testing. The decision to perform genetic testing should be based on the clinical value of thegenetic information and should be performed with consideration of ethical and psychosocial issues. Thisrequires a multidisciplinary approach including qualified arrhythmia specialists and counsellors.Specialized clinics with a focused clinical care approach to inherited arrhythmia syndromes areencouraged, with the aim of discouraging random genetic testing after inadequate evaluation and absenceof appropriate counseling. Implicit is the assumption that a specialized clinic approach will provide the mostcomprehensive and cost-effective management of patients and their families.The present recommendations are based on contemporary knowledge. The field of cardiovasculargenetics is rapidly evolving, and surveillance for future developments in the field by expert panels remainsnecessary. Health insurance providers and government funding agencies may require restructuring toallow for financial coverage of genetic testing to optimize patient care.


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Supplementary dataSupplementary Material. ReferencesN.W. Taggart, C.M. Haglund, D.J. Tester, M.J. AckermanDiagnostic miscues in congenital long QT syndromeDiagnostic miscues in congenital long QT syndromeDiagnostic miscues in congenital long QT syndromeDiagnostic miscues in congenital long QT syndromeCirculation, 115 (2007), pp. 2613–2620[SD-008]R. Bai, C. Napolitano, R. Bloise, N. Monteforte, S.G. PrioriYield of genetic screening in inherited cardiac channelopathies: how to prioritize access toYield of genetic screening in inherited cardiac channelopathies: how to prioritize access toYield of genetic screening in inherited cardiac channelopathies: how to prioritize access toYield of genetic screening in inherited cardiac channelopathies: how to prioritize access togenetic testinggenetic testinggenetic testinggenetic testingCirc Arrhythm Electrophysiol, 2 (2009), pp. 6–15[SD-008]M.J. AckermanThe long QT syndrome: ion channel diseases of the heartThe long QT syndrome: ion channel diseases of the heartThe long QT syndrome: ion channel diseases of the heartThe long QT syndrome: ion channel diseases of the heartMayo Clin Proc, 73 (1998), pp. 250–269[SD-008]G.M. VincentThe molecular genetics of the long QT syndrome: genes causing fainting and sudden deathThe molecular genetics of the long QT syndrome: genes causing fainting and sudden deathThe molecular genetics of the long QT syndrome: genes causing fainting and sudden deathThe molecular genetics of the long QT syndrome: genes causing fainting and sudden deathAnnu Rev Med, 49 (1998), pp. 263–274[SD-008]S.G. Priori, P.J. Schwartz, C. Napolitano, et al.Risk stratification in the long-QT syndromeRisk stratification in the long-QT syndromeRisk stratification in the long-QT syndromeRisk stratification in the long-QT syndromeN Engl J Med, 348 (2003), pp. 1866–1874[SD-008]W. Shimizu, M. Horie, S. Ohno, et al.Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation inMutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation inMutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation inMutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation inthe LQT1 form of congenital long QT syndrome: multicenter study in Japanthe LQT1 form of congenital long QT syndrome: multicenter study in Japanthe LQT1 form of congenital long QT syndrome: multicenter study in Japanthe LQT1 form of congenital long QT syndrome: multicenter study in JapanJ Am Coll Cardiol, 44 (2004), pp. 117–125[SD-008]J. Kimbrough, A.J. Moss, W. Zareba, et al.Clinical implications for affected parents and siblings of probands with long-QT syndromeClinical implications for affected parents and siblings of probands with long-QT syndromeClinical implications for affected parents and siblings of probands with long-QT syndromeClinical implications for affected parents and siblings of probands with long-QT syndromeCirculation, 104 (2001), pp. 557–562[SD-008]E.H. Locati, W. Zareba, A.J. Moss, et al.Age- and sex-related differences in clinical manifestations in patients with congenital long-QTAge- and sex-related differences in clinical manifestations in patients with congenital long-QTAge- and sex-related differences in clinical manifestations in patients with congenital long-QTAge- and sex-related differences in clinical manifestations in patients with congenital long-QTsyndrome: findings from the International LQTS Registrysyndrome: findings from the International LQTS Registrysyndrome: findings from the International LQTS Registrysyndrome: findings from the International LQTS RegistryCirculation, 97 (1998), pp. 2237–2244[SD-008]A.J. Moss, P.J. Schwartz, R.S. Crampton, et al.The long QT syndrome: prospective longitudinal study of 328 familiesThe long QT syndrome: prospective longitudinal study of 328 familiesThe long QT syndrome: prospective longitudinal study of 328 familiesThe long QT syndrome: prospective longitudinal study of 328 familiesCirculation, 84 (1991), pp. 1136–1144[SD-008]P.J. Schwartz, A.M. Moss, G.M. Vincent, et al.Diagnostic criteria for the long QT syndromeDiagnostic criteria for the long QT syndromeDiagnostic criteria for the long QT syndromeDiagnostic criteria for the long QT syndromeCirculation, 88 (1993), pp. 782–784[SD-008]H. Swan, K. Saarinen, K. Kontula, et al.Evaluation of QT interval duration and dispersion and proposed clinical criteria in diagnosis ofEvaluation of QT interval duration and dispersion and proposed clinical criteria in diagnosis ofEvaluation of QT interval duration and dispersion and proposed clinical criteria in diagnosis ofEvaluation of QT interval duration and dispersion and proposed clinical criteria in diagnosis oflong QT syndrome in patients with a genetically uniform type of LQT1long QT syndrome in patients with a genetically uniform type of LQT1long QT syndrome in patients with a genetically uniform type of LQT1long QT syndrome in patients with a genetically uniform type of LQT1J Am Coll Cardiol, 32 (1998), pp. 486–491

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[SD-008]N. Neyroud, P. Maison-Blanche, I. Denjoy, et al.Diagnostic performance of QT interval variables from 24-h electrocardiography in the long QTDiagnostic performance of QT interval variables from 24-h electrocardiography in the long QTDiagnostic performance of QT interval variables from 24-h electrocardiography in the long QTDiagnostic performance of QT interval variables from 24-h electrocardiography in the long QTsyndromesyndromesyndromesyndromeEur Heart J, 19 (1998), pp. 158–165[SD-008]M. Stramba-Badiale, E.H. Locati, A. Martinelli, et al.Gender and the relationship between ventricular repolarization and cardiac cycle length duringGender and the relationship between ventricular repolarization and cardiac cycle length duringGender and the relationship between ventricular repolarization and cardiac cycle length duringGender and the relationship between ventricular repolarization and cardiac cycle length during24-h Holter recordings24-h Holter recordings24-h Holter recordings24-h Holter recordingsEur Heart J, 18 (1997), pp. 1000–1006[SD-008]A.D. Krahn, G.J. Klein, R. YeeHysteresis of the RT interval with exercise: a new marker for the long-QT syndrome?Hysteresis of the RT interval with exercise: a new marker for the long-QT syndrome?Hysteresis of the RT interval with exercise: a new marker for the long-QT syndrome?Hysteresis of the RT interval with exercise: a new marker for the long-QT syndrome?Circulation, 96 (1997), pp. 1551–1556[SD-008]M.H. Lehmann, F. Suzuki, B.S. Fromm, et al.T wave “humps” as a potential electrocardiographic marker of the long QT syndromeT wave “humps” as a potential electrocardiographic marker of the long QT syndromeT wave “humps” as a potential electrocardiographic marker of the long QT syndromeT wave “humps” as a potential electrocardiographic marker of the long QT syndromeJ Am Coll Cardiol, 24 (1994), pp. 746–754[SD-008]A. Khositseth, J. Hejlik, W.K. Shen, et al.Epinephrine-induced T-wave notching in congenital long QT syndromeEpinephrine-induced T-wave notching in congenital long QT syndromeEpinephrine-induced T-wave notching in congenital long QT syndromeEpinephrine-induced T-wave notching in congenital long QT syndromeHeart Rhythm, 2 (2005), pp. 141–146[SD-008]W. Shimizu, T. Noda, H. Takaki, et al.Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenitalDiagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenitalDiagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenitalDiagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenitallong QT syndromelong QT syndromelong QT syndromelong QT syndromeHeart Rhythm, 1 (2004), pp. 276–283[SD-008]H. Heidbuchel, D. Corrado, A. Biffi, et al.Recommendations for participation in leisure-time physical activity and competitive sports ofRecommendations for participation in leisure-time physical activity and competitive sports ofRecommendations for participation in leisure-time physical activity and competitive sports ofRecommendations for participation in leisure-time physical activity and competitive sports ofpatients with arrhythmias and potentially arrhythmogenic conditions: Part II: ventricularpatients with arrhythmias and potentially arrhythmogenic conditions: Part II: ventricularpatients with arrhythmias and potentially arrhythmogenic conditions: Part II: ventricularpatients with arrhythmias and potentially arrhythmogenic conditions: Part II: ventriculararrhythmias, channelopathies and implantable defibrillatorsarrhythmias, channelopathies and implantable defibrillatorsarrhythmias, channelopathies and implantable defibrillatorsarrhythmias, channelopathies and implantable defibrillatorsEur J Cardiovasc Prev Rehabil, 13 (2006), pp. 676–686[SD-008]B.J. Maron, B.R. Chaitman, M.J. Ackerman, et al.Recommendations for physical activity and recreational sports participation for young patientsRecommendations for physical activity and recreational sports participation for young patientsRecommendations for physical activity and recreational sports participation for young patientsRecommendations for physical activity and recreational sports participation for young patientswith genetic cardiovascular diseaseswith genetic cardiovascular diseaseswith genetic cardiovascular diseaseswith genetic cardiovascular diseasesCirculation, 109 (2004), pp. 2807–2816[SD-008]C. Napolitano, S.G. Priori, P.J. Schwartz, et al.Genetic testing in the long QT syndrome: development and validation of an efficient approach toGenetic testing in the long QT syndrome: development and validation of an efficient approach toGenetic testing in the long QT syndrome: development and validation of an efficient approach toGenetic testing in the long QT syndrome: development and validation of an efficient approach togenotyping in clinical practicegenotyping in clinical practicegenotyping in clinical practicegenotyping in clinical practiceJAMA, 294 (2005), pp. 2975–2980[SD-008]D.J. Tester, M.L. Will, C.M. Haglund, et al.Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for longCompendium of cardiac channel mutations in 541 consecutive unrelated patients referred for longCompendium of cardiac channel mutations in 541 consecutive unrelated patients referred for longCompendium of cardiac channel mutations in 541 consecutive unrelated patients referred for longQT syndrome genetic testingQT syndrome genetic testingQT syndrome genetic testingQT syndrome genetic testingHeart Rhythm, 2 (2005), pp. 507–517[SD-008]I. Splawski, J. Shen, K.W. Timothy, et al.Spectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, andSpectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, andSpectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, andSpectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, andKCNE2KCNE2KCNE2KCNE2Circulation, 102 (2000), pp. 1178–1185[SD-008]J. Brugada, R. Brugada, P. Brugada


15 of 24 2/10/2015 9:24 PM

2425262728293031323334

Right bundle-branch block and ST-segment elevation in leads V1 through V3: a marker forRight bundle-branch block and ST-segment elevation in leads V1 through V3: a marker forRight bundle-branch block and ST-segment elevation in leads V1 through V3: a marker forRight bundle-branch block and ST-segment elevation in leads V1 through V3: a marker forsudden death in patients without demonstrable structural heart diseasesudden death in patients without demonstrable structural heart diseasesudden death in patients without demonstrable structural heart diseasesudden death in patients without demonstrable structural heart diseaseCirculation, 97 (1998), pp. 457–460[SD-008]S. Viskin, R. Fish, M. Eldar, et al.Prevalence of the Brugada sign in idiopathic ventricular fibrillation and healthy controlsPrevalence of the Brugada sign in idiopathic ventricular fibrillation and healthy controlsPrevalence of the Brugada sign in idiopathic ventricular fibrillation and healthy controlsPrevalence of the Brugada sign in idiopathic ventricular fibrillation and healthy controls[see comments] Heart, 84 (2000), pp. 31–36[SD-008]C. Veltmann, R. Schimpf, C. Echternach, et al.A prospective study on spontaneous fluctuations between diagnostic and non-diagnostic ECGs inA prospective study on spontaneous fluctuations between diagnostic and non-diagnostic ECGs inA prospective study on spontaneous fluctuations between diagnostic and non-diagnostic ECGs inA prospective study on spontaneous fluctuations between diagnostic and non-diagnostic ECGs inBrugada syndrome: implications for correct phenotyping and risk stratificationBrugada syndrome: implications for correct phenotyping and risk stratificationBrugada syndrome: implications for correct phenotyping and risk stratificationBrugada syndrome: implications for correct phenotyping and risk stratificationEur Heart J, 27 (2006), pp. 2544–2552[SD-008]K. Matsuo, M. Akahoshi, E. Nakashima, et al.Clinical characteristics of subjects with the Brugada-type electrocardiogramClinical characteristics of subjects with the Brugada-type electrocardiogramClinical characteristics of subjects with the Brugada-type electrocardiogramClinical characteristics of subjects with the Brugada-type electrocardiogramJ Cardiovasc Electrophysiol, 15 (2004), pp. 653–657[SD-008]M. Furuhashi, K. Uno, K. Tsuchihashi, et al.Prevalence of asymptomatic ST segment elevation in right precordial leads with right bundlePrevalence of asymptomatic ST segment elevation in right precordial leads with right bundlePrevalence of asymptomatic ST segment elevation in right precordial leads with right bundlePrevalence of asymptomatic ST segment elevation in right precordial leads with right bundlebranch block (Brugada-type ST shift) among the general Japanese populationbranch block (Brugada-type ST shift) among the general Japanese populationbranch block (Brugada-type ST shift) among the general Japanese populationbranch block (Brugada-type ST shift) among the general Japanese populationHeart, 86 (2001), pp. 161–166[SD-008]C. Antzelevitch, P. Brugada, M. Borggrefe, et al.Brugada syndrome: report of the second consensus conferenceBrugada syndrome: report of the second consensus conferenceBrugada syndrome: report of the second consensus conferenceBrugada syndrome: report of the second consensus conferenceHeart Rhythm, 2 (2005), pp. 429–440[SD-008]A.O. Grant, M.P. Carboni, V. Neplioueva, et al.Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a singleLong QT syndrome, Brugada syndrome, and conduction system disease are linked to a singleLong QT syndrome, Brugada syndrome, and conduction system disease are linked to a singleLong QT syndrome, Brugada syndrome, and conduction system disease are linked to a singlesodium channel mutationsodium channel mutationsodium channel mutationsodium channel mutationJ Clin Invest, 110 (2002), pp. 1201–1209[SD-008]A. Sarkozy, T. Boussy, G. Kourgiannides, et al.Long-term follow-up of primary prophylactic implantable cardioverter-defibrillator therapy inLong-term follow-up of primary prophylactic implantable cardioverter-defibrillator therapy inLong-term follow-up of primary prophylactic implantable cardioverter-defibrillator therapy inLong-term follow-up of primary prophylactic implantable cardioverter-defibrillator therapy inBrugada syndromeBrugada syndromeBrugada syndromeBrugada syndromeEur Heart J, 28 (2007), pp. 334–344[SD-008]B. Belhassen, A. Glick, S. ViskinEfficacy of quinidine in high-risk patients with Brugada syndromeEfficacy of quinidine in high-risk patients with Brugada syndromeEfficacy of quinidine in high-risk patients with Brugada syndromeEfficacy of quinidine in high-risk patients with Brugada syndromeCirculation, 110 (2004), pp. 1731–1737[SD-008]V. Probst, C. Veltmann, L. Eckardt, et al.Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGERLong-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGERLong-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGERLong-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGERBrugada Syndrome RegistryBrugada Syndrome RegistryBrugada Syndrome RegistryBrugada Syndrome RegistryCirculation, 121 (2010), pp. 635–643[SD-008]S.G. Priori, C. NapolitanoShould patients with an asymptomatic Brugada electrocardiogram undergo pharmacological andShould patients with an asymptomatic Brugada electrocardiogram undergo pharmacological andShould patients with an asymptomatic Brugada electrocardiogram undergo pharmacological andShould patients with an asymptomatic Brugada electrocardiogram undergo pharmacological andelectrophysiological testing?electrophysiological testing?electrophysiological testing?electrophysiological testing?Circulation, 112 (2005), pp. 279–292 discussion 279-92[SD-008]P. Brugada, R. Brugada, J. BrugadaShould patients with an asymptomatic Brugada electrocardiogram undergo pharmacological andShould patients with an asymptomatic Brugada electrocardiogram undergo pharmacological andShould patients with an asymptomatic Brugada electrocardiogram undergo pharmacological andShould patients with an asymptomatic Brugada electrocardiogram undergo pharmacological andelectrophysiological testing?electrophysiological testing?electrophysiological testing?electrophysiological testing?Circulation, 112 (2005), pp. 279–292 discussion 279-292[SD-008]


16 of 24 2/10/2015 9:24 PM

353637383940414243444546

A.K. Gehi, T.D. Duong, L.D. Metz, et al.Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysisRisk stratification of individuals with the Brugada electrocardiogram: a meta-analysisRisk stratification of individuals with the Brugada electrocardiogram: a meta-analysisRisk stratification of individuals with the Brugada electrocardiogram: a meta-analysisJ Cardiovasc Electrophysiol, 17 (2006), pp. 577–583[SD-008]J. Brugada, R. Brugada, P. BrugadaDeterminants of sudden cardiac death in individuals with the electrocardiographic pattern ofDeterminants of sudden cardiac death in individuals with the electrocardiographic pattern ofDeterminants of sudden cardiac death in individuals with the electrocardiographic pattern ofDeterminants of sudden cardiac death in individuals with the electrocardiographic pattern ofBrugada syndrome and no previous cardiac arrestBrugada syndrome and no previous cardiac arrestBrugada syndrome and no previous cardiac arrestBrugada syndrome and no previous cardiac arrestCirculation, 108 (2003), pp. 3092–3096[SD-008]S.G. Priori, C. Napolitano, M. Gasparini, et al.Clinical and genetic heterogeneity of right bundle branch block and ST-segment elevationClinical and genetic heterogeneity of right bundle branch block and ST-segment elevationClinical and genetic heterogeneity of right bundle branch block and ST-segment elevationClinical and genetic heterogeneity of right bundle branch block and ST-segment elevationsyndrome: a prospective evaluation of 52 familiessyndrome: a prospective evaluation of 52 familiessyndrome: a prospective evaluation of 52 familiessyndrome: a prospective evaluation of 52 familiesCirculation, 102 (2000), pp. 2509–2515[SD-008]S.G. Priori, C. Napolitano, M. Gasparini, et al.Natural history of Brugada syndrome: insights for risk stratification and managementNatural history of Brugada syndrome: insights for risk stratification and managementNatural history of Brugada syndrome: insights for risk stratification and managementNatural history of Brugada syndrome: insights for risk stratification and managementCirculation, 105 (2002), pp. 1342–1347[SD-008]E. Schulze-Bahr, L. Eckardt, G. Breithardt, et al.Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: differentSodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: differentSodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: differentSodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: differentincidences in familial and sporadic diseaseincidences in familial and sporadic diseaseincidences in familial and sporadic diseaseincidences in familial and sporadic diseaseHum Mutat, 21 (2003), pp. 651–652[SD-008]J.D. Roberts, M.H. GollobThe genetic and clinical features of cardiac channelopathiesThe genetic and clinical features of cardiac channelopathiesThe genetic and clinical features of cardiac channelopathiesThe genetic and clinical features of cardiac channelopathiesFuture Cardiol, 6 (2010), pp. 491–506[SD-008]C. Antzelevitch, G.D. Pollevick, J.M. Cordeiro, et al.Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entityLoss-of-function mutations in the cardiac calcium channel underlie a new clinical entityLoss-of-function mutations in the cardiac calcium channel underlie a new clinical entityLoss-of-function mutations in the cardiac calcium channel underlie a new clinical entitycharacterized by ST-segment elevation, short QT intervals, and sudden cardiac deathcharacterized by ST-segment elevation, short QT intervals, and sudden cardiac deathcharacterized by ST-segment elevation, short QT intervals, and sudden cardiac deathcharacterized by ST-segment elevation, short QT intervals, and sudden cardiac deathCirculation, 115 (2007), pp. 442–449[SD-008]B. London, M. Michalec, H. Mehdi, et al.Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+current and causes inherited arrhythmiascurrent and causes inherited arrhythmiascurrent and causes inherited arrhythmiascurrent and causes inherited arrhythmiasCirculation, 116 (2007), pp. 2260–2268[SD-008]C. Basso, D. Corrado, F.I. Marcus, A. Nava, G. ThieneArrhythmogenic right ventricular cardiomyopathyArrhythmogenic right ventricular cardiomyopathyArrhythmogenic right ventricular cardiomyopathyArrhythmogenic right ventricular cardiomyopathyLancet, 373 (2009), pp. 1289–1300[SD-008]P. Muthappan, H. CalkinsArrhythmogenic right ventricular dysplasia, 51 (2008), pp. 31–43[SD-008]W.J. McKenna, G. Thiene, A. Nava, et al.Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy: Task Force of theDiagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy: Task Force of theDiagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy: Task Force of theDiagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy: Task Force of theWorking Group Myocardial and Pericardial Disease of the European Society of Cardiology and ofWorking Group Myocardial and Pericardial Disease of the European Society of Cardiology and ofWorking Group Myocardial and Pericardial Disease of the European Society of Cardiology and ofWorking Group Myocardial and Pericardial Disease of the European Society of Cardiology and ofthe Scientific Council on Cardiomyopathies of the International Federation of Cardiologythe Scientific Council on Cardiomyopathies of the International Federation of Cardiologythe Scientific Council on Cardiomyopathies of the International Federation of Cardiologythe Scientific Council on Cardiomyopathies of the International Federation of CardiologyBr Heart J, 71 (1994), pp. 215–218[SD-008]F.I. Marcus, W.J. McKenna, D. Sherrill, et al.Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modificationDiagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modificationDiagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modificationDiagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modificationof the task force criteriaof the task force criteriaof the task force criteriaof the task force criteriaCirculation, 121 (2010), pp. 1533–1541[SD-008]


17 of 24 2/10/2015 9:24 PM

474849505152535455565758

S.C. Vasaiwala, C. Finn, J. Delpriore, et al.Prospective study of cardiac sarcoid mimicking arrhythmogenic right ventricular dysplasiaProspective study of cardiac sarcoid mimicking arrhythmogenic right ventricular dysplasiaProspective study of cardiac sarcoid mimicking arrhythmogenic right ventricular dysplasiaProspective study of cardiac sarcoid mimicking arrhythmogenic right ventricular dysplasiaJ Cardiovasc Electrophysiol, 20 (2009), pp. 473–476[SD-008]J.D. Roberts, J.P. Veinot, J. Rutberg, M.H. GollobInherited cardiomyopathies mimicking arrhythmogenic right ventricular cardiomyopathyInherited cardiomyopathies mimicking arrhythmogenic right ventricular cardiomyopathyInherited cardiomyopathies mimicking arrhythmogenic right ventricular cardiomyopathyInherited cardiomyopathies mimicking arrhythmogenic right ventricular cardiomyopathyCardiovasc Pathol, 19 (2010), pp. 316–320[SD-008]S. Sen-Chowdhry, P. Syrris, W.J. McKennaRole of genetic analysis in the management of patients with arrhythmogenic right ventricularRole of genetic analysis in the management of patients with arrhythmogenic right ventricularRole of genetic analysis in the management of patients with arrhythmogenic right ventricularRole of genetic analysis in the management of patients with arrhythmogenic right ventriculardysplasia/cardiomyopathydysplasia/cardiomyopathydysplasia/cardiomyopathydysplasia/cardiomyopathyJ Am Coll Cardiol, 50 (2007), pp. 1813–1821[SD-008]G. McKoy, N. Protonotarios, A. Crosby, et al.Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy withIdentification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy withIdentification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy withIdentification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy withpalmo-plantar keratoderma and wooly hair (Naxos disease)palmo-plantar keratoderma and wooly hair (Naxos disease)palmo-plantar keratoderma and wooly hair (Naxos disease)palmo-plantar keratoderma and wooly hair (Naxos disease)Lancet, 355 (2000), pp. 2119–2124[SD-008]A. Rampazzo, A. Nava, S. Malacirda, et al.Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form ofMutation in human desmoplakin domain binding to plakoglobin causes a dominant form ofMutation in human desmoplakin domain binding to plakoglobin causes a dominant form ofMutation in human desmoplakin domain binding to plakoglobin causes a dominant form ofarrhythmogenic right ventricular cardiomyopathyarrhythmogenic right ventricular cardiomyopathyarrhythmogenic right ventricular cardiomyopathyarrhythmogenic right ventricular cardiomyopathyAm J Hum Genet, 71 (2002), pp. 1200–1206[SD-008]B. Gerull, A. Heuser, T. Wichter, et al.Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic rightMutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic rightMutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic rightMutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic rightventricular cardiomyopathyventricular cardiomyopathyventricular cardiomyopathyventricular cardiomyopathyNat Genet, 36 (2004), pp. 1162–1164[SD-008]K. Pilichou, A. Nava, C. Basso, et al.Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricularMutations in desmoglein-2 gene are associated with arrhythmogenic right ventricularMutations in desmoglein-2 gene are associated with arrhythmogenic right ventricularMutations in desmoglein-2 gene are associated with arrhythmogenic right ventricularcardiomyopathycardiomyopathycardiomyopathycardiomyopathyCirculation, 113 (2006), pp. 1171–1179[SD-008]A. Heuser, E.R. Plovie, P.T. Elinor, et al.Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathyMutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathyMutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathyMutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathyAm J Hum Genet, 71 (2006), pp. 1081–1088[SD-008]N.D. Merner, K.A. Hodgkinson, A.F.M. Haywood, et al.Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmicArrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmicArrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmicArrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmicdisorder caused by a missense mutation in the TMEM43 genedisorder caused by a missense mutation in the TMEM43 genedisorder caused by a missense mutation in the TMEM43 genedisorder caused by a missense mutation in the TMEM43 geneAm J Human Genet, 82 (2008), pp. 1–13[SD-008]P. Syrris, D. Ward, A. Asimaki, et al.Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricularClinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricularClinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricularClinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricularcardiomyopathycardiomyopathycardiomyopathycardiomyopathyCirculation, 113 (2006), pp. 356–364[SD-008]D. Dalal, L.H. Molin, J. Piccini, et al.Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated withClinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated withClinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated withClinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated withmutations in plakophilin-2mutations in plakophilin-2mutations in plakophilin-2mutations in plakophilin-2Circulation, 113 (2006), pp. 1641–1649[SD-008]Z. Yang, N.E. Bowles, S.E. Scherer, et al.Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic rightDesmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic rightDesmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic rightDesmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic rightventricular dysplasia/cardiomyopathyventricular dysplasia/cardiomyopathyventricular dysplasia/cardiomyopathyventricular dysplasia/cardiomyopathyCirc Res, 99 (2006), pp. 646–655


18 of 24 2/10/2015 9:24 PM

5960616263646566676869

[SD-008]E.E. Norgett, S.J. Hatsell, L. Carvajal-Huerta, et al.Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions andRecessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions andRecessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions andRecessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions andcauses dilated cardiomyopathy, wooly hair and keratodermacauses dilated cardiomyopathy, wooly hair and keratodermacauses dilated cardiomyopathy, wooly hair and keratodermacauses dilated cardiomyopathy, wooly hair and keratodermaHum Mol Genet, 9 (2000), pp. 2761–2766[SD-008]P. Syrris, D. Ward, A. Evans, et al.Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in theArrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in theArrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in theArrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in thedesmosomal gene desmocollin-2desmosomal gene desmocollin-2desmosomal gene desmocollin-2desmosomal gene desmocollin-2Am J Hum Genet, 79 (2006), pp. 978–984[SD-008]S. Priori, C. Napolitano, M. Memmi, et al.Clinical and molecular characterization of patients with catecholaminergic polymorphicClinical and molecular characterization of patients with catecholaminergic polymorphicClinical and molecular characterization of patients with catecholaminergic polymorphicClinical and molecular characterization of patients with catecholaminergic polymorphicventricular tachycardiaventricular tachycardiaventricular tachycardiaventricular tachycardiaCirculation, 106 (2002), pp. 69–74[SD-008]A. Leenhardt, V. Lucet, I. Denjoy, F. Grau, D.D. Ngoc, P. CoumelCatecholaminergic polymorphic ventricular tachycardia in children: a 7-year follow-up of 21Catecholaminergic polymorphic ventricular tachycardia in children: a 7-year follow-up of 21Catecholaminergic polymorphic ventricular tachycardia in children: a 7-year follow-up of 21Catecholaminergic polymorphic ventricular tachycardia in children: a 7-year follow-up of 21patientspatientspatientspatientsCirculation, 91 (1995), pp. 1512–1519[SD-008]A.D. Krahn, M. Gollob, R. Yee, et al.Diagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusionDiagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusionDiagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusionDiagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusionCirculation, 112 (2005), pp. 2228–2234[SD-008]H. Watanabe, N. Chopra, D. Laver, et al.Flecainide prevents catecholamineregic polymorphic ventricular tachycardia in mice and humansFlecainide prevents catecholamineregic polymorphic ventricular tachycardia in mice and humansFlecainide prevents catecholamineregic polymorphic ventricular tachycardia in mice and humansFlecainide prevents catecholamineregic polymorphic ventricular tachycardia in mice and humansNat Med, 15 (2009), pp. 380–383[SD-008]B. Makanjee, M.H. Gollob, G.J. Klein, A.D. KrahnTen-year follow-up of cardiac sympathectomy in a young woman with catecholaminergicTen-year follow-up of cardiac sympathectomy in a young woman with catecholaminergicTen-year follow-up of cardiac sympathectomy in a young woman with catecholaminergicTen-year follow-up of cardiac sympathectomy in a young woman with catecholaminergicpolymorphic ventricular tachycardia and an implantable cardioverter defibrillatorpolymorphic ventricular tachycardia and an implantable cardioverter defibrillatorpolymorphic ventricular tachycardia and an implantable cardioverter defibrillatorpolymorphic ventricular tachycardia and an implantable cardioverter defibrillatorJ Cardiovasc Electrophysiol, 20 (2009), pp. 1167–1169[SD-008]S.G. Priori, C. Napolitano, N. Tiso, et al.Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergicMutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergicMutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergicMutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergicpolymorphic ventricular tachycardiapolymorphic ventricular tachycardiapolymorphic ventricular tachycardiapolymorphic ventricular tachycardiaCirculation, 103 (2001), pp. 196–200[SD-008]H. Lahat, E. Pras, T. Olender, et al.A missense mutation in a highly conserved region of CASQ2 is associated with autosomalA missense mutation in a highly conserved region of CASQ2 is associated with autosomalA missense mutation in a highly conserved region of CASQ2 is associated with autosomalA missense mutation in a highly conserved region of CASQ2 is associated with autosomalrecessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families fromrecessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families fromrecessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families fromrecessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families fromIsraelIsraelIsraelIsraelAm J Hum Genet, 69 (2001), pp. 1378–1384[SD-008]D. Tester, P. Arya, M. Will, et al.Genotypic heterogeneity and phenotypic mimicry among unrelated patients referred forGenotypic heterogeneity and phenotypic mimicry among unrelated patients referred forGenotypic heterogeneity and phenotypic mimicry among unrelated patients referred forGenotypic heterogeneity and phenotypic mimicry among unrelated patients referred forcatecholaminergic polymorphic ventricular tachycardia genetic testingcatecholaminergic polymorphic ventricular tachycardia genetic testingcatecholaminergic polymorphic ventricular tachycardia genetic testingcatecholaminergic polymorphic ventricular tachycardia genetic testingHeart Rhythm, 3 (2006), pp. 800–805[SD-008]B.J. Maron, W.J. McKenna, G.K. Danielson, Task Force on Clinical Expert Consensus Documents.American College of Cardiology; Committee for Practice Guidelines. European Society ofCardiology, et al.American College of Cardiology/European Society of Cardiology clinical expert consensusAmerican College of Cardiology/European Society of Cardiology clinical expert consensusAmerican College of Cardiology/European Society of Cardiology clinical expert consensusAmerican College of Cardiology/European Society of Cardiology clinical expert consensusdocument on hypertrophic cardiomyopathy: a report of the American College of Cardiologydocument on hypertrophic cardiomyopathy: a report of the American College of Cardiologydocument on hypertrophic cardiomyopathy: a report of the American College of Cardiologydocument on hypertrophic cardiomyopathy: a report of the American College of CardiologyFoundation Task Force on Clinical Expert Consensus Documents and the European Society ofFoundation Task Force on Clinical Expert Consensus Documents and the European Society ofFoundation Task Force on Clinical Expert Consensus Documents and the European Society ofFoundation Task Force on Clinical Expert Consensus Documents and the European Society of


19 of 24 2/10/2015 9:24 PM

707172737475767778798081

Cardiology Committee for Practice GuidelinesCardiology Committee for Practice GuidelinesCardiology Committee for Practice GuidelinesCardiology Committee for Practice GuidelinesJ Am Coll Cardiol, 42 (2003), pp. 1687–1713[SD-008]E.D. WigleDiagnosis of hypertrophic cardiomyopathyDiagnosis of hypertrophic cardiomyopathyDiagnosis of hypertrophic cardiomyopathyDiagnosis of hypertrophic cardiomyopathyHeart, 86 (2001), pp. 709–714[SD-008]M.P. Ryan, J.G.F. Cleland, J.A. French, et al.The standard electrocardiogram as a screening test for hypertrophic cardiomyopathyThe standard electrocardiogram as a screening test for hypertrophic cardiomyopathyThe standard electrocardiogram as a screening test for hypertrophic cardiomyopathyThe standard electrocardiogram as a screening test for hypertrophic cardiomyopathyAm J Cardiol, 76 (1995), pp. 689–694[SD-008]B.J. Maron, A. Pelliccia, P. SpiritoCardiac disease in young trained athletes: insights into methods for distinguishing athlete's heartCardiac disease in young trained athletes: insights into methods for distinguishing athlete's heartCardiac disease in young trained athletes: insights into methods for distinguishing athlete's heartCardiac disease in young trained athletes: insights into methods for distinguishing athlete's heartfrom structural heart disease, with particular emphasis on hypertrophic cardiomyopathyfrom structural heart disease, with particular emphasis on hypertrophic cardiomyopathyfrom structural heart disease, with particular emphasis on hypertrophic cardiomyopathyfrom structural heart disease, with particular emphasis on hypertrophic cardiomyopathyCirculation, 91 (1995), pp. 1596–1601[SD-008]M.H. Gollob, M.S. Green, A. Tang, R. RobertsThe PRKAG2 cardiac syndrome: familial ventricular preexcitation, conduction system disease,The PRKAG2 cardiac syndrome: familial ventricular preexcitation, conduction system disease,The PRKAG2 cardiac syndrome: familial ventricular preexcitation, conduction system disease,The PRKAG2 cardiac syndrome: familial ventricular preexcitation, conduction system disease,and cardiac hypertrophyand cardiac hypertrophyand cardiac hypertrophyand cardiac hypertrophyCurr Opin Cardiol, 17 (2002), pp. 229–234[SD-008]B. Guertl, C. Noehammer, G. HoeflerMetabolic cardiomyopathiesMetabolic cardiomyopathiesMetabolic cardiomyopathiesMetabolic cardiomyopathiesInt J Exp Pathol, 81 (2000), pp. 349–372[SD-008]W.J. McKenna, E.R. BehrHypertrophic cardiomyopathy: management, risk stratification, and prevention of sudden deathHypertrophic cardiomyopathy: management, risk stratification, and prevention of sudden deathHypertrophic cardiomyopathy: management, risk stratification, and prevention of sudden deathHypertrophic cardiomyopathy: management, risk stratification, and prevention of sudden deathHeart, 87 (2002), pp. 169–176[SD-008]J.M. Bos, J.A. Towbin, M.J. AckermanDiagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophicDiagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophicDiagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophicDiagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophiccardiomyopathycardiomyopathycardiomyopathycardiomyopathyJ Am Coll Cardiol, 54 (2009), pp. 201–211[SD-008]P. Richard, P. Charron, L. Carrier, EUROGENE Heart Failure Project, et al.Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, andHypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, andHypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, andHypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, andimplications for a molecular diagnosis strategyimplications for a molecular diagnosis strategyimplications for a molecular diagnosis strategyimplications for a molecular diagnosis strategyCirculation, 107 (2003), pp. 2227–2232[SD-008]B. Sachdev, T. Takenaka, H. Teraguchi, et al.Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophicPrevalence of Anderson-Fabry disease in male patients with late onset hypertrophicPrevalence of Anderson-Fabry disease in male patients with late onset hypertrophicPrevalence of Anderson-Fabry disease in male patients with late onset hypertrophiccardiomyopathycardiomyopathycardiomyopathycardiomyopathyCirculation, 105 (2002), pp. 1407–1411[SD-008]R. Schiffman, J.B. Kopp, J.B. Austin III, et al.Enzyme replacement therapy in Fabry disease: a randomized controlled trialEnzyme replacement therapy in Fabry disease: a randomized controlled trialEnzyme replacement therapy in Fabry disease: a randomized controlled trialEnzyme replacement therapy in Fabry disease: a randomized controlled trialJ Am Med Assoc, 285 (2001), pp. 2743–2759[SD-008]G.M. Pastores, R. ThadhaniEnzyme-replacement therapy for Anderson-Fabry diseaseEnzyme-replacement therapy for Anderson-Fabry diseaseEnzyme-replacement therapy for Anderson-Fabry diseaseEnzyme-replacement therapy for Anderson-Fabry diseaseLancet, 358 (2001), pp. 601–603[SD-008]Z. Yang, C.J. McMahon, L.R. Smith, et al.Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in childrenDanon disease as an underrecognized cause of hypertrophic cardiomyopathy in childrenDanon disease as an underrecognized cause of hypertrophic cardiomyopathy in childrenDanon disease as an underrecognized cause of hypertrophic cardiomyopathy in childrenCirculation, 112 (2005), pp. 1612–1617


20 of 24 2/10/2015 9:24 PM

828384858687888990919293

[SD-008]M.H. Gollob, M.S. Green, A.S.-L. Tang, et al.Identification of a gene responsible for Familial Wolff-Parkinson-White SyndromeIdentification of a gene responsible for Familial Wolff-Parkinson-White SyndromeIdentification of a gene responsible for Familial Wolff-Parkinson-White SyndromeIdentification of a gene responsible for Familial Wolff-Parkinson-White SyndromeNew Engl J Med, 344 (2001), pp. 1823–1831[SD-008]M.B. Codd, D.D. Sugrue, B.J. Gersh, L.J. Melton IIIEpidemiology of idiopathic dilated and hypertrophic cardiomyopathy: a population-based study inEpidemiology of idiopathic dilated and hypertrophic cardiomyopathy: a population-based study inEpidemiology of idiopathic dilated and hypertrophic cardiomyopathy: a population-based study inEpidemiology of idiopathic dilated and hypertrophic cardiomyopathy: a population-based study inOlmsted County, Minnesota, 1975-1984Olmsted County, Minnesota, 1975-1984Olmsted County, Minnesota, 1975-1984Olmsted County, Minnesota, 1975-1984Circulation, 80 (1989), pp. 564–572[SD-008]E. Grünig, J.A. Tasman, H. Kücherer, W. Franz, W. Kübler, H.A. KatusFrequency and phenotypes of familial dilated cardiomyopathyFrequency and phenotypes of familial dilated cardiomyopathyFrequency and phenotypes of familial dilated cardiomyopathyFrequency and phenotypes of familial dilated cardiomyopathyJ Am Coll Cardiol, 31 (1998), pp. 186–194[SD-008]R.E. Hershberger, J. Lindenfeld, L. Mestroni, C.E. Seidman, M.R. Taylor, J.A. Towbin, HeartFailure Society of AmericaGenetic evaluation of cardiomyopathy: a Heart Failure Society of America practice guidelineGenetic evaluation of cardiomyopathy: a Heart Failure Society of America practice guidelineGenetic evaluation of cardiomyopathy: a Heart Failure Society of America practice guidelineGenetic evaluation of cardiomyopathy: a Heart Failure Society of America practice guidelineJ Card Fail, 15 (2009), pp. 83–97[SD-008]A.J. Moss, W.J. Hall, D.S. Cannom, MADIT-CRT Trial Investigators, et al.Cardiac-resynchronization therapy for the prevention of heart-failure eventsCardiac-resynchronization therapy for the prevention of heart-failure eventsCardiac-resynchronization therapy for the prevention of heart-failure eventsCardiac-resynchronization therapy for the prevention of heart-failure eventsN Engl J Med, 361 (2009), pp. 1329–1338[SD-008]D.P. JudgeUse of genetics in the clinical evaluation of cardiomyopathyUse of genetics in the clinical evaluation of cardiomyopathyUse of genetics in the clinical evaluation of cardiomyopathyUse of genetics in the clinical evaluation of cardiomyopathyJAMA, 302 (2009), pp. 2471–2476[SD-008]E.L. Burkett, R.E. HershbergerClinical and genetic issues in familial dilated cardiomyopathyClinical and genetic issues in familial dilated cardiomyopathyClinical and genetic issues in familial dilated cardiomyopathyClinical and genetic issues in familial dilated cardiomyopathyJ Am Coll Cardiol, 45 (2005), pp. 969–981[SD-008]R.E. Hershberger, S.B. Parks, J.D. Kushner, et al.Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP fromCoding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP fromCoding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP fromCoding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from313 patients with familial or idiopathic dilated cardiomyopathy313 patients with familial or idiopathic dilated cardiomyopathy313 patients with familial or idiopathic dilated cardiomyopathy313 patients with familial or idiopathic dilated cardiomyopathyClin Transl Sci, 1 (2008), pp. 21–26[SD-008]Survivors of out-of-hospital cardiac arrest with apparently normal heart: need for definition andSurvivors of out-of-hospital cardiac arrest with apparently normal heart: need for definition andSurvivors of out-of-hospital cardiac arrest with apparently normal heart: need for definition andSurvivors of out-of-hospital cardiac arrest with apparently normal heart: need for definition andstandardized clinical evaluation: consensus statement of the Joint Steering Committees of thestandardized clinical evaluation: consensus statement of the Joint Steering Committees of thestandardized clinical evaluation: consensus statement of the Joint Steering Committees of thestandardized clinical evaluation: consensus statement of the Joint Steering Committees of theUnexplained Cardiac Arrest Registry of Europe and of the Idiopathic Ventricular FibrillationUnexplained Cardiac Arrest Registry of Europe and of the Idiopathic Ventricular FibrillationUnexplained Cardiac Arrest Registry of Europe and of the Idiopathic Ventricular FibrillationUnexplained Cardiac Arrest Registry of Europe and of the Idiopathic Ventricular FibrillationRegistry of the United StatesRegistry of the United StatesRegistry of the United StatesRegistry of the United StatesCirculation, 95 (1997), pp. 265–272[SD-008]E.F. Wever, E.O. Robles de MedinaSudden death in patients without structural heart diseaseSudden death in patients without structural heart diseaseSudden death in patients without structural heart diseaseSudden death in patients without structural heart diseaseJ Am Coll Cardiol, 43 (2004), pp. 1137–1144[SD-008]B.J. Maron, J. Shirani, L.C. Poliac, R. Mathenge, W.C. Roberts, F.O. MuellerSudden death in young competitive athletes: clinical, demographic, and pathological profilesSudden death in young competitive athletes: clinical, demographic, and pathological profilesSudden death in young competitive athletes: clinical, demographic, and pathological profilesSudden death in young competitive athletes: clinical, demographic, and pathological profilesJAMA, 276 (1996), pp. 199–204[SD-008]R.E. Eckart, S.L. Scoville, C.L. Campbell, et al.Sudden death in young adults: a 25-year review of autopsies in military recruitsSudden death in young adults: a 25-year review of autopsies in military recruitsSudden death in young adults: a 25-year review of autopsies in military recruitsSudden death in young adults: a 25-year review of autopsies in military recruitsAnn Intern Med, 141 (2004), pp. 829–834[SD-008]


21 of 24 2/10/2015 9:24 PM

949596979899100101102103104105106

T.J. Bowker, D.A. Wood, M.J. Davies, et al.Sudden, unexpected cardiac or unexplained death in England: a national surveySudden, unexpected cardiac or unexplained death in England: a national surveySudden, unexpected cardiac or unexplained death in England: a national surveySudden, unexpected cardiac or unexplained death in England: a national surveyQJM, 96 (2003), pp. 269–279[SD-008]M. Willinger, L.S. James, C. CatzDefining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened byDefining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened byDefining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened byDefining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened bythe National Institute of Child Health and Human Developmentthe National Institute of Child Health and Human Developmentthe National Institute of Child Health and Human Developmentthe National Institute of Child Health and Human DevelopmentPediatr Pathol, 11 (1991), pp. 677–684[SD-008]S.D. Cohle, B.A. SampsonThe negative autopsy: sudden cardiac death or other?The negative autopsy: sudden cardiac death or other?The negative autopsy: sudden cardiac death or other?The negative autopsy: sudden cardiac death or other?Cardiovasc Pathol, 10 (2001), pp. 219–222[SD-008]S.G. Priori, C. Napolitano, M. Memmi, et al.Clinical and molecular characterization of patients with catecholaminergic polymorphicClinical and molecular characterization of patients with catecholaminergic polymorphicClinical and molecular characterization of patients with catecholaminergic polymorphicClinical and molecular characterization of patients with catecholaminergic polymorphicventricular tachycardiaventricular tachycardiaventricular tachycardiaventricular tachycardiaCirculation, 106 (2002), pp. 69–74[SD-008]D.J. Tester, L.J. Kopplin, W. Creighton, A.P. Burke, M.J. AckermanPathogenesis of unexplained drowning: new insights from a molecular autopsyPathogenesis of unexplained drowning: new insights from a molecular autopsyPathogenesis of unexplained drowning: new insights from a molecular autopsyPathogenesis of unexplained drowning: new insights from a molecular autopsyMayo Clin Proc, 80 (2005), pp. 596–600[SD-008]A.J. Moss, J.L. Robinson, L. Gessman, et al.Comparison of clinical and genetic variables of cardiac events associated with loud noise versusComparison of clinical and genetic variables of cardiac events associated with loud noise versusComparison of clinical and genetic variables of cardiac events associated with loud noise versusComparison of clinical and genetic variables of cardiac events associated with loud noise versusswimming among subjects with the long QT syndromeswimming among subjects with the long QT syndromeswimming among subjects with the long QT syndromeswimming among subjects with the long QT syndromeAm J Cardiol, 84 (1999), pp. 876–879[SD-008]D.J. Tester, D.B. Spoon, H.H. Valdivia, J.C. Makielski, M.J. AckermanTargeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in suddenTargeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in suddenTargeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in suddenTargeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in suddenunexplained death: a molecular autopsy of 49 medical examiner/coroner's casesunexplained death: a molecular autopsy of 49 medical examiner/coroner's casesunexplained death: a molecular autopsy of 49 medical examiner/coroner's casesunexplained death: a molecular autopsy of 49 medical examiner/coroner's casesMayo Clin Proc, 79 (2004), pp. 1380–1384[SD-008]S.S. Chugh, O. Senashova, A. Watts, et al.Postmortem molecular screening in unexplained sudden deathPostmortem molecular screening in unexplained sudden deathPostmortem molecular screening in unexplained sudden deathPostmortem molecular screening in unexplained sudden deathJ Am Coll Cardiol, 43 (2004), pp. 1625–1629[SD-008]D.J. Tester, M.J. AckermanPostmortem long QT syndrome genetic testing for sudden unexplained death in the youngPostmortem long QT syndrome genetic testing for sudden unexplained death in the youngPostmortem long QT syndrome genetic testing for sudden unexplained death in the youngPostmortem long QT syndrome genetic testing for sudden unexplained death in the youngJ Am Coll Cardiol, 49 (2007), pp. 240–246[SD-008]A.D. Krahn, J.S. Healey, V. Chauhan, et al.Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest SurvivorsSystematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest SurvivorsSystematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest SurvivorsSystematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest SurvivorsWith Preserved Ejection Fraction Registry (CASPER)With Preserved Ejection Fraction Registry (CASPER)With Preserved Ejection Fraction Registry (CASPER)With Preserved Ejection Fraction Registry (CASPER)Circulation, 120 (2009), pp. 278–285[SD-008]E. Behr, D.A. Wood, M. Wright, et al.Cardiological assessment of first-degree relatives in sudden arrhythmic death syndromeCardiological assessment of first-degree relatives in sudden arrhythmic death syndromeCardiological assessment of first-degree relatives in sudden arrhythmic death syndromeCardiological assessment of first-degree relatives in sudden arrhythmic death syndromeLancet, 362 (2003), pp. 1457–1459[SD-008]H.L. Tan, N. Hofman, I.M. van Langen, A.C. van der Wal, A.A. WildeSudden unexplained death: heritability and diagnostic yield of cardiological and geneticSudden unexplained death: heritability and diagnostic yield of cardiological and geneticSudden unexplained death: heritability and diagnostic yield of cardiological and geneticSudden unexplained death: heritability and diagnostic yield of cardiological and geneticexamination in surviving relativesexamination in surviving relativesexamination in surviving relativesexamination in surviving relativesCirculation, 112 (2005), pp. 207–213[SD-008]C.E. Leach, P.S. Blair, P.J. Fleming, et al.


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Epidemiology of SIDS and explained sudden infant deaths: CESDI SUDI Research GroupEpidemiology of SIDS and explained sudden infant deaths: CESDI SUDI Research GroupEpidemiology of SIDS and explained sudden infant deaths: CESDI SUDI Research GroupEpidemiology of SIDS and explained sudden infant deaths: CESDI SUDI Research GroupPediatrics, 104 (1999), p. e43[SD-008]T. Bajanowski, A. Vege, R.W. Byard, et al.Sudden infant death syndrome (SIDS)—standardised investigations and classification:Sudden infant death syndrome (SIDS)—standardised investigations and classification:Sudden infant death syndrome (SIDS)—standardised investigations and classification:Sudden infant death syndrome (SIDS)—standardised investigations and classification:recommendationsrecommendationsrecommendationsrecommendationsForensic Sci Int, 165 (2007), pp. 129–143[SD-008]M.J. Bennett, P. RinaldoThe metabolic autopsy comes of ageThe metabolic autopsy comes of ageThe metabolic autopsy comes of ageThe metabolic autopsy comes of ageClin Chem, 47 (2001), pp. 1145–1146[SD-008]M. Arnestad, L. Crotti, T.O. Rognum, et al.Prevalence of long-QT syndrome gene variants in sudden infant death syndromePrevalence of long-QT syndrome gene variants in sudden infant death syndromePrevalence of long-QT syndrome gene variants in sudden infant death syndromePrevalence of long-QT syndrome gene variants in sudden infant death syndromeCirculation, 115 (2007), pp. 361–367[SD-008]D.J. Tester, M.J. AckermanSudden infant death syndrome: how significant are the cardiac channelopathies?Sudden infant death syndrome: how significant are the cardiac channelopathies?Sudden infant death syndrome: how significant are the cardiac channelopathies?Sudden infant death syndrome: how significant are the cardiac channelopathies?Cardiovasc Res, 67 (2005), pp. 388–396[SD-008]The disclosure information of the authors and reviewers is available from the CCS on the followingwebsites: www.ccs.ca and www.ccsguidelineprograms.ca.This statement was developed following a thorough consideration of medical literature and the bestavailable evidence and clinical experience. It represents the consensus of a Canadian panel comprised ofmultidisciplinary experts on this topic with a mandate to formulate disease-specific recommendations.These recommendations are aimed to provide a reasonable and practical approach to care for specialistsand allied health professionals obliged with the duty of bestowing optimal care to patients and families, andcan be subject to change as scientific knowledge and technology advance and as practice patterns evolve.The statement is not intended to be a substitute for physicians using their individual judgment in managingclinical care in consultation with the patient, with appropriate regard to all the individual circumstances ofthe patient, diagnostic and treatment options available and available resources. Adherence to theserecommendations will not necessarily produce successful outcomes in every case.Corresponding author: (Committee Chair) Dr Michael H. Gollob, Director, Inherited Arrhythmia Clinic,Division of Cardiology and Department of Cellular and Molecular Medicine, University of OttawaHeart Institute, Rm H3228, Ottawa, Ontario K1Y 4W7, CanadaCopyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.Copyright © 2015 Elsevier B.V. or its licensors or contributors. ScienceDirect® is a registered trademark of Elsevier B.V.Cookies are used by this site. To decline or learn more, visit our Cookies page.Switch to Mobile Site


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