Download Genetic Testing is a Blessing: Cardiac Channelopathies

Genetic Testing is a Blessing:
Cardiac Channelopathies
Anjan S Batra, M.D
Director of Electrophysiology
Associate Professor of Pediatrics
University of California-Irvine
Common Inherited Diseases that Cause
Sudden Arrhythmic Death Syndrome (SADS)
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More than 50% of SADS deaths are genetic in nature.1
Reference: 1. Behr ER, Dalageorgou C, Christiansen M, et al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in
majority of families. Eur Heart J. 2008;29:1670-1680.
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The Family of Genetic Tests for
Inherited Cardiac Syndromes
Increased Awareness of and Improved Testing for
LQTS Are Revealing a Higher Prevalence
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Inherited LQTS is now known to affect 1:2,500 people.1
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It is estimated that 2,000-3,000 children and young adults die
each year in the United States due to LQTS
LQTS.2
References: 1. Crotti L, et al. Congenital long QT syndrome. Orphanet Journal of Rare Diseases. 2008;3:18. 2. Sudden Arrhythmia Death Syndromes
(SADS) Foundation. LQTS brochure. Available at: http://www.sads.org. Accessed November 30, 2007.
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Challenges in Diagnosing LQTS –
ECG Variability
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~33%
33% off mutationt ti
positive LQTS
patients
have a QT interval
(≤ 480 msec) that
overlaps normal,
healthy individuals.2
Adapted from: Taggart NW, et al. Diagnostic miscues in congenital long-QT syndrome. Circulation.
2007;115:2613-2620.Cell. 2001;104:569-580.
References: 1. Maron BJ, Moller JH, Seidman CE, et al. Impact of laboratory molecular diagnosis on contemporary diagnostic criteria for genetically transmitted
cardiovascular diseases: hypertrophic cardiomyopathy, long-QT syndrome, and marfan syndrome. Circulation. 1998;98:1460-1471. 2. Taggart NW, Haglund CM,
Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation. 2007;115:2613-2620.
Schwartz Score
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Schwartz score results
are frequently
inconclusive 1
inconclusive.
Probability
Pts
High
4
intermediate
2-3
Low
1
Reference: 1. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999;99:529-533.
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THE BENEFITS OF
GENETIC TESTING?
Genetic Testing for Prevention
Frequency of Cardiac Events
Subjects from the International LQTS Registry & BIOMED LQTS Research Group
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Gene Mutation Location Further Defines LQTS Risk
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LQT1
LQT2
Adapted from: Moss AJ, et al. Clinical aspects of type-1 long-QT syndrome by
location, coding type, and biophysical function of mutations involving the
KCNQ1 gene. Circulation. 2007;115:2481-2489.
Adapted from: Moss AJ, et al. Increased risk of arrhythmic events in long-QT
syndrome with mutations in the pore region of the human ether-a-go-go-related
gene potassium channel. Circulation. 2002;105:794-799.
For LQT1 and LQT2 patients, there is significantly higher risk for cardiac events
when mutations are located in the transmembrane/pore region.1,2
References: 1. Moss AJ, Shimizu W, Wilde AAM. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations
involving the KCNQ1 gene. Circulation. 2007;115:2481-2489. 2. Moss AJ, Zareba W, Kaufman ES, et al. Increased risk of arrhythmic events in long-QT syndrome
with mutations in the pore region of the human ether-a-go-go-related gene potassium channel. Circulation. 2002;105:794-799.
Examples of LQT1 and LQT2 Transmembrane Mutations
KCNQ1/KvLQT1
KCNH2/HERG
Genetic testing is the only method available to determine mutation location.
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Risk for Asymptomatic Parents of Probands
Risk of an Initial Cardiac Event for Asymptomatic Parents of Probands
Extends Into Adulthood.
Adapted from: Kimbrough J, Moss AJ, Zareba W, et al. Clinical implications for affected
parents and siblings of probands with long-QT syndrome. Circulation. 2001;104:557-562.
Reference: 1. Kimbrough J, Moss AJ, Zareba W, et al. Clinical implications for affected parents and siblings of probands with long-QT syndrome. Circulation.
2001;104:557-562.
Genetic Testing for Therapy
Effectiveness of β-Blocker Treatment
Rate of cardiac events over five years for subjects from the International LQTS Registry
Mohammed et al.J Cardiovasc Electrophysiol. 2007;18(7):791-797.
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Genetic Testing for Therapy
TEST
RESULTS
ISSUE
DIRECTED
THERAPY
LQT 1
Experience events
Avoid competitive sports.
during exercise.
Beta blocker therapy
Endangered by exercise. advised.
LQT 2
Auditory stimuli trigger
events.
Remove alarm clocks
etc. from bedroom. Beta
blocker therapy advised.
LQT 3
Relatively low risk of
exercise. High mortality
rates despite beta
blocker therapy.
Supervised recreational
activity could be
considered.
ICD therapy advised.
Genetic Testing for Prognosis
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LQT1 patients are more likely than either LQT2 or LQT3 patients to
experience a cardiac event.1
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Although the incidence of cardiac events is lower for LQT3 patients, the
probability of death per cardiac event is increased.1
Adapted from: Zareba W et al. Influence of the genotype on the clinical course of the long-QT
syndrome. N Engl J Med. 1998;339:14:960-965.
Reference: 1. Zareba W, Moss AJ, Schwartz PJ, et al. Influence of the genotype on the clinical course of the long-QT syndrome. N Engl J Med. 1998;339:14:960965.
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Symptoms in CPVT
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If left untreated, 30% of CPVT patients will develop symptoms by age
10, and ~80% by age 40.1
Adapted from: Napolitano C, Priori SG. Diagnosis and treatment of catecholaminergic polymorphic ventricular
tachycardia. Heart Rhythm. 2007;4:675-678.
Reference: 1. Mohamed U, Napolitano C, Priori SG. Molecular and electrophysiological bases of catecholaminergic polymorphic ventricular tachycardia. J
Cardiovasc Electrophysiol. 2007;18:791-797.
Challenges in Diagnosing CPVT
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CPVT cannot be diagnosed on the basis of a resting ECG.1,2
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Exercise stress testing is an important part of a CPVT workup.
» However, in as many as 20% of CPVT patients, formal exercise
stress testing will not produce ventricular ectopy
ectopy.1
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During exercise stress testing, bidirectional VT with a beat-to-beat 180degree rotation of the QRS complex is often observed.1
References: 1. Mohamed U, Napolitano C, Priori SG. Molecular and electrophysiological bases of catecholaminergic polymorphic ventricular tachycardia. J
Cardiovasc Electrophysiol. 2007;18:791-797. 2. Kontula K, Laitinen PJ, Lehtonen A, Toivonen L, Viitasalo M, Swan H. Catecholaminergic polymorphic
ventricular tachycardia: recent mechanistic insights. Cardiovasc Res. 2005;67:379-387.
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Differentiate CPVT from LQTS
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CPVT is a LQTS mimicker.1
As many as 30% of CPVT patients have been
misdiagnosed as having “Long QT with normal
QTc.”2,3
Genotyping Family Members of Known Probands Is
Essential to Risk Management
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All first-degree relatives, regardless of age, should be genotyped for the
proband’s gene mutation(s).1,2,3
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An asymptomatic parent with an LQTS mutation has a high probability of having
children at risk for cardiac events.1
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Approximately 33% of untreated siblings carry the proband’s gene mutation(s)
and will have a cardiac event by 40 years of age.2
References: 1. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999;99:529-533. 2. Kimbrough J,
Moss AJ, Zareba W, et al. Clinical implications for affected parents and siblings of probands with long-QT syndrome. Circulation. 2001;104:557-562. 3. Zipes DP,
Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac
death. J Am Coll Cardiol. 2006;48:1065-1102.
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CASE
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A 12 year old boy passes out while swimming. He is
appropriately resuscitated. The QTc on the ECG is 455 msec
(indeterminate). Genetic testing comes back positive for long QT
type 1.
1
» Subsequent genetic testing in his 8 year old sibling is positive
but negative in the 6 year old sibling. Parents also undergo
testing and the mother is found to be a carrier. Genetic
testing in this scenario was helpful for which of the following?
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A. The 12 year old boy
B The
B.
Th 8 year old
ld sibling
ibli
C. The 6 year old sibling
D. Future offspring off all 3 children
E. The parents
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Index Case (12 year old)
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Probability of LQTS:
» intermediate (Schwartz Score: 3)
» High with genetic testing
Therapy:
» Initiate beta blockers but no need for ICD
Prevention:
» Limit strenuous activities
activities.
Prognosis:
» good
Helpful:
» yes
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8 year old sibling
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Probability of LQTS:
» intermediate (Schwartz Score: 2)
» High with genetic testing (Positive family history and
genotype positive)
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Therapy:
» Initiate beta blockers but no need for ICD
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Prevention:
» Limit strenuous activities.
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P
Prognosis:
i
» good
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Helpful:
» yes
6 year old sibling
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Probability of LQTS:
» intermediate (Schwartz Score: 2)
» Low with genetic testing (Positive family history
and genotype negative)
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Therapy:
» No need to initiate beta blockers or ICD
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Prevention:
» No limitations
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Prognosis:
» good
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Helpful:
» yes
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Future offspring off all 3
children
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Probability of LQTS:
» Depends on genetic test of parent
Recommendation
» genetic testing for all offspring of genotype
positive subjects but not of genotype
negative subjects.
subjects
Helpful:
» yes
The Parents
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Probability of LQTS:
» High in mother
» Low in father
Recommend
» genetic testing for all siblings of mother but
not of father.
Therapy:
» Initiate beta blockers but no need for ICD
Prognosis:
» good
Helpful:
» yes
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On 15 February 2006, 14 year old Shauna Stuewe was lost to Sudden
Cardiac Arrest (SCA). An accomplished Gymnast and talented
cheerleader, Shauna was both physically fit and the picture of health
at the time her death.
Shauna had been seen by a Pediatric Cardiologist who performed
various tests including EKGs, Echocardiogram and Holter Monitor and
concluded that Shauna was in good health, no further cardiac
evaluation was needed and no restrictions were placed on her
activities.
Genetic autopsy testing on Shauna later revealed a gene mutation for
CPVT.
Her younger sister, who was also completely asympyomatic and an
athlete, was subsequently found to be positive for CPVT by genetic
testing. She now has an ICD.
The Role of Genetic Testing
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Questions
Concerns with genetic testing
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Cost
Cost:
» Make testing less expensive
» bundle all channelopathy tests into one test.
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Insurability
» Universal insurance for all
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Psychological trauma to families
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False positives and false negatives
» Availability of genetic councilors
» Improve sensitivity and specificity of test
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Significance of rare genotypes
» Increase awareness of clinical significance of rare genotypes
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Test Yield
Channelopathy
Sensitivity
Long QT Syndrome (LQTS)
75%
Brugada Syndrome
15-20%
Catecholaminergic
Polymorphic Ventricular
Tachycardia (CPVT)
50-55%
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