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Canadian Journal of Cardiology

Recommendations for the Use of Genetic Testing in the Clinical Evaluation of Inherited Cardiac Arrhythmias Associated with Sudden Cardiac Death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society Joint Position Paper

      Abstract

      The 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 enhance diagnostic accuracy and influence treatment decisions. In cardiovascular disease, gene discovery for inherited arrhythmia syndromes has advanced most rapidly. The arrhythmia specialist is often confronted with the challenge of diagnosing and managing genetic arrhythmia syndromes. There is now a clear need for guidelines on the appropriate use of genetic testing for the most common genetic conditions associated with a risk of sudden cardiac death. This document represents the first ever published recommendations outlining the role of genetic testing in various clinical scenarios, the specific genes to be considered for testing, and the utility of test results in the management of patients and their families.

      Résumé

      L'ère de la découverte génétique et de la médecine moléculaire a eu un impact significatif dans la pratique clinique. La connaissance des découvertes génétiques spécifiques causales ou reliées à la maladie humaine peut améliorer la précision diagnostique et influencer les décisions de traitement. Dans la maladie cardiovasculaire, la découverte génétique dans les syndromes d'arythmie héréditaire a progressé plus rapidement. Le spécialiste de l'arythmie est souvent confronté au défi du diagnostic et de la gestion des syndromes d'arythmie génétique. Il y a maintenant un besoin évident de lignes directrices sur l'utilisation appropriée de tests génétiques pour les conditions génétiques les plus communes associées à un risque de mort cardiaque subite. Ce document est le tout premier à publier les recommandations décrivant le rôle des tests génétiques dans des scénarios cliniques variés, les gènes spécifiques à considérer dans les tests, et l'utilité des résultats de tests dans la gestion des patients et de leur famille.

      Introduction

      The evolution of knowledge in cardiovascular genetics over the past 15 years has refined our mechanistic understanding of inherited cardiac syndromes associated with sudden cardiac death (SCD) and has led to changes 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 known to physicians. This novel testing has been embraced with marked enthusiasm, often with little regard for the 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, genetic counsellors, and a medical ethicist. The mandate of the panel was to formulate disease-specific recommendations for the use of genetic testing in the care of patients and families with documented or suspected genetic conditions associated with SCD. In the context of contemporary knowledge, the panel deliberated on the clinical value of genetic testing with reference to the potential yield of positive and interpretable 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 reach consensus based on their collective experience. Not all regions of Canada have available the resources to provide care according to all the recommendations of this document. In such circumstances, physicians are encouraged to consult with expert colleagues elsewhere while attempting to develop the necessary resources locally.

      Decision making for genetic testing

      Decisions regarding the need to proceed with genetic testing should be based primarily on the clinical value 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 members to 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 the genetic information may require cautious interpretation, similar to other clinical tests (eg, cardiac magnetic resonance imaging) that provide helpful but often inconclusive diagnostic results.
      In light of the low prevalence of inherited arrhythmia syndromes, clinical evaluation and decisions regarding the utility of genetic testing should be made by physicians with a dedicated practice. The physician expert should have knowledge in the interpretation of genetic data. Specialized arrhythmia clinics with the involvement of trained genetic counsellors focused on inherited arrhythmias are strongly encouraged. 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 in diagnostic 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 in a dedicated inherited arrhythmia clinic.
      • Taggart N.W.
      • Haglund C.M.
      • Tester D.J.
      • Ackerman M.J.
      Diagnostic miscues in congenital long QT syndrome.
      Specialized clinics also serve to improve cost-effectiveness and yield from genetic testing.
      • Bai R.
      • Napolitano C.
      • Bloise R.
      • Monteforte N.
      • Priori S.G.
      Yield of genetic screening in inherited cardiac channelopathies: how to prioritize access to genetic testing.
      Diagnostic evaluation for a potential inherited arrhythmia syndrome should be performed by a physician 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 collaboration with 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 parallel clinical assessment and discussion with a physician expert.

      Ethical issues in genetic testing

      Genetic testing for SCD susceptibility raises issues such as stigma, privacy, and insurance and employment discrimination. Novel issues include possible child protection obligations under provincial statutes and the possibility of public protection or “duty to warn” scenarios. Whereas genetic testing for susceptibility for later-onset conditions (eg, breast cancer) has typically been deferred until patients attain capacity to make their own decisions, the availability of effective prophylaxis treatment in genetic arrhythmia 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 is refused. These emerging issues are now being explored, and the ethical, legal, and social contexts are complex. A thorough discussion of these issues is available in the on-line supplement (see Supplementary Material).

      Disease-Specific Recommendations for Clinical Genetic Testing

      The role of genetic testing in LQTS

      LQTS (incidence, 1 per 3000)
      • Ackerman M.J.
      The long QT syndrome: ion channel diseases of the heart.
      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.
      • Vincent G.M.
      The molecular genetics of the long QT syndrome: genes causing fainting and sudden death.
      The risk of cardiac arrhythmias is directly proportional to the duration of the corrected QT interval (QTc) duration.
      • Priori S.G.
      • Schwartz P.J.
      • Napolitano C.
      • et al.
      Risk stratification in the long-QT syndrome.
      • Shimizu W.
      • Horie M.
      • Ohno S.
      • et al.
      Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: multicenter study in Japan.
      • Kimbrough J.
      • Moss A.J.
      • Zareba W.
      • et al.
      Clinical implications for affected parents and siblings of probands with long-QT syndrome.
      Diagnosis. Most patients with LQTS have a QTc > 460 milliseconds, but up to 40% of gene carriers will have a normal QTc, reflecting variable disease penetrance.
      • Locati E.H.
      • Zareba W.
      • Moss A.J.
      • et al.
      Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry.
      • Moss A.J.
      • Schwartz P.J.
      • Crampton R.S.
      • et al.
      The long QT syndrome: prospective longitudinal study of 328 families.
      The Schwartz diagnostic criteria have been established to facilitate the diagnosis of LQTS.
      • Schwartz P.J.
      • Moss A.M.
      • Vincent G.M.
      • et al.
      Diagnostic criteria for the long QT syndrome.
      • Swan H.
      • Saarinen K.
      • Kontula K.
      • et al.
      Evaluation of QT interval duration and dispersion and proposed clinical criteria in diagnosis of long QT syndrome in patients with a genetically uniform type of LQT1.
      In the normal population, the QTc is longer in adult women than in men.
      • Neyroud N.
      • Maison-Blanche P.
      • Denjoy I.
      • et al.
      Diagnostic performance of QT interval variables from 24-h electrocardiography in the long QT syndrome.
      • Stramba-Badiale M.
      • Locati E.H.
      • Martinelli A.
      • et al.
      Gender and the relationship between ventricular repolarization and cardiac cycle length during 24-h Holter recordings.
      There may be considerable temporal variation in QTc as repolarization is affected by factors such as autonomic tone, electrolyte balance, and pharmacologic agents. Numerous diagnostic tests have been proposed to facilitate the diagnosis of LQTS, including exercise testing and pharmacologic provocation.
      • Krahn A.D.
      • Klein G.J.
      • Yee R.
      Hysteresis of the RT interval with exercise: a new marker for the long-QT syndrome?.
      • Lehmann M.H.
      • Suzuki F.
      • Fromm B.S.
      • et al.
      T wave “humps” as a potential electrocardiographic marker of the long QT syndrome.
      • Khositseth A.
      • Hejlik J.
      • Shen W.K.
      • et al.
      Epinephrine-induced T-wave notching in congenital long QT syndrome.
      • Shimizu W.
      • Noda T.
      • Takaki H.
      • et al.
      Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome.
      Management. Risk stratification in LQTS classifies patients as low, intermediate, and high risk, based on their gender, QT interval, and genotype.
      • Priori S.G.
      • Schwartz P.J.
      • Napolitano C.
      • et al.
      Risk stratification in the long-QT syndrome.
      Female gender, LQT2 genotype, and QTc prolongation > 500 milliseconds 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 often have 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 genetic forms of LQTS (LQT4-13) to assist in management. LQTS patients should avoid exposure to QT-prolonging drugs, a list of which is kept current at www.qtdrugs.org. Exercise “prescriptions” to minimize event risk have been provided by both European and American bodies.
      • Heidbuchel H.
      • Corrado D.
      • Biffi A.
      • et al.
      Recommendations for participation in leisure-time physical activity and competitive sports of patients with arrhythmias and potentially arrhythmogenic conditions Part II: ventricular arrhythmias, channelopathies and implantable defibrillators.
      • Maron B.J.
      • Chaitman B.R.
      • Ackerman M.J.
      • et al.
      Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases.
      In LQT3 and other rare forms of LQTS, the value of exercise restriction in avoiding cardiac events is uncertain.
      Genetics. LQTS is caused by genetic defects in genes that encode proteins responsible for regulating the cardiac action potential duration. Impaired function of these proteins results in prolongation of the action potential duration, which manifests as QT prolongation on the electrocardiogram (ECG). Genetic testing may identify responsible genotypes in approximately 35% to 70% of suspected LQTS probands,
      • Taggart N.W.
      • Haglund C.M.
      • Tester D.J.
      • Ackerman M.J.
      Diagnostic miscues in congenital long QT syndrome.
      • Napolitano C.
      • Priori S.G.
      • Schwartz P.J.
      • et al.
      Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice.
      the wide range likely reflecting differences in the clinical expertise of ordering physicians. The majority of genetically confirmed cases are the result of mutations in 3 genes. In 90% of cases, defects in the KCNQ1 and KCNH2 genes, which encode for cardiac potassium channels, are identified in LQT1 and LQT2, respectively.
      • Tester D.J.
      • Will M.L.
      • Haglund C.M.
      • et al.
      Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.
      • Splawski I.
      • Shen J.
      • Timothy K.W.
      • et al.
      Spectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.
      LQT3 is caused by mutations in the SCN5A cardiac sodium channel gene, accounting for approximately 5% to 10% of cases. More rare genetic causes for LQTS collectively account for <5% of cases.

      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 not recommended. Given the small number of variants described in these genes, results are more likely to be of 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 to assessing rare genes on a case-by-case basis.
      Table 1Summary recommendations for genetic testing in long QT syndrome
      SymptomTestingComment
      Cardiac arrest survivor
      Secondary causes of QT prolongation ruled out (structural heart disease, electrolyte abnormalities, provoking drugs).
      with QT prolongation on resting ECGs
      ++Exception is the patient with transient QT prolongation that is commonly seen with anoxic brain injury immediately after cardiac arrest
      Syncope
       QTc abnormal
      QTc > 480 milliseconds in women, > 460 milliseconds in men.
      ++Not necessary for diagnostic purposes but plays a role in risk stratification, family screening, and therapeutic decisions
       QTc borderline
      QTc 460 to 480 milliseconds in women, 450 to 460 milliseconds in men.
      +/−Not recommended unless characteristic abnormal T wave morphology is present and/or a concerning family history exists
       QTc normal
      QTc < 460 milliseconds in women, <450 milliseconds in men.
      Genetic testing is not recommended
      Asymptomatic
      Secondary causes of QT prolongation ruled out (structural heart disease, electrolyte abnormalities, provoking drugs).
       QTc abnormal
      QTc > 480 milliseconds in women, > 460 milliseconds in men.
      ++May be useful for diagnosis, risk stratification, choice of therapy, and family screening
       QTc borderline
      QTc 460 to 480 milliseconds in women, 450 to 460 milliseconds in men.
      Not recommended unless abnormal T wave morphology is present and/or a concerning family history exists
      First-degree relative
       Proband genotype positive++Useful for diagnostic and therapeutic purposes
       Proband genotype negativeIn rare circumstances, if QTc is consistently borderline or prolonged, genetic testing may be considered
      Recommendations: ++ (strongly recommended), + (recommended), − (not recommended).
      low asterisk 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).
      Cardiac Arrest Survivor: Genetic testing is recommended in the cardiac arrest survivor with LQTS for the primary purpose of screening first-degree relatives.
      Survived SCD may be the first presentation of patients with LQTS. Genetic testing should be performed in patients in whom the event is attributed to LQTS only if first-degree relatives will be assessed, as the proband will invariably receive an ICD and β-blocker therapy regardless of genetic results. Diagnosis of LQTS immediately post–cardiac arrest may be challenging because myocardial and cerebral anoxia as well as electrolyte abnormalities may produce transient QT prolongation.
      All first-degree relatives of a genetically confirmed case of LQTS should be offered genetic testing regardless of symptom status or baseline ECG to determine whether they are gene carriers.
      Syncope with QTc prolongation: Genetic testing is recommended in the patient with syncope and QTc prolongation that is attributed to LQTS.
      Patients with syncope and QTc prolongation (>480 milliseconds) with characteristic T-wave abnormalities do not need genetic testing for a diagnosis of LQTS. However, genetic testing plays a role in assessing risk of sudden death in combination with the corrected QT interval,
      • Priori S.G.
      • Schwartz P.J.
      • Napolitano C.
      • et al.
      Risk stratification in the long-QT syndrome.
      as well as predicting efficacy of beta blockade, and is therefore recommended. In patients with a borderline QTc interval (450-460 milliseconds), genetic testing is not recommended unless there are characteristic T-wave morphologies consistent with LQTS and/or a family history of premature SCD (age < 40 years). Asymptomatic individuals with borderline QTc prolongation (460-480 milliseconds) warrant evaluation by a clinical expert prior to receiving genetic testing.
      Asymptomatic patient with QTc prolongation: Genetic testing is recommended in the asymptomatic patient 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 heart disease. The role of genetic testing to confirm the diagnosis of LQTS in these patients is unclear, although genetic confirmation may be helpful for risk stratification and family screening. Given the low yield of genetic testing in asymptomatic patients with borderline QTc prolongation (450-460 milliseconds), routine genetic testing is not recommended. Genetic testing for asymptomatic individuals with QTc intervals in the 460- to 480-millisecond range should be considered only in the setting of a specialized inherited arrhythmia clinic.

      The role of genetic testing in Brugada syndrome

      Brugada syndrome is characterized by anterior precordial ST elevation on ECG and risk of ventricular fibrillation, most commonly at rest or during sleep.
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Right bundle-branch block and ST-segment elevation in leads V1 through V3: a marker for sudden death in patients without demonstrable structural heart disease.
      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 by ethnicity.
      • Viskin S.
      • Fish R.
      • Eldar M.
      • et al.
      Prevalence of the Brugada sign in idiopathic ventricular fibrillation and healthy controls.
      • Veltmann C.
      • Schimpf R.
      • Echternach C.
      • et al.
      A prospective study on spontaneous fluctuations between diagnostic and non-diagnostic ECGs in Brugada syndrome: implications for correct phenotyping and risk stratification.
      • Matsuo K.
      • Akahoshi M.
      • Nakashima E.
      • et al.
      Clinical characteristics of subjects with the Brugada-type electrocardiogram.
      • Furuhashi M.
      • Uno K.
      • Tsuchihashi K.
      • et al.
      Prevalence of asymptomatic ST segment elevation in right precordial leads with right bundle branch block (Brugada-type ST shift) among the general Japanese population.
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      Diagnosis. The diagnosis of Brugada syndrome follows an index event of syncope or cardiac arrest and ECG recognition of ST elevation of a coved-shaped pattern (type 1 ECG pattern) in leads V1 and V2. Type 2 and type 3 Brugada ECG patterns are characterized by a saddleback pattern in V1 and V2, with or without ST elevation, respectively. These additional ECG patterns are not considered diagnostic of the Brugada syndrome.
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      The various Brugada ECG patterns may be intermittent. Patients with a type 2 or 3 pattern with unheralded syncope should undergo evaluation for Brugada syndrome. Intravenous administration of a sodium channel blocker may convert a type 2 or 3 ECG pattern into a type I pattern, raising the suspicion of Brugada syndrome. The type 1 Brugada ECG pattern may be provoked by fever or medications with sodium channel blocking properties.
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      In some patients, conduction system disease coincides with the Brugada ECG pattern or may be the only ECG abnormality observed in family members.
      • Grant A.O.
      • Carboni M.P.
      • Neplioueva V.
      • et al.
      Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation.
      • Sarkozy A.
      • Boussy T.
      • Kourgiannides G.
      • et al.
      Long-term follow-up of primary prophylactic implantable cardioverter-defibrillator therapy in Brugada syndrome.
      Management. Patients with resuscitated cardiac arrest are managed with an ICD, which is also recommended for those with a history of syncope suspicious for arrhythmia.
      • Sarkozy A.
      • Boussy T.
      • Kourgiannides G.
      • et al.
      Long-term follow-up of primary prophylactic implantable cardioverter-defibrillator therapy in Brugada syndrome.
      Drug therapy with β-blockers or amiodarone has not been useful. Quinidine has shown promise in one series, although efficacy based on data from randomized controls does not exist.
      • Belhassen B.
      • Glick A.
      • Viskin S.
      Efficacy of quinidine in high-risk patients with Brugada syndrome.
      Patients should avoid drugs with sodium channel blocking effects, comprehensively listed at www.brugadadrugs.org. Aggressive temperature lowering during febrile illnesses is necessary. There is considerable controversy regarding SCD risk in asymptomatic patients with type I Brugada ECG pattern. Data from a large cohort of patients suggest that asymptomatic individuals have a low event rate (<1%/y).
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      The value of electrophysiological testing for risk stratification is not clearly established.
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      • Priori S.G.
      • Napolitano C.
      Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing?.
      • Brugada P.
      • Brugada R.
      • Brugada J.
      Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing?.
      • Gehi A.K.
      • Duong T.D.
      • Metz L.D.
      • et al.
      Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysis.
      A positive family history of Brugada syndrome–related SCD does not appear to confer a worse prognosis.
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      • Priori S.G.
      • Napolitano C.
      • Gasparini M.
      • et al.
      Clinical and genetic heterogeneity of right bundle branch block and ST-segment elevation syndrome: a prospective evaluation of 52 families.
      • Priori S.G.
      • Napolitano C.
      • Gasparini M.
      • et al.
      Natural history of Brugada syndrome: insights for risk stratification and management.
      Genetics. The most commonly identified genetic defects are in the SCN5A gene, accounting for approximately 20% of cases. However, sporadic cases without evident family history have a much lower yield.
      • Schulze-Bahr E.
      • Eckardt L.
      • Breithardt G.
      • et al.
      Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: different incidences in familial and sporadic disease.
      Five additional genes (SCNB1, SCNB3, KCNE3, CACNA1C, and CACNB2b) encoding subunits of sodium, potassium, and calcium channels have been implicated in Brugada syndrome but collectively account for a small proportion of cases (<3%).
      • Roberts J.D.
      • Gollob M.H.
      The genetic and clinical features of cardiac channelopathies.
      • Antzelevitch C.
      • Pollevick G.D.
      • Cordeiro J.M.
      • et al.
      Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.
      In a single family of Italian descent, a mutation in the glycerol-3-phosphate dehydrogenase 1–like gene (GPD1L) was identified and found to segregate with affected members.
      • London B.
      • Michalec M.
      • Mehdi H.
      • et al.
      Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias.

      Recommendations for genetic testing in Brugada syndrome (Table 2)

      Since genetic testing identifies responsible genotypes in only 20% of patients, a negative genotype should not reassure physicians that symptoms are on the basis of a benign condition when a Brugada ECG pattern exists. Presently, genetic testing should be limited to analysis of the SCN5A gene. Testing for mutations in SCNB1, SCNB3, KCNE3, CACNA1C, CACNB2b, CACNA1C, and GPD1L are not clinically indicated, because of their rarity, and should be considered only under special circumstances.
      Table 2Summary recommendations for genetic testing in Brugada syndrome
      SymptomTestingComment
      Cardiac arrest survivor
       Persistent or provocable type 1 Brugada ECG pattern++Not for diagnostic or therapeutic purposes but plays a role in family screening
       Apparent type 2 or 3 ECG pattern
      Type 2 or 3 ECG patterns may resemble early repolarization or variations of normal ST segments.
      with nonprovocable type 1 ECG pattern
      Genetic testing is not recommended as the diagnosis of Brugada syndrome requires evidence of the type 1 ECG pattern
      Syncope
       Persistent or provocable type 1 Brugada ECG pattern++Principally for the purpose of family screening
       Apparent type 2 or 3 ECG pattern with nonprovocable type 1 ECG patternNot recommended in the absence of observed type 1 ECG pattern
      Asymptomatic
       Persistent type 1 Brugada ECG patter++Not useful for risk stratification; principally for the purpose of family screening
       Apparent type 2 or 3 ECG pattern with nonprovocable type 1 ECG patternGenetic testing is not recommended
      First-degree relative
       Proband genotype positive++Clinical implications of an isolated positive genotype in the absence of a phenotype are unknown
       Proband genotype negativeNot recommended
      Recommendations: ++ (strongly recommended), − (not recommended).
      low asterisk Type 2 or 3 ECG patterns may resemble early repolarization or variations of normal ST segments.
      Cardiac arrest survivor: Genetic testing in the cardiac arrest survivor with a persistent or provocable type 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 in this scenario is to develop a screening tool for family members. While the clinical implications of a positive genotype in the absence of a phenotypic correlate in a family member is unknown, knowledge of gene-carrier status provides the opportunity to counsel family members on issues related to fever and medication use. In cardiac arrest patients with an apparent type 2 or 3 ECG pattern but no provocable type 1 pattern, genetic testing is not recommended as the diagnosis of Brugada syndrome requires evidence of the characteristic type 1 ECG pattern.
      Syncope and Brugada ECG pattern: Genetic testing in the patient with syncope and a permanent or provocable type 1 Brugada ECG pattern is recommended for the primary purpose of screening of family members.
      The diagnosis of Brugada syndrome should be based on clinical grounds, with genetic testing used only as a family screening tool.
      Asymptomatic persistent or provocable type 1 Brugada ECG pattern: Genetic testing in the asymptomatic patient with persistent or provocable type 1 Brugada ECG pattern is recommended for the primary purpose of screening family members.
      In asymptomatic patients, genetic testing should not be performed with the intent of risk stratification. At present, there is no genotype that reliably determines prognosis in Brugada syndrome.
      Type 2 or type 3 Brugada ECG pattern in symptomatic or asymptomatic individuals without evidence for 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 Brugada ECG pattern but without provocable type 1 pattern.

      The role of genetic testing in arrhythmogenic right ventricular cardiomyopathy

      Arrhythmogenic right ventricular cardiomyopathy (ARVC), with an estimated prevalence of ARVC 1 per 5000, is characterized by fibrofatty replacement of myocardium. It affects the right ventricle predominantly but may have left ventricular involvement.
      • Basso C.
      • Corrado D.
      • Marcus F.I.
      • Nava A.
      • Thiene G.
      Arrhythmogenic right ventricular cardiomyopathy.
      ARVC can result in ventricular arrhythmias, SCD, and right or biventricular dysfunction. Often sporadic, the condition is familial in up to 50% of index cases.
      • Basso C.
      • Corrado D.
      • Marcus F.I.
      • Nava A.
      • Thiene G.
      Arrhythmogenic right ventricular cardiomyopathy.
      • Muthappan P.
      • Calkins H.
      Diagnosis. Task Force criteria for the diagnosis were originally proposed in 1994 and updated in 2010.
      • McKenna W.J.
      • Thiene G.
      • Nava A.
      • et al.
      Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Federation of Cardiology.
      • Marcus F.I.
      • McKenna W.J.
      • Sherrill D.
      • et al.
      Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria.
      Criteria are grouped into those involving right ventricular function, tissue characteristics of the myocardium, ECG repolarization abnormalities, ECG depolarization abnormalities, arrhythmias, family history, 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 the clinical and imaging features of ARVC.
      • Vasaiwala S.C.
      • Finn C.
      • Delpriore J.
      • et al.
      Prospective study of cardiac sarcoid mimicking arrhythmogenic right ventricular dysplasia.
      • Roberts J.D.
      • Veinot J.P.
      • Rutberg J.
      • Gollob M.H.
      Inherited cardiomyopathies mimicking arrhythmogenic right ventricular cardiomyopathy.
      As ARVC may be a progressive disease, patients suspected of having ARVC who have initial equivocal diagnostic test results should undergo reevaluation at least annually.
      Management. Patients with proven or suspected ARVC are discouraged from participation in competitive sports or endurance training, and activity should be modified according to American Heart Association recommendations.
      • Maron B.J.
      • Chaitman B.R.
      • Ackerman M.J.
      • et al.
      Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases.
      Patients with documented ventricular arrhythmias should receive an ICD as first-line therapy. It is not known whether an ICD or pharmacologic treatment will affect outcome in asymptomatic or gene-positive patients without overt disease. However, close medical surveillance for disease development is necessary.
      Genetics. A pathogenetic theme for ARVC is the presence of mutations in genes encoding desmosomal proteins.
      • Sen-Chowdhry S.
      • Syrris P.
      • McKenna W.J.
      Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy.
      Desmosomes are a primary component of cell adhesion junctions, ensuring the structural and functional integrity of cardiomyocytes. Mutations have been identified in genes encoding for desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), plakoglobin (JUP), desmocollin (DSC2), and desmoglein (DSG2).
      • Sen-Chowdhry S.
      • Syrris P.
      • McKenna W.J.
      Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy.
      • McKoy G.
      • Protonotarios N.
      • Crosby A.
      • et al.
      Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmo-plantar keratoderma and wooly hair (Naxos disease).
      • Rampazzo A.
      • Nava A.
      • Malacirda S.
      • et al.
      Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy.
      • Gerull B.
      • Heuser A.
      • Wichter T.
      • et al.
      Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy.
      • Pilichou K.
      • Nava A.
      • Basso C.
      • et al.
      Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy.
      • Heuser A.
      • Plovie E.R.
      • Elinor P.T.
      • et al.
      Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy.
      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.
      • Merner N.D.
      • Hodgkinson K.A.
      • Haywood A.F.M.
      • et al.
      Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene.
      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.
      • Syrris P.
      • Ward D.
      • Asimaki A.
      • et al.
      Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy.
      • Dalal D.
      • Molin L.H.
      • Piccini J.
      • et al.
      Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2.
      The yield of PKP2 testing may approach 70% when familial ARVC is confirmed, in contrast to a lower yield in sporadic cases. Variable disease penetrance and expression in PKP2 mutation carriers is common. Desmoplakin (DSP) mutations occur in 6% to 16% of ARVC cases.
      • Rampazzo A.
      • Nava A.
      • Malacirda S.
      • et al.
      Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy.
      • Yang Z.
      • Bowles N.E.
      • Scherer S.E.
      • et al.
      Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy.
      A rare autosomal recessive syndrome related to desmoplakin mutations is Carvajal syndrome, characterized by dilated cardiomyopathy, wooly hair, and plantar keratoderma.
      • Norgett E.E.
      • Hatsell S.J.
      • Carvajal-Huerta L.
      • et al.
      Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, wooly hair and keratoderma.
      In patients with negative genetic findings of PKP2 and DSP, 5% to 10% of cases have mutations in the DSG2 and DSC2 genes.
      • Pilichou K.
      • Nava A.
      • Basso C.
      • et al.
      Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy.
      • Syrris P.
      • Ward D.
      • Evans A.
      • et al.
      Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2.
      A specific plakoglobin (JUP) mutation causes a rare form of autosomal recessive ARVC known as Naxos disease.
      • McKoy G.
      • Protonotarios N.
      • Crosby A.
      • et al.
      Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmo-plantar keratoderma and wooly hair (Naxos disease).

      Recommendations for genetic testing in ARVC (Table 3)

      In view of the differing yields for the known causative genes, stepwise or tiered genetic testing should be performed. Genetic testing of the PKP2 and DSP genes should be performed first, which may yield a positive test in up to 50% of Task Force positive cases. If negative, additional testing of the DSG2 and DSC2 may identify a mutation in an additional 5% to 10% of cases. In patients with ancestry linked to Newfoundland, genetic testing of TMEM43 should be considered. Lastly, it should be emphasized that given the relatively recent history of gene discovery in ARVC and the natural genetic variability that occurs in culprit genes in apparently healthy controls, interpretation of genetic testing results for this condition is complex, necessitating the involvement of a specialized clinic.
      Table 3Summary recommendations for genetic testing in arrhythmogenic right ventricular cardiomyopathy
      Clinical scenarioTestingComment
      Clinical ARVC in accordance with Task Force criteria++Genetic testing plays a role in the screening of identified family members
      Clinical ARVC in accordance with Task Force criteria in the absence of identified at-risk family membersARVC is often sporadic, and genetic results do not provide risk stratification assistance
      Clinically suspected ARVC not meeting Task Force criteria++Current diagnostic criteria are specific but insensitive. Genetic testing may be useful in establishing a diagnosis of ARVC and subsequent screening of at-risk family members
      First-degree relative of genotype-positive proband++Useful for decisions of medical surveillance and lifestyle modification
      First-degree relative of genotype-negative probandGenetic testing not indicated
      Recommendations: ++ (strongly recommended), − (not recommended).
      ARVC, arrhythmogenic right ventricular cardiomyopathy.
      Clinical ARVC in accordance with Task Force criteria: Genetic testing is recommended for the primary purpose of screening family members.
      Timely genetic diagnosis may lead to prevention of morbidity or mortality in family members by increasing medical 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 be performed in the proband to limit the uncertainty of the genetic variations identified in asymptomatic family members without overt clinical disease. Genetic testing should not be performed in a diagnosed proband solely for the intent of risk stratification as data for this purpose do not exist.
      Clinically suspected ARVC not meeting Task Force criteria: Genetic testing is recommended for the purpose of assisting in the diagnosis of ARVC.
      Satisfying Task Force criteria for ARVC may be challenging because of variations in clinical expression of the disease. Addition of genetic testing in the 2010 Task Force criteria indicates the utility of including genetic testing results in arriving at a diagnosis. Although the genetic test result may not provide the definitive answer for diagnosis, the information gained can be weighed in the context of other clinical tests in diagnostic decision making and potentially confirm a diagnosis if a known disease-causing mutation is identified.

      The role of genetic testing in catecholaminergic polymorphic ventricular tachycardia

      Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by emotion- or exercise-induced syncope or cardiac arrest in structurally normal hearts.
      • Priori S.
      • Napolitano C.
      • Memmi M.
      • et al.
      Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.
      Diagnosis. The rhythm disturbance of CPVT is polymorphic ventricular tachycardia (VT) that is induced during high adrenaline states. Clinical presentation is most common in prepubertal or adolescent years.
      • Priori S.
      • Napolitano C.
      • Memmi M.
      • et al.
      Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.
      • Leenhardt A.
      • Lucet V.
      • Denjoy I.
      • Grau F.
      • Ngoc D.D.
      • Coumel P.
      Catecholaminergic polymorphic ventricular tachycardia in children: a 7-year follow-up of 21 patients.
      In contrast to other channelopathies, baseline ECGs are usually normal. Bidirectional VT with exercise is a diagnostic hallmark of CPVT, although Andersen-Tawil syndrome (LQTS type 7) caused by KCNJ2 mutations may also demonstrate bidirectional VT, usually with a resting ECG showing prominent U waves. CPVT should be considered in the differential diagnosis of all adrenergic-mediated syncopal or cardiac arrest events, particularly in young individuals (aged < 20 years). Diagnosis is supported by reproducing the typical bidirectional VT or polymorphic VT induced by exercise or infusion of an adrenergic agonist, while confirming no evidence of structural heart disease.
      • Krahn A.D.
      • Gollob M.
      • Yee R.
      • et al.
      Diagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusion.
      However, many arrhythmogenic cardiac conditions may manifest exercise-induced polymorphic VT (eg. ischemia, ARVC), and therefore careful diagnostic workup is required before diagnosing CPVT.
      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 of exercise-induced ventricular arrhythmias. Typically, high-dose β-blockers are required (eg, atenolol ≥ 2 mg/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 recurrent syncope despite high-dose β-blockers, flecainide, cardiac sympathectomy, or ICD placement should be considered.
      • Watanabe H.
      • Chopra N.
      • Laver D.
      • et al.
      Flecainide prevents catecholamineregic polymorphic ventricular tachycardia in mice and humans.
      • Makanjee B.
      • Gollob M.H.
      • Klein G.J.
      • Krahn A.D.
      Ten-year follow-up of cardiac sympathectomy in a young woman with catecholaminergic polymorphic ventricular tachycardia and an implantable cardioverter defibrillator.
      Genetics. Two genetic forms of CPVT have been described: an autosomal dominant form, due to mutations in the cardiac ryanodine receptor gene (RYR2), and a rare autosomal recessive form with mutations in calsequestrin (CASQ2).
      • Priori S.G.
      • Napolitano C.
      • Tiso N.
      • et al.
      Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia.
      • Lahat H.
      • Pras E.
      • Olender T.
      • et al.
      A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.
      These genes encode proteins critical in intracellular calcium handling. Their dysfunction leads to inappropriate levels of cytosolic calcium during cardiac diastole, causing afterdepolarizations and ventricular arrhythmias. Adrenergic stimulation enhances cellular calcium load, increasing the susceptibility to arrhythmias.
      Genetic defects in the RYR2 gene are detected in up to 50% of cases.
      • Krahn A.D.
      • Gollob M.
      • Yee R.
      • et al.
      Diagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusion.
      Traditionally, genetic screening of this gene has been limited to so-called hotspot exons, regions of the gene presumed to most likely harbour disease-causing mutations. Because of the very large size of the RYR2 gene, such limited screening has been considered cost-effective. However, disease-causing mutations have been identified outside hotspot regions.
      • Tester D.
      • Arya P.
      • Will M.
      • et al.
      Genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing.

      Recommendations 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 targeted exons is negative and clinical suspicion remains high, screening of the remaining RYR2 exons is recommended. In RYR2-negative cases, or when autosomal recessive inheritance is noted, screening of the CASQ2 gene is warranted. Patients demonstrating prominent U waves and negative RYR2 testing should be considered for testing of the KCNJ2 gene. Overall yield of genetic testing for clinical CPVT is in the range of 50% to 60%.
      Table 4Summary recommendations for genetic testing in catecholaminergic polymorphic ventricular tachycardia
      Clinical scenarioTestingComment
      Clinically suspected CPVT++Genetic testing useful for the primary purpose of identifying at-risk family members
      First-degree relative
       Proband genotype positive++Useful for decisions of medical surveillance and lifestyle modification
      Recommendations: ++ (strongly recommended).
      CPVT, catecholaminergic polymorphic ventricular tachycardia.
      Clinically suspected CPVT: Genetic testing is recommended for the primary purpose of screening family 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 cardiomyopathy

      Hypertrophic cardiomyopathy (HCM) is characterized by cardiac hypertrophy in the absence of another cardiac or systemic disease. HCM is relatively common, estimated to have a prevalence of 1 per 500, and is the most common cause of SCD in the young.
      • Maron B.J.
      • McKenna W.J.
      • Danielson G.K.
      • et al.
      Task Force on Clinical Expert Consensus Documents. American College of Cardiology; Committee for Practice Guidelines. European Society of Cardiology
      American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines.
      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 the echocardiogram.
      • Wigle E.D.
      Diagnosis of hypertrophic cardiomyopathy.
      • Ryan M.P.
      • Cleland J.G.F.
      • French J.A.
      • et al.
      The standard electrocardiogram as a screening test for hypertrophic cardiomyopathy.
      In children, ECG and echocardiographic abnormalities may not develop until late adolescence 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.
      • Maron B.J.
      • Pelliccia A.
      • Spirito P.
      Cardiac disease in young trained athletes: insights into methods for distinguishing athlete's heart from structural heart disease, with particular emphasis on hypertrophic cardiomyopathy.
      • Gollob M.H.
      • Green M.S.
      • Tang A.
      • Roberts R.
      The PRKAG2 cardiac syndrome: familial ventricular preexcitation, conduction system disease, and cardiac hypertrophy.
      • Guertl B.
      • Noehammer C.
      • Hoefler G.
      Metabolic cardiomyopathies.
      Management. Risk stratification of patients is recommended to determine the risk for SCD.
      • Maron B.J.
      • McKenna W.J.
      • Danielson G.K.
      • et al.
      Task Force on Clinical Expert Consensus Documents. American College of Cardiology; Committee for Practice Guidelines. European Society of Cardiology
      American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines.
      • McKenna W.J.
      • Behr E.R.
      Hypertrophic cardiomyopathy: management, risk stratification, and prevention of sudden death.
      Major risk factors are a family history of premature SCD, unexplained syncope, nonsustained VT, an abnormal blood pressure response to exercise, and massive left ventricular hypertrophy (maximum left ventricular wall thickness ≥30 mm).
      • Maron B.J.
      • McKenna W.J.
      • Danielson G.K.
      • et al.
      Task Force on Clinical Expert Consensus Documents. American College of Cardiology; Committee for Practice Guidelines. European Society of Cardiology
      American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines.
      • McKenna W.J.
      • Behr E.R.
      Hypertrophic cardiomyopathy: management, risk stratification, and prevention of sudden death.
      In patients considered high risk for SCD, an ICD is indicated. Exercise restriction is recommended to minimize arrhythmia provocation in high-risk individuals.
      Genetics. HCM arises from genetic defects in close to 20 different genes, although the most common forms of HCM result from mutations in genes encoding proteins of the cardiac sarcomeric apparatus (Table 5).
      • Bos J.M.
      • Towbin J.A.
      • Ackerman M.J.
      Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy.
      Genetic testing may detect a gene defect in 40% to 60% of patients.
      • Bos J.M.
      • Towbin J.A.
      • Ackerman M.J.
      Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy.
      • Richard P.
      • Charron P.
      • Carrier L.
      • et al.
      EUROGENE Heart Failure Project
      Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy.
      Mutations of the MYH7 and MYBPC3 genes account for the majority of cases.
      • Bos J.M.
      • Towbin J.A.
      • Ackerman M.J.
      Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy.
      Approximately 3% of patients with HCM may have more than once pathogenic mutation, which may be associated with a more severe phenotype.
      • Bos J.M.
      • Towbin J.A.
      • Ackerman M.J.
      Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy.
      Table 5Genes associated with hypertrophic cardiomyopathy
      GeneProteinFrequency
      MYH7β-Myosin heavy chain15%-30%
      MYBPCMyosin-binding protein C15%-30%
      TNNT2Troponin T5%-10%
      TNNI3Troponin I2%-5%
      TPM1α-Tropomyosin2%-5%
      TTNTitin<1%
      MYH6α-Myosin heavy chain<1%
      MYL2Ventricular regulatory myosin light chain<1%
      MYL3Ventricular essential myosin light chain<1%
      ACTCα-Cardiac actin<1%
      TNNC1Troponin C<1%
      LBD3Limb binding domain 3<1%
      CSRP3Muscle LIM protein<1%
      TCAPTelethonin<1%
      VCLVinculin<1%
      ACTN2α-Actinin 2<1%
      MYOZ2Myozenin 2<1%
      JPH2Junctophilin-2<1%
      PLNPhospholamban<1%
      Infiltrative or storage diseases may show similar findings on cardiac imaging and incorrectly lead to a diagnosis of HCM. Fabry's disease (caused by genetic defects in the GLA gene) was detected in 6% of male patients diagnosed with presumed HCM at age ≥40 years.
      • Sachdev B.
      • Takenaka T.
      • Teraguchi H.
      • et al.
      Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy.
      The identification of patients with this condition is important since enzyme replacement therapy is effective.
      • Schiffman R.
      • Kopp J.B.
      • Austin III, J.B.
      • et al.
      Enzyme replacement therapy in Fabry disease: a randomized controlled trial.
      • Pastores G.M.
      • Thadhani R.
      Enzyme-replacement therapy for Anderson-Fabry disease.
      Other inherited storage diseases showing features of HCM commonly have the ECG finding of ventricular preexcitation. These conditions include the glycogen storage conditions of Danon's disease (LAMP2 gene), and the PRKAG2 cardiac syndrome (PRKAG2 gene).
      • Gollob M.H.
      • Green M.S.
      • Tang A.
      • Roberts R.
      The PRKAG2 cardiac syndrome: familial ventricular preexcitation, conduction system disease, and cardiac hypertrophy.
      • Yang Z.
      • McMahon C.J.
      • Smith L.R.
      • et al.
      Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children.
      • Gollob M.H.
      • Green M.S.
      • Tang A.S.-L.
      • et al.
      Identification of a gene responsible for Familial Wolff-Parkinson-White Syndrome.

      Recommendations for genetic testing in HCM (Table 6)

      Since HCM is diagnosed by imaging studies, the principal role of genetic testing is not to confirm a diagnosis but rather to provide a clinical tool for screening family members at risk of developing the disease. In light of the large number of genes associated with HCM and their respective yields of mutation detection, a tiered genetic testing approach is recommended. Initial testing for the 2 most common genetic causes, MYH7 and MYBPC3, yields a positive result in 30% to 50% of cases. A second tiered approach with testing of TNNT2, TNNI3, and TMP1 may be considered if results are negative and succeeds in detecting 10% to 15% of cases. Genetic testing of rare genes (<1% detection rate) associated with HCM is not likely to be clinically useful or cost-effective. Given the small number of variants described in these genes, results are more likely to be of unknown significance if a clear familial pattern of disease is not recognized. Lastly, in apparent HCM in which ventricular preexcitation is evident, genetic testing for cardiac storage diseases should be considered as first tier, including the genes PRKAG2, LAMP2, and GLA.
      Table 6Summary recommendations for genetic testing in hypertrophic cardiomyopathy
      Clinical scenarioTestingComment
      Clinically diagnosed HCM++Genetic testing is recommended for the primary purpose of screening family members
       Tier 1 gene testingMYH7, MYBPC
       Tier II gene testingTNNT2, TNNI3, TPM1
      Clinically diagnosed HCM with ECG features of ventricular preexcitation++Genetic testing is recommended for the primary purpose of screening family members
       Tier I gene testingPRKAG2, LAMP2, GLA
       Tier II gene testingMYH7, MYBPC, TNNT2, TNNI3, TPM1
      Clinically diagnosed HCMGenetic testing is NOT recommended for the purpose of diagnostic confirmation
      Clinically diagnosed HCMGenetic testing is NOT recommended for the purpose of risk stratification and treatment decisions
      Clinically suspected HCMGenetic testing is NOT recommended for the purpose of differentiating HCM from other causes of cardiac hypertrophy, including athletes heart, hypertensive heart disease, and cardiac amyloidosis
      Recommendations: ++ (strongly recommended), − (not recommended).
      HCM, hypertrophic cardiomyopathy.
      Clinically diagnosed HCM: Genetic testing is recommended for the primary purpose of screening family members.
      Although imaging studies represent a reasonable tool to screen for disease, incomplete disease penetrance of familial HCM warrants genetic testing. The identification of a disease-causing mutation may encourage appropriate medical surveillance of family members or, conversely, may avoid unnecessary long-term clinical testing in family members, particularly children, without the genotype.
      Clinically diagnosed HCM: Genetic testing is not recommended for the purpose of diagnostic confirmation.
      In the absence of known at-risk family members who may benefit from genetic screening, there exists no clinical utility in identifying the culprit genotype. In addition, genetic testing may not exclude the possibility that the patient has HCM, since genetic testing is not 100% sensitive.
      Clinically diagnosed HCM: Genetic testing is not recommended for the purpose of risk stratification and treatment decisions.
      The use of genetic information to predict clinical progression of disease or risk of fatal arrhythmia is not currently supported by the medical literature. Prediction of event risk should be guided by clinical testing.
      Clinically suspected HCM: Genetic testing is not recommended for the purpose of differentiating HCM from other causes of cardiac hypertrophy, including athlete's heart, hypertensive heart disease, and cardiac amyloidosis.
      HCM can usually be differentiated from other causes of increased wall thickness on the basis of standard clinical history and objective tests.

      The role of genetic testing in dilated cardiomyopathy

      Dilated cardiomyopathy (DCM) has a prevalence of 1 per 2500 and is characterized by dilation and dysfunction of the left or both ventricles.
      • Codd M.B.
      • Sugrue D.D.
      • Gersh B.J.
      • Melton III, L.J.
      Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy: a population-based study in Olmsted County, Minnesota, 1975-1984.
      Often, the etiology remains unknown. The potential causes are vast 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 inflammatory diseases, such as hemochromatosis, amyloidosis, or sarcoidosis. Familial DCM is estimated to occur in 20% to 35% of cases and most commonly involves genes encoding components of the myocyte sarcomere or cytoskeleton.
      • Grünig E.
      • Tasman J.A.
      • Kücherer H.
      • Franz W.
      • Kübler W.
      • Katus H.A.
      Frequency and phenotypes of familial dilated cardiomyopathy.
      • Hershberger R.E.
      • Lindenfeld J.
      • Mestroni L.
      • Seidman C.E.
      • Taylor M.R.
      • Towbin J.A.
      Heart Failure Society of America
      Genetic evaluation of cardiomyopathy: a Heart Failure Society of America practice guideline.
      Diagnosis. The diagnosis may be readily made by cardiac imaging studies and the exclusion of significant coronary disease. Cardiac biopsy may be considered as a diagnostic tool.
      • Hershberger R.E.
      • Lindenfeld J.
      • Mestroni L.
      • Seidman C.E.
      • Taylor M.R.
      • Towbin J.A.
      Heart Failure Society of America
      Genetic evaluation of cardiomyopathy: a Heart Failure Society of America practice guideline.
      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.
      • Hershberger R.E.
      • Lindenfeld J.
      • Mestroni L.
      • Seidman C.E.
      • Taylor M.R.
      • Towbin J.A.
      Heart Failure Society of America
      Genetic evaluation of cardiomyopathy: a Heart Failure Society of America practice guideline.
      Electrophysiological 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 the prophylaxis of SCD should be considered. In patients with a significantly widened QRS duration (>150 milliseconds) and impaired New York Heart Association functional class, biventricular pacing may improve heart failure symptoms.
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • et al.
      MADIT-CRT Trial Investigators
      Cardiac-resynchronization therapy for the prevention of heart-failure events.
      Genetics. Over 30 genes have been reported to cause DCM.
      • Judge D.P.
      Use of genetics in the clinical evaluation of cardiomyopathy.
      The yield of genetic testing is significantly enhanced when a family history is evident.
      • Hershberger R.E.
      • Lindenfeld J.
      • Mestroni L.
      • Seidman C.E.
      • Taylor M.R.
      • Towbin J.A.
      Heart Failure Society of America
      Genetic evaluation of cardiomyopathy: a Heart Failure Society of America practice guideline.
      • Burkett E.L.
      • Hershberger R.E.
      Clinical and genetic issues in familial dilated cardiomyopathy.
      In familial disease, the most common causes include genetic defects in the MYBPC3, MYH7, TNNT2, LMNA, and SCN5A genes, which collectively account for 15% to 30% of familial DCM.
      • Hershberger R.E.
      • Lindenfeld J.
      • Mestroni L.
      • Seidman C.E.
      • Taylor M.R.
      • Towbin J.A.
      Heart Failure Society of America
      Genetic evaluation of cardiomyopathy: a Heart Failure Society of America practice guideline.
      • Burkett E.L.
      • Hershberger R.E.
      Clinical and genetic issues in familial dilated cardiomyopathy.
      • Hershberger R.E.
      • Parks S.B.
      • Kushner J.D.
      • et al.
      Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy.
      Familial DCM with atrial arrhythmias and high-grade conduction disease is most commonly due to mutations of the LMNA gene.
      • Hershberger R.E.
      • Lindenfeld J.
      • Mestroni L.
      • Seidman C.E.
      • Taylor M.R.
      • Towbin J.A.
      Heart Failure Society of America
      Genetic evaluation of cardiomyopathy: a Heart Failure Society of America practice guideline.
      Familial DCM demonstrating an X-linked pattern of inheritance and skeletal muscle weakness raises the suspicion of dystrophin (DMD) gene mutations.
      • Hershberger R.E.
      • Lindenfeld J.
      • Mestroni L.
      • Seidman C.E.
      • Taylor M.R.
      • Towbin J.A.
      Heart Failure Society of America
      Genetic evaluation of cardiomyopathy: a Heart Failure Society of America practice guideline.

      Recommendations for genetic testing in DCM (Table 7)

      Genetic determinants of sporadic DCM have not been routinely described. Thus, in the absence of a family history determined either by history or by clinical evaluation of relatives, genetic testing is likely of limited value.
      Table 7Summary recommendations for genetic testing in dilated cardiomyopathy
      Clinical scenarioTestingComment
      Clinically diagnosed DCMGenetic testing is NOT recommended in the absence of established or probable familial disease as determined by family history or clinical testing of first-degree relatives
      Clinically diagnosed DCM with evidence of probable familial DCM++Genetic testing is recommended for the primary purpose of screening family members
       Genetic testingMYH7, MYPBC, TNNT2, LMNA, SCN5A
      Clinically diagnosed familial DCM with evidence of atrial arrhythmias and high-grade conduction disease++Genetic testing is recommended for the primary purpose of screening family members
       Genetic testingLMNA, SCN5A
      Clinically diagnosed familial DCM with evidence of X-linked inheritance++Genetic testing is recommended for the primary purpose of screening family members
       Genetic testingDMD
      Recommendations: ++ (strongly recommended), − (not recommended).
      DCM, dilated cardiomyopathy.
      Probands should be questioned about family members with cardiac devices, unexpected SCD (at age < 50 years), skeletal muscle disorders, or heart failure. The presence of family members with any of these characteristics increases the probability of familial disease. Since familial DCM has an autosomal dominant 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 genes with the most likely chance for a positive finding or interpretable test result in familial DCM is most reasonable and includes the following genes: MYH7, TNNT2, MYBPC, TNNT, LMNA, and SCN5A. Should evaluation 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 is present, testing of LMNA or SCN5A should be prioritized. In X-linked inheritance, the dystrophin gene (DMD) should be targeted.
      Clinically diagnosed DCM: Genetic testing is not recommended in the absence of established or probable 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 interpretable genetic findings in isolated cases are scarce, and unique patient results will most often fall under the category of “variant of unknown significance.”
      Clinically diagnosed DCM with evidence of probable familial disease: Genetic testing is recommended for the primary purpose of screening family members.
      The clinical penetrance of disease and age of onset may be variable in familial DCM, warranting genetic testing as a potential tool for screening family members.

      The role of genetic testing in unexplained SCD, sudden cardiac arrest, and the sudden infant death syndrome

      SCD is defined as unexpected cardiac death within 1 hour of the onset of symptoms in individuals without a prior known condition that would appear to be fatal.
      Survivors of out-of-hospital cardiac arrest with apparently normal heart: need for definition and standardized clinical evaluation: consensus statement of the Joint Steering Committees of the Unexplained Cardiac Arrest Registry of Europe and of the Idiopathic Ventricular Fibrillation Registry of the United States.
      • Wever E.F.
      • Robles de Medina E.O.
      Sudden death in patients without structural heart disease.
      Despite a complete investigation, autopsy may fail to establish a diagnosis, and the event remains unexplained. The prevalence of these “autopsy negative” cases of SCD has been reported in between 3% of a general young population and 35% in young military recruits.
      • Maron B.J.
      • Shirani J.
      • Poliac L.C.
      • Mathenge R.
      • Roberts W.C.
      • Mueller F.O.
      Sudden death in young competitive athletes: clinical, demographic, and pathological profiles.
      • Eckart R.E.
      • Scoville S.L.
      • Campbell C.L.
      • et al.
      Sudden death in young adults: a 25-year review of autopsies in military recruits.
      • Bowker T.J.
      • Wood D.A.
      • Davies M.J.
      • et al.
      Sudden, unexpected cardiac or unexplained death in England: a national survey.
      When SCD occurs in infancy without predisposing or precipitating clinical conditions and with a negative autopsy, the diagnosis of sudden infant death syndrome (SIDS) is applied.
      • Willinger M.
      • James L.S.
      • Catz C.
      Defining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened by the National Institute of Child Health and Human Development.
      Similarly, in the survivor of a sudden cardiac arrest (SCA), evaluation may determine that there is a structurally normal heart. This is the clinical equivalent of a negative autopsy and is found in about 5% of cases.
      This section describes the background for considering genetic testing in (1) the autopsy negative unexpected 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 autopsy is negative have been published.
      • Cohle S.D.
      • Sampson B.A.
      The negative autopsy: sudden cardiac death or other?.
      A thorough assessment to rule out a structural cause of SCD should include a rigourous cardiac autopsy, including comprehensive evaluation of the right ventricle to assess for ARVC. 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 guide targeted genetic testing.
      • Priori S.G.
      • Napolitano C.
      • Memmi M.
      • et al.
      Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.
      • Tester D.J.
      • Kopplin L.J.
      • Creighton W.
      • Burke A.P.
      • Ackerman M.J.
      Pathogenesis of unexplained drowning: new insights from a molecular autopsy.
      • Moss A.J.
      • Robinson J.L.
      • Gessman L.
      • et al.
      Comparison of clinical and genetic variables of cardiac events associated with loud noise versus swimming among subjects with the long QT syndrome.
      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% of cases, and mutations of LQTS-associated genes have been identified in 16% to 20% of cases.
      • Tester D.J.
      • Spoon D.B.
      • Valdivia H.H.
      • Makielski J.C.
      • Ackerman M.J.
      Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: a molecular autopsy of 49 medical examiner/coroner's cases.
      • Chugh S.S.
      • Senashova O.
      • Watts A.
      • et al.
      Postmortem molecular screening in unexplained sudden death.
      • Tester D.J.
      • Ackerman M.J.
      Postmortem long QT syndrome genetic testing for sudden unexplained death in the young.
      Overall, 35% of unexpected SCD victims with a negative autopsy were diagnosed with either LQTS or CPVT by postmortem genetic testing in a specialized research setting.
      • Tester D.J.
      • Spoon D.B.
      • Valdivia H.H.
      • Makielski J.C.
      • Ackerman M.J.
      Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: a molecular autopsy of 49 medical examiner/coroner's cases.
      • Tester D.J.
      • Ackerman M.J.
      Postmortem long QT syndrome genetic testing for sudden unexplained death in the young.
      From current evidence, collection and storage of tissue and/or DNA for possible future molecular analysis is warranted.
      Table 8The role of genetic testing in unexplained sudden cardiac death, resuscitated sudden cardiac death, and sudden infant death syndrome
      Clinical scenarioTestingComment
      Unexplained sudden death (negative autopsy)++Targeted gene screening of retained tissue of the deceased based on evidence of specific genetic syndrome from medical history or evaluation of first- degree relatives
      In the absence of guiding clinical information, empirical gene screening for multiple possible conditions is not recommended
      Resuscitated sudden cardiac 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 clinical information is not recommended
      Sudden infant death syndrome++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 the discretion of a clinical expert
      Comprehensive empirical gene screening for all possible genetic arrhythmia syndromes is not recommended
      First-degree relative
       Proband genotype positive++Useful for diagnostic and therapeutic purposes
      Recommendations: ++ (strongly recommended), + (recommended), − (not recommended).

      Clinical evaluation of the individual with a first-degree relative with unexplained SCD

      Prior to clinical assessment, background details of the deceased and family history may assist in focusing the cardiac investigation. Relevant medical history includes events of near drowning or drowning, a family member with seizures and a diagnosis of epilepsy, or a history of SIDS in the family. Initial cardiac testing includes a resting and signal-averaged ECG; an exercise test; Holter monitoring; an echocardiogram; and provocative drug testing for LQT1, Brugada syndrome, or CPVT. The value of provocative drug testing has been demonstrated, unmasking either CPVT or Brugada syndrome in 16% of relatives of SCA survivors, when patients with obvious LQTS were excluded.
      • Krahn A.D.
      • Gollob M.
      • Yee R.
      • et al.
      Diagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusion.
      • Krahn A.D.
      • Healey J.S.
      • Chauhan V.
      • et al.
      Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER).
      Similarly, Behr et al found evidence of an inherited arrhythmia syndrome in 16% of first-degree relatives following clinical assessment.
      • Behr E.
      • Wood D.A.
      • Wright M.
      • et al.
      Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome.
      Tan et al identified a channelopathy in a total of 28% of surviving relatives of SCD victims.
      • Tan H.L.
      • Hofman N.
      • van Langen I.M.
      • van der Wal A.C.
      • Wilde A.A.
      Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives.

      Clinical evaluation in the patient with resuscitated SCA

      Clinical workup includes resting and signal-averaged ECG, exercise testing, telemetry or Holter monitoring, echocardiography, and magnetic resonance imaging. Coronary angiography is usually performed in adults, with discretionary use of electrophysiological testing including endocardial voltage mapping, cardiac biopsy, and left and right ventricular angiography. Provocative adrenaline and sodium channel blocker infusion should be considered for the potential unmasking of LQTS, CPVT, and Brugada syndrome.
      • Krahn A.D.
      • Gollob M.
      • Yee R.
      • et al.
      Diagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusion.
      • Krahn A.D.
      • Healey J.S.
      • Chauhan V.
      • et al.
      Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER).

      Clinical and molecular considerations in SIDS

      SIDS 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.
      • Leach C.E.
      • Blair P.S.
      • Fleming P.J.
      • et al.
      Epidemiology of SIDS and explained sudden infant deaths CESDI SUDI Research Group.
      International standards define the process and information required to classify an infant death as SIDS.
      • Bajanowski T.
      • Vege A.
      • Byard R.W.
      • et al.
      Sudden infant death syndrome (SIDS)—standardised investigations and classification: recommendations.
      Routine biochemical analysis of SIDS victims is performed to diagnose metabolic abnormalities that are responsible for about 5% of cases.
      • Bennett M.J.
      • Rinaldo P.
      The metabolic autopsy comes of age.
      Mutations associated with LQTS can be found in 2% to 9.5% of victims of SIDS.
      • Arnestad M.
      • Crotti L.
      • Rognum T.O.
      • et al.
      Prevalence of long-QT syndrome gene variants in sudden infant death syndrome.
      • Tester D.J.
      • Ackerman M.J.
      Sudden infant death syndrome: how significant are the cardiac channelopathies?.
      In the absence of a pathologic diagnosis, referral of siblings and parents to a physician expert for clinical assessment is warranted and may provide information leading to targeted genetic testing of the deceased and family members.
      Autopsy-negative, unexpected SCD: Genetic testing of retained tissue is recommended only when there is evidence of a clinical phenotype in family members.
      In the absence of guiding clinical information, comprehensive screening of all possible genes responsible for inherited arrhythmias is not recommended. Proceeding with genetic testing in the absence of any correlating clinical phenotype may raise significant issues in the management of family members when genetic results of “unknown significance” are identified. When clinical history or family evaluation provides evidence for a specific genetic condition, screening of the appropriate genes should be undertaken in both the proband and the identified affected family member to corroborate clinical suspicion.
      Survivor of SCA: Genetic testing of the survivor should be directed by the results of the survivor's medical evaluation or that of his or her first-degree relatives.
      Comprehensive molecular screening for all possible genetic arrhythmias as part of the medical evaluation is not recommended. Genetic testing should be performed only on the basis of clinical evidence supporting a specific diagnosis.
      SIDS: Genetic testing of retained tissue should be directed by history and clinical investigation of any first-degree relatives.
      Consideration may be given to screening KCNH2, KCNQ1, and SCN5A under the direction of a clinical expert.

      Conclusion

      The clinical care of patients and families with suspected genetic arrhythmia syndromes may warrant the use of genetic testing. The decision to perform genetic testing should be based on the clinical value of the genetic information and should be performed with consideration of ethical and psychosocial issues. This requires a multidisciplinary approach including qualified arrhythmia specialists and counsellors. Specialized clinics with a focused clinical care approach to inherited arrhythmia syndromes are encouraged, with the aim of discouraging random genetic testing after inadequate evaluation and absence of appropriate counseling. Implicit is the assumption that a specialized clinic approach will provide the most comprehensive and cost-effective management of patients and their families.
      The present recommendations are based on contemporary knowledge. The field of cardiovascular genetics is rapidly evolving, and surveillance for future developments in the field by expert panels remains necessary. Health insurance providers and government funding agencies may require restructuring to allow for financial coverage of genetic testing to optimize patient care.

      Supplementary data

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