Canadian Journal of Cardiology 27 (2011) 232–245
Society Position Statement
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
a
b
c
Michael H. Gollob, MD (Chair), Louis Blier, MD, Ramon Brugada, MD,
Jean Champagne, MD,b Vijay Chauhan, MD,d Sean Connors, MD,e Martin Gardner, MD,f
Martin S. Green, MD,a Robert Gow, MB, BS,g Robert Hamilton, MD,h Louise Harris, MB,d
Jeff S. Healey, MD,i Kathleen Hodgkinson, PhD,j Christina Honeywell, MSc,g
Michael Kantoch, MD,k Joel Kirsh, MD,h Andrew Krahn, MD,n Michelle Mullen, PhD,o
Ratika Parkash, MD,f Damian Redfearn, MB,l Julie Rutberg, MSc,a Shubhayan Sanatani, MD,m
and Anna Woo, MDd
b
a
Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada;
Québec Heart Institute, Laval University, Laval, Québec, Canada; c Montreal Heart Institute, University of Montreal, Montreal, Québec, Canada;
d
Toronto General Hospital, University Health Networks, Toronto, Ontario, Canada; e Memorial University Health Sciences Centre, St.
John’s, Newfoundland, Canada; f Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, Nova Scotia, Canada;
g
Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada; h Hospital for Sick Children, University of
Toronto, Toronto, Ontario, Canada; i Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada; j Epidemiology and
Genetics, Memorial University, St. John’s, Newfoundland, Canada; k University of Alberta Hospital, Edmonton, Alberta, Canada;
l
Kingston General Hospital, Queen’s University, Kingston, Ontario, Canada; m British Columbia Children’s Hospital, University of British
Columbia, Vancouver, British Columbia, Canada; n London Health Sciences Centre, University of Western Ontario, London, Ontario,
Canada; o University of Ottawa, Bioethics, Children’s Hospital of Eastern Ontario, Canada
ABSTRACT
RÉSUMÉ
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
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 géné-
Received for publication September 27, 2010. Accepted December 23,
2010.
consensus of a Canadian panel comprised of multidisciplinary 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 specialists and allied health professionals obliged with the duty of bestowing optimal
care to patients and families, and can 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 managing clinical care in consultation with the patient, with appropriate regard to all
the individual circumstances of the patient, diagnostic and treatment options available and available resources. Adherence to these recommendations 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 Ottawa Heart Institute, Rm
H3228, Ottawa, Ontario K1Y 4W7, Canada.
E-mail: [email protected]
The disclosure information of the authors and reviewers is available from the
CCS on the following websites: www.ccs.ca and www.ccsguidelineprograms.ca.
This statement was developed following a thorough consideration of medical
literature and the best available evidence and clinical experience. It represents the
0828-282X/$ – see front matter © 2011 American Society for Histocompatibility and Immunogenetics All rights reserved.
doi:10.1016/j.cjca.2010.12.078
Gollob et al.
Genetic Testing in Arrhythmia Syndromes
233
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.
tique 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.
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.1 Specialized clinics also serve to improve cost-effectiveness and yield from genetic testing.2
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.
RECOMMENDATION
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), dutyto-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
234
these issues is available in the on-line supplement (see Supplementary Material).
Canadian Journal of Cardiology
Volume 27 2011
Table 1. Summary recommendations for genetic testing in long QT
syndrome
Symptom
Testing
Comment
Cardiac arrest survivor
with QT
prolongation
on resting
ECGs
Syncope
QTc abnormal*
⫹⫹
Exception is the patient with transient
QT prolongation that is commonly
seen with anoxic brain injury
immediately after cardiac arrest
⫹⫹
QTc borderline†
⫹/⫺
Not necessary for diagnostic purposes
but plays a role in risk
stratification, family screening, and
therapeutic decisions
Not recommended unless characteristic
abnormal T wave morphology is
present and/or a concerning family
history exists
Genetic testing is not recommended
§
Disease-Specific Recommendations for Clinical
Genetic Testing
The role of genetic testing in LQTS
LQTS (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 The risk of cardiac arrhythmias is
directly proportional to the duration of the corrected QT interval (QTc) duration.5-7
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.8,9 The Schwartz
diagnostic criteria have been established to facilitate the diagnosis of LQTS.10,11 In the normal population, the QTc is
longer in adult women than in men.12,13 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.14-17
Management. Risk stratification in LQTS classifies patients as low, intermediate, and high risk, based on their gender, QT interval, and genotype.5 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, ␤-blockers are
the mainstay of treatment. The role for ␤-blockade is less clear
in LQT3 patients, who often have events that occur at rest or
during sleep, and proceeding with an implantable cardioverterdefibrillator (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.18,19
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,1,20 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.21,22 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.
QTc normal‡
Asymptomatic§
QTc abnormal*
⫺
QTc borderline†
⫺
First-degree relative
Proband genotype
positive
Proband genotype
negative
⫹⫹
⫹⫹
⫺
May be useful for diagnosis, risk
stratification, choice of therapy,
and family screening
Not recommended unless abnormal T
wave morphology is present and/or
a concerning family history exists
Useful for diagnostic and therapeutic
purposes
In rare circumstances, if QTc is
consistently borderline or
prolonged, genetic testing may be
considered
Recommendations: ⫹⫹ (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).
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.
RECOMMENDATION
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 ␤-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.
Gollob et al.
Genetic Testing in Arrhythmia Syndromes
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.
RECOMMENDATION
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,5 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.
RECOMMENDATION
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 ⱖ 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 460to 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.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 by ethnicity.24-28
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.28
The various Brugada ECG patterns may be intermittent. Patients with a type 2 or 3 pattern with unheralded syncope
235
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.28 In some patients, conduction system
disease coincides with the Brugada ECG pattern or may be the
only ECG abnormality observed in family members.29,30
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.30 Drug
therapy with ␤-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.31 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).32 The
value of electrophysiological testing for risk stratification is not
clearly established.32-35 A positive family history of Brugada
syndrome–related SCD does not appear to confer a worse
prognosis.36-38
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.39 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%).40,41 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.42
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.
RECOMMENDATION
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-
236
Canadian Journal of Cardiology
Volume 27 2011
Table 2. Summary recommendations for genetic testing in Brugada
syndrome
Symptom
Cardiac arrest survivor
Persistent or provocable type 1
Brugada ECG pattern
Apparent type 2 or 3 ECG pattern*
with nonprovocable type 1
ECG pattern
Syncope
Persistent or provocable type 1
Brugada ECG pattern
Apparent type 2 or 3 ECG pattern
with nonprovocable type 1
ECG pattern
Asymptomatic
Persistent type 1 Brugada ECG
patter
Apparent type 2 or 3 ECG pattern
with nonprovocable type 1
ECG pattern
First-degree relative
Proband genotype positive
Proband genotype negative
Testing
Comment
⫹⫹
Not for diagnostic or therapeutic
purposes but plays a role in
family screening
Genetic testing is not recommended
as the diagnosis of Brugada
syndrome requires evidence of
the type 1 ECG pattern
⫺
⫹⫹
⫺
⫹⫹
⫺
⫹⫹
⫺
Principally for the purpose of family
screening
Not recommended in the absence of
observed type 1 ECG pattern
Not useful for risk stratification;
principally for the purpose of
family screening
Genetic testing is not recommended
Clinical implications of an isolated
positive genotype in the
absence of a phenotype are
unknown
Not recommended
Recommendations: ⫹⫹ (strongly recommended), ⫺ (not recommended).
* Type 2 or 3 ECG patterns may resemble early repolarization or variations
of normal ST segments.
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.
RECOMMENDATION
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.
RECOMMENDATION
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.
RECOMMENDATION
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.43 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.43,44
Diagnosis. Task Force criteria for the diagnosis were originally proposed in 1994 and updated in 2010.45,46 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.47,48 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.19 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.49 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).49-54 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.56,57 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.51,58 A rare
autosomal recessive syndrome related to desmoplakin mutations is
Gollob et al.
Genetic Testing in Arrhythmia Syndromes
237
Table 3. Summary recommendations for genetic testing in
arrhythmogenic right ventricular cardiomyopathy
Clinical scenario
Testing
Comment
Clinical ARVC in
accordance with
Task Force criteria
Clinical ARVC in
accordance with
Task Force criteria
in the absence of
identified at-risk
family members
Clinically suspected
ARVC not
meeting Task
Force criteria
⫹⫹
Genetic testing plays a role in the
screening of identified family
members
ARVC is often sporadic, and genetic
results do not provide risk
stratification assistance
First-degree relative of
genotype-positive
proband
First-degree relative of
genotype-negative
proband
⫹⫹
⫺
⫹⫹
⫺
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
Useful for decisions of medical
surveillance and lifestyle
modification
Genetic testing not indicated
Recommendations: ⫹⫹ (strongly recommended), ⫺ (not recommended).
ARVC, arrhythmogenic right ventricular cardiomyopathy.
Carvajal syndrome, characterized by dilated cardiomyopathy,
wooly hair, and plantar keratoderma.59 In patients with negative
genetic findings of PKP2 and DSP, 5% to 10% of cases have
mutations in the DSG2 and DSC2 genes.53,60 A specific plakoglobin (JUP) mutation causes a rare form of autosomal recessive
ARVC known as Naxos disease.50
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.
RECOMMENDATION
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.
RECOMMENDATION
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.61
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.61,62 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.63 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. ␤-Blockers are highly effective in suppressing adrenergic-mediated arrhythmias in CPVT. Treadmill
testing should be performed to titrate ␤-blocker dosage to ensure adequate suppression of exercise-induced ventricular arrhythmias. Typically, high-dose ␤-blockers are required (eg,
atenolol ⱖ 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
␤-blockers, flecainide, cardiac sympathectomy, or ICD placement should be considered.64,65
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).66,67 These genes
238
Canadian Journal of Cardiology
Volume 27 2011
Table 4. Summary recommendations for genetic testing in
catecholaminergic polymorphic ventricular tachycardia
Clinical scenario
Clinically suspected
CPVT
First-degree relative
Proband genotype
positive
Testing
Comment
⫹⫹
Genetic testing useful for the primary
purpose of identifying at-risk
family members
⫹⫹
Useful for decisions of medical
surveillance and lifestyle
modification
Recommendations: ⫹⫹ (strongly recommended).
CPVT, catecholaminergic polymorphic ventricular tachycardia.
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.63 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.68
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%.
RECOMMENDATION
Clinically suspected CPVT: Genetic testing is recommended for the primary purpose of screening family members.
trophy on the echocardiogram.70,71 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.72-74
Management. Risk stratification of patients is recommended to determine the risk for SCD.69,75 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 ⱖ30 mm).69,75 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).76 Genetic testing may detect a
gene defect in 40% to 60% of patients.76,77 Mutations of the
MYH7 and MYBPC3 genes account for the majority of cases.76
Approximately 3% of patients with HCM may have more than
once pathogenic mutation, which may be associated with a
more severe phenotype.76
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 ⱖ40 years.78 The identification of patients with
this condition is important since enzyme replacement therapy
is effective.79,80 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).73,81,82
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
Table 5. Genes associated with hypertrophic cardiomyopathy
Gene
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.69
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 hyper-
MYH7
MYBPC
TNNT2
TNNI3
TPM1
TTN
MYH6
MYL2
MYL3
ACTC
TNNC1
LBD3
CSRP3
TCAP
VCL
ACTN2
MYOZ2
JPH2
PLN
Protein
Frequency
␤-Myosin heavy chain
Myosin-binding protein C
Troponin T
Troponin I
␣-Tropomyosin
Titin
␣-Myosin heavy chain
Ventricular regulatory myosin light chain
Ventricular essential myosin light chain
␣-Cardiac actin
Troponin C
Limb binding domain 3
Muscle LIM protein
Telethonin
Vinculin
␣-Actinin 2
Myozenin 2
Junctophilin-2
Phospholamban
15%-30%
15%-30%
5%-10%
2%-5%
2%-5%
⬍1%
⬍1%
⬍1%
⬍1%
⬍1%
⬍1%
⬍1%
⬍1%
⬍1%
⬍1%
⬍1%
⬍1%
⬍1%
⬍1%
Gollob et al.
Genetic Testing in Arrhythmia Syndromes
239
Table 6. Summary recommendations for genetic testing in
hypertrophic cardiomyopathy
Clinical scenario
Testing
Comment
⫹⫹
Genetic testing is recommended for
the primary purpose of
screening family members
MYH7, MYBPC
TNNT2, TNNI3, TPM1
Genetic testing is recommended for
the primary purpose of
screening family members
Clinically diagnosed HCM
Tier 1 gene testing
Tier II gene testing
Clinically diagnosed HCM
with ECG features
of ventricular
preexcitation
Tier I gene testing
Tier II gene testing
Clinically diagnosed HCM
⫹⫹
⫺
Clinically diagnosed HCM
⫺
Clinically suspected HCM
⫺
PRKAG2, LAMP2, GLA
MYH7, MYBPC, TNNT2, TNNI3,
TPM1
Genetic testing is NOT
recommended for the purpose
of diagnostic confirmation
Genetic testing is NOT
recommended for the purpose
of risk stratification and
treatment decisions
Genetic 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.
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.
RECOMMENDATION
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 diseasecausing 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.
RECOMMENDATION
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.
RECOMMENDATION
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.
RECOMMENDATION
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.83 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.84,85
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.85
Management. Medical therapy includes the use of angiotensin-converting enzyme inhibitors, ␤-blockers, and spironolactone to minimize disease progression, control symptoms,
and decrease arrhythmic risk.85 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 sig-
240
Canadian Journal of Cardiology
Volume 27 2011
Table 7. Summary recommendations for genetic testing in dilated
cardiomyopathy
Clinical scenario
Testing
Clinically diagnosed DCM
⫺
Clinically diagnosed DCM
with evidence of
probable familial
DCM
Genetic testing
⫹⫹
Clinically diagnosed
familial DCM with
evidence of atrial
arrhythmias and
high-grade
conduction disease
Genetic testing
Clinically diagnosed
familial DCM with
evidence of Xlinked inheritance
Genetic testing
⫹⫹
⫹⫹
Comment
Genetic 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
Genetic testing is recommended
for the primary purpose of
screening family members
MYH7, MYPBC, TNNT2, LMNA,
SCN5A
Genetic testing is recommended
for the primary purpose of
screening family members
LMNA, SCN5A
Genetic testing is recommended
for the primary purpose of
screening family members
DMD
Recommendations: ⫹⫹ (strongly recommended), ⫺ (not recommended).
DCM, dilated cardiomyopathy.
nificantly widened QRS duration (⬎150 milliseconds) and
impaired New York Heart Association functional class, biventricular pacing may improve heart failure symptoms.86
Genetics. Over 30 genes have been reported to cause
DCM.87 The yield of genetic testing is significantly enhanced
when a family history is evident.85,88 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.85,88,89
Familial DCM with atrial arrhythmias and high-grade conduction disease is most commonly due to mutations of the
LMNA gene.85 Familial DCM demonstrating an X-linked pattern of inheritance and skeletal muscle weakness raises the suspicion of dystrophin (DMD) gene mutations.85
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.
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.
RECOMMENDATION
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.”
RECOMMENDATION
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.90,91 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.92-94 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.95
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.96 A thorough assessment to rule out a
structural cause of SCD should include a rigourous cardiac
Gollob et al.
Genetic Testing in Arrhythmia Syndromes
241
Table 8. The role of genetic testing in unexplained sudden cardiac
death, resuscitated sudden cardiac death, and sudden infant death
syndrome
Clinical scenario
Unexplained sudden
death
(negative
autopsy)
Testing
Comment
⫹⫹
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
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
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
⫺
Resuscitated sudden
cardiac death
⫹⫹
⫺
Sudden infant death
syndrome
⫹⫹
⫹
⫺
First-degree relative
Proband genotype
positive
⫹⫹
Useful for diagnostic and therapeutic
purposes
Recommendations: ⫹⫹ (strongly recommended), ⫹ (recommended), ⫺
(not recommended).
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.97-99 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% of cases, and mutations of LQTS-associated genes have
been identified in 16% to 20% of cases.100-102 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.100,102 From current evidence, collection and storage of tissue and/or DNA for possible
future molecular analysis is warranted.
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 ei-
ther CPVT or Brugada syndrome in 16% of relatives of SCA
survivors, when patients with obvious LQTS were excluded.63,103
Similarly, Behr et al found evidence of an inherited arrhythmia
syndrome in 16% of first-degree relatives following clinical assessment.104 Tan et al identified a channelopathy in a total of 28% of
surviving relatives of SCD victims.105
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.63,103
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.106 International standards define the process and information required to classify an infant death as SIDS.107
Routine biochemical analysis of SIDS victims is performed
to diagnose metabolic abnormalities that are responsible for
about 5% of cases.108 Mutations associated with LQTS can be
found in 2% to 9.5% of victims of SIDS.109,110
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.
RECOMMENDATION
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.
RECOMMENDATION
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 recom-
242
mended. Genetic testing should be performed only on the basis
of clinical evidence supporting a specific diagnosis.
RECOMMENDATION
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 Material
To access the supplementary material accompanying this
article, visit the online version of the Canadian Journal of
Cardiology at www.onlinecjc.ca and at doi:10.1016/j.cjca.
2010.12.078.
Canadian Journal of Cardiology
Volume 27 2011
7. Kimbrough J, Moss AJ, Zareba W, et al. Clinical implications for affected parents and siblings of probands with long-QT syndrome. Circulation 2001;104:557-62.
8. Locati EH, Zareba W, Moss AJ, et al. Age- and sex-related differences in
clinical manifestations in patients with congenital long-QT syndrome:
findings from the International LQTS Registry. Circulation 1998;97:
2237-44.
9. Moss AJ, Schwartz PJ, Crampton RS, et al. The long QT syndrome:
prospective longitudinal study of 328 families. Circulation 1991;84:
1136-44.
10. Schwartz PJ, Moss AM, Vincent GM, et al. Diagnostic criteria for the
long QT syndrome. Circulation 1993;88:782-4.
11. 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. J Am
Coll Cardiol 1998;32:486-91.
12. Neyroud N, Maison-Blanche P, Denjoy I, et al. Diagnostic performance
of QT interval variables from 24-h electrocardiography in the long QT
syndrome. Eur Heart J 1998;19:158-65.
13. Stramba-Badiale M, Locati EH, Martinelli A, et al. Gender and the
relationship between ventricular repolarization and cardiac cycle length
during 24-h Holter recordings. Eur Heart J 1997;18:1000-6.
14. Krahn AD, Klein GJ, Yee R. Hysteresis of the RT interval with exercise:
a new marker for the long-QT syndrome? Circulation 1997;96:1551-6.
15. Lehmann MH, Suzuki F, Fromm BS, et al. T wave “humps” as a potential electrocardiographic marker of the long QT syndrome. J Am Coll
Cardiol 1994;24:746-54.
16. Khositseth A, Hejlik J, Shen WK, et al. Epinephrine-induced T-wave
notching in congenital long QT syndrome. Heart Rhythm 2005;2:
141-6.
17. 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. Heart Rhythm 2004;1:276-83.
18. 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.
Eur J Cardiovasc Prev Rehabil 2006;13:676-86.
1. Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long QT syndrome. Circulation 2007;115:2613-20.
19. Maron BJ, Chaitman BR, Ackerman MJ, et al. Recommendations for
physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation 2004;109:
2807-16.
2. Bai R, Napolitano C, Bloise R, Monteforte N, Priori SG. Yield of genetic
screening in inherited cardiac channelopathies: how to prioritize access
to genetic testing. Circ Arrhythm Electrophysiol 2009;2:6-15.
20. Napolitano C, Priori SG, Schwartz PJ, et al. Genetic testing in the long
QT syndrome: development and validation of an efficient approach to
genotyping in clinical practice. JAMA 2005;294:2975-80.
3. Ackerman MJ. The long QT syndrome: ion channel diseases of the heart.
Mayo Clin Proc 1998;73:250-69.
21. Tester DJ, Will ML, Haglund CM, et al. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT
syndrome genetic testing. Heart Rhythm 2005;2:507-17.
References
4. Vincent GM. The molecular genetics of the long QT syndrome: genes
causing fainting and sudden death. Annu Rev Med 1998;49:263-74.
5. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the
long-QT syndrome. N Engl J Med 2003;348:1866-74.
22. Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in
long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and
KCNE2. Circulation 2000;102:1178-85.
6. 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. J Am
Coll Cardiol 2004;44:117-25.
23. Brugada J, Brugada R, Brugada P. Right bundle-branch block and STsegment elevation in leads V1 through V3: a marker for sudden death in
patients without demonstrable structural heart disease. Circulation
1998;97:457-60.
Gollob et al.
Genetic Testing in Arrhythmia Syndromes
243
24. Viskin S, Fish R, Eldar M, et al. Prevalence of the Brugada sign in
idiopathic ventricular fibrillation and healthy controls [see comments].
Heart 2000;84:31-6.
42. 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. Circulation 2007;116:2260-8.
25. 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. Eur Heart J 2006;27:2544-52.
43. Basso C, Corrado D, Marcus FI, Nava A, Thiene G. Arrhythmogenic
right ventricular cardiomyopathy. Lancet 2009;373:1289-300.
26. Matsuo K, Akahoshi M, Nakashima E, et al. Clinical characteristics of
subjects with the Brugada-type electrocardiogram. J Cardiovasc Electrophysiol 2004;15:653-7.
27. 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.
Heart 2001;86:161-6.
28. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report
of the second consensus conference. Heart Rhythm 2005;2:429-40.
29. Grant AO, Carboni MP, Neplioueva V, et al. Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single
sodium channel mutation. J Clin Invest 2002;110:1201-9.
30. Sarkozy A, Boussy T, Kourgiannides G, et al. Long-term follow-up of
primary prophylactic implantable cardioverter-defibrillator therapy in
Brugada syndrome. Eur Heart J 2007;28:334-44.
31. Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients
with Brugada syndrome. Circulation 2004;110:1731-7.
32. Probst V, Veltmann C, Eckardt L, et al. Long-term prognosis of patients
diagnosed with Brugada syndrome: results from the FINGER Brugada
Syndrome Registry. Circulation 2010; 121:635-43.
33. Priori SG, Napolitano C. Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing? Circulation 2005;112:279-92; discussion 279-92.
34. Brugada P, Brugada R, Brugada J. Should patients with an asymptomatic
Brugada electrocardiogram undergo pharmacological and electrophysiological testing? Circulation 2005;112:279-292; discussion 279-292.
35. Gehi AK, Duong TD, Metz LD, et al. Risk stratification of individuals
with the Brugada electrocardiogram: a meta-analysis. J Cardiovasc Electrophysiol 2006;17:577-83.
36. 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. Circulation 2003;108:3092-6.
37. Priori SG, 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. Circulation 2000;102:
2509-15.
38. Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada
syndrome: insights for risk stratification and management. Circulation
2002;105:1342-7.
39. Schulze-Bahr E, Eckardt L, Breithardt G, et al. Sodium channel gene
(SCN5A) mutations in 44 index patients with Brugada syndrome: different incidences in familial and sporadic disease. Hum Mutat 2003;
21:651-2.
40. Roberts JD, Gollob MH. The genetic and clinical features of cardiac
channelopathies. Future Cardiol 2010;6:491-506.
41. Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity
characterized by ST-segment elevation, short QT intervals, and sudden
cardiac death. Circulation 2007;115:442-9.
44. Muthappan P, Calkins H. Arrhythmogenic right ventricular dysplasia.
2008;51:31-43.
45. McKenna WJ, 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. Br Heart J 1994;71:215-18.
46. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic
right ventricular cardiomyopathy/dysplasia: proposed modification of
the task force criteria. Circulation 2010; 121:1533-41.
47. Vasaiwala SC, Finn C, Delpriore J, et al. Prospective study of cardiac
sarcoid mimicking arrhythmogenic right ventricular dysplasia. J Cardiovasc Electrophysiol 2009;20:473-6.
48. Roberts JD, Veinot JP, Rutberg J, Gollob MH. Inherited cardiomyopathies mimicking arrhythmogenic right ventricular cardiomyopathy.
Cardiovasc Pathol 2010;19:316-20.
49. Sen-Chowdhry S, Syrris P, McKenna WJ. Role of genetic analysis in the
management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol 2007;50:1813-21.
50. 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). Lancet
2000;355:2119-24.
51. 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. Am J Hum Genet
2002;71:1200-6.
52. Gerull B, Heuser A, Wichter T, et al. Mutations in the desmosomal
protein plakophilin-2 are common in arrhythmogenic right ventricular
cardiomyopathy. Nat Genet 2004;36:1162-4.
53. Pilichou K, Nava A, Basso C, et al. Mutations in desmoglein-2 gene are
associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 2006;113:1171-9.
54. Heuser A, Plovie ER, Elinor PT, et al. Mutant desmocollin-2 causes
arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet
2006;71:1081-8.
55. Merner ND, Hodgkinson KA, Haywood AFM, et al. Arrhythmogenic
right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene.
Am J Human Genet 2008;82:1-13.
56. Syrris P, Ward D, Asimaki A, et al. Clinical expression of plakophilin-2
mutations in familial arrhythmogenic right ventricular cardiomyopathy.
Circulation 2006;113:356-64.
57. Dalal D, Molin LH, Piccini J, et al. Clinical features of arrhythmogenic
right ventricular dysplasia/cardiomyopathy associated with mutations in
plakophilin-2. Circulation 2006;113:1641-9.
58. Yang Z, Bowles NE, Scherer SE, et al. Desmosomal dysfunction due to
mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Res 2006;99:646-55.
59. Norgett EE, Hatsell SJ, Carvajal-Huerta L, et al. Recessive mutation in
desmoplakin disrupts desmoplakin-intermediate filament interactions
244
Canadian Journal of Cardiology
Volume 27 2011
and causes dilated cardiomyopathy, wooly hair and keratoderma. Hum
Mol Genet 2000;9:2761-6.
60. Syrris P, Ward D, Evans A, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal
gene desmocollin-2. Am J Hum Genet 2006;79:978-84.
61. Priori S, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular
tachycardia. Circulation 2002;106:69-74.
62. Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children: a 7-year
follow-up of 21 patients. Circulation 1995;91:1512-9.
63. Krahn AD, Gollob M, Yee R, et al. Diagnosis of unexplained cardiac
arrest: role of adrenaline and procainamide infusion. Circulation 2005;
112:2228-34.
64. Watanabe H, Chopra N, Laver D, et al. Flecainide prevents catecholamineregic polymorphic ventricular tachycardia in mice and humans. Nat
Med 2009;15:380-3.
65. Makanjee B, Gollob MH, Klein GJ, Krahn AD. Ten-year follow-up
of cardiac sympathectomy in a young woman with catecholaminergic
polymorphic ventricular tachycardia and an implantable cardioverter
defibrillator. J Cardiovasc Electrophysiol 2009;20:1167-9.
66. Priori SG, Napolitano C, Tiso N, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic
ventricular tachycardia. Circulation 2001;103:196-200.
67. Lahat H, Pras E, Olender T,et al. A missense mutation in a highly
conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin
families from Israel. Am J Hum Genet 2001;69:1378-84.
68. Tester D, Arya P, Will M, et al. Genotypic heterogeneity and phenotypic
mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing. Heart Rhythm 2006;3:
800-5.
69. Maron BJ, McKenna WJ, Danielson GK, 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. J Am Coll Cardiol 2003;42:
1687-1713.
70. Wigle ED. Diagnosis of hypertrophic cardiomyopathy. Heart 2001;86:
709-14.
71. Ryan MP, Cleland JGF, French JA, et al. The standard electrocardiogram as a screening test for hypertrophic cardiomyopathy. Am J Cardiol
1995;76:689-94.
72. Maron BJ, 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. Circulation 1995;91:1596-1601.
73. Gollob MH, Green MS, Tang A, Roberts R. The PRKAG2 cardiac
syndrome: familial ventricular preexcitation, conduction system
disease, and cardiac hypertrophy. Curr Opin Cardiol 2002;17:
229-34.
74. Guertl B, Noehammer C, Hoefler G. Metabolic cardiomyopathies. Int J
Exp Pathol 2000;81:349-72.
75. McKenna WJ, Behr ER. Hypertrophic cardiomyopathy: management,
risk stratification, and prevention of sudden death. Heart 2002;87:16976.
76. Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy.
J Am Coll Cardiol 2009;54:201-11.
77. 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. Circulation 2003;107:2227-32.
78. Sachdev B, Takenaka T, Teraguchi H, et al. Prevalence of AndersonFabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation 2002;105:1407-11.
79. Schiffman R, Kopp JB, Austin JB III, et al. Enzyme replacement therapy
in Fabry disease: a randomized controlled trial. J Am Med Assoc 2001;
285:2743-59.
80. Pastores GM, Thadhani R. Enzyme-replacement therapy for AndersonFabry disease. Lancet 2001;358:601-3.
81. Yang Z, McMahon CJ, Smith LR, et al. Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children. Circulation
2005;112:1612-7.
82. Gollob MH, Green MS, Tang A S-L, et al. Identification of a gene
responsible for Familial Wolff-Parkinson-White Syndrome. New Engl
J Med 2001;344:1823-31.
83. Codd MB, Sugrue DD, Gersh BJ, Melton LJ III. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy: a population-based
study in Olmsted County, Minnesota, 1975-1984. Circulation 1989;80:
564-72.
84. Grünig E, Tasman JA, Kücherer H, Franz W, Kübler W, Katus HA.
Frequency and phenotypes of familial dilated cardiomyopathy. J Am
Coll Cardiol 1998;31:186-94.
85. Hershberger RE, Lindenfeld J, Mestroni L, Seidman CE, Taylor MR,
Towbin JA; Heart Failure Society of America. Genetic evaluation of
cardiomyopathy: a Heart Failure Society of America practice guideline.
J Card Fail 2009;15:83-97.
86. Moss AJ, Hall WJ, Cannom DS, et al; MADIT-CRT Trial Investigators.
Cardiac-resynchronization therapy for the prevention of heart-failure
events. N Engl J Med 2009;361:1329-38.
87. Judge DP. Use of genetics in the clinical evaluation of cardiomyopathy.
JAMA 2009;302:2471-6.
88. Burkett EL, Hershberger RE. Clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol 2005;45:969-81.
89. Hershberger RE, Parks SB, Kushner JD, et al. Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and
TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy. Clin Transl Sci 2008;1:21-6.
90. 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. Circulation 1997;95:265-72.
91. Wever EF, Robles de Medina EO. Sudden death in patients without
structural heart disease. J Am Coll Cardiol 2004;43:1137-44.
92. Maron BJ, Shirani J, Poliac LC, Mathenge R, Roberts WC, Mueller FO.
Sudden death in young competitive athletes: clinical, demographic, and
pathological profiles. JAMA 1996;276:199-204.
Gollob et al.
Genetic Testing in Arrhythmia Syndromes
245
93. Eckart RE, Scoville SL, Campbell CL, et al. Sudden death in young
adults: a 25-year review of autopsies in military recruits. Ann Intern Med
2004;141:829-34.
102. Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. J Am Coll Cardiol
2007;49:240-6.
94. Bowker TJ, Wood DA, Davies MJ, et al. Sudden, unexpected cardiac or
unexplained death in England: a national survey. QJM 2003;96:269-79.
103. Krahn AD, Healey JS, Chauhan V, et al. Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors With
Preserved Ejection Fraction Registry (CASPER). Circulation 2009;120:
278-85.
95. Willinger M, James LS, 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. Pediatr Pathol
1991;11:677-84.
96. Cohle SD, Sampson BA. The negative autopsy: sudden cardiac death or
other? Cardiovasc Pathol 2001;10:219-22.
104. Behr E, Wood DA, Wright M, et al. Cardiological assessment of firstdegree relatives in sudden arrhythmic death syndrome. Lancet 2003;362:
1457-9.
97. Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular
tachycardia. Circulation 2002;106:69-74.
105. Tan HL, Hofman N, van Langen IM, van der Wal AC, Wilde AA.
Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives. Circulation 2005;
112:207-13.
98. Tester DJ, Kopplin LJ, Creighton W, Burke AP, Ackerman MJ. Pathogenesis of unexplained drowning: new insights from a molecular autopsy.
Mayo Clin Proc 2005;80:596-600.
106. Leach CE, Blair PS, Fleming PJ, et al. Epidemiology of SIDS and explained sudden infant deaths. CESDI SUDI Research Group. Pediatrics
1999;104:e43.
99. Moss AJ, Robinson JL, 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. Am J Cardiol 1999;
84:876-9.
107. Bajanowski T, Vege A, Byard RW, et al. Sudden infant death syndrome
(SIDS)—standardised investigations and classification: recommendations. Forensic Sci Int 2007;165:129-43.
100. Tester DJ, Spoon DB, Valdivia HH, Makielski JC, Ackerman MJ. Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: a molecular autopsy of 49 medical
examiner/coroner’s cases. Mayo Clin Proc 2004;79:1380-4.
101. Chugh SS, Senashova O, Watts A, et al. Postmortem molecular
screening in unexplained sudden death. J Am Coll Cardiol 2004;43:
1625-9.
108. Bennett MJ, Rinaldo P. The metabolic autopsy comes of age. Clin Chem
2001;47:1145-6.
109. Arnestad M, Crotti L, Rognum TO, et al. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation 2007;
115:361-7.
110. Tester DJ, Ackerman MJ. Sudden infant death syndrome: how significant are the cardiac channelopathies? Cardiovasc Res 2005;67:388-96.