Download Inherited Arrhythmia Testing

Inherited Arrhythmia Testing
clinician guide
Ambry’s test offerings are designed to provide flexible,
comprehensive options tailored to your patients’
personal and family histories.
Genetic Testing for Inherited Arrhythmias
Understanding the genetic contribution to arrhythmias allows for individualized
disease management, and provides insight into personal and familial risks for
cardiovascular disease. Modified treatment, surveillance, and risk-reducing options
may be appropriate. Patients with an inherited arrhythmia may be asymptomatic and
experience sudden cardiac death without warning; the abnormal electrocardiogram
(EKG) pattern can be transitory, absent or uncertain. Thus, genetic testing may be the
most effective way of confirming a diagnosis or identifying at-risk individuals.
What are Next Generation Sequencing Panels?
Next generation sequencing (NGS) panels are tests that analyze multiple genes
simultaneously at a lower cost than traditional sequencing methods.
Ambry Genetics was one of the first labs to introduce NGS into the clinical setting.
Even when a specific arrhythmia is present, there are many possible genes that can be
the underlying cause. An NGS panel is the most efficient approach in many inherited
cardiovascular conditions.
Our experienced team of Board-certified genetic counselors, geneticists, and
scientists has designed our comprehensive reports to provide clear results,
interpretations, and details about any results identified.
Benefits of Multi-Gene Cardiovascular Panels
SPEED
Simultaneous
analysis of multiple
genes.
Reduces need for
multiple follow-up
appointments to
discuss additional
testing
ANSWERS
Higher likelihood of
identifying a
causative mutation
COST
A more cost-effective
approach
Ambry Genetics Hereditary Cardiovascular
Testing Options
cardiomyopathy
•HCMFirst/HCMNext
(hypertrophic cardiomyopathy)
•DCMNext (dilated
cardiomyopathy)
arrhythmia
•RhythmFirst/RhythmNext
•CPVTNext
(catecholaminergic
polymorphic ventricular
tachycardia)
•ARVDNext (arrhythmogenic
right ventricular dysplasia)
•LVNCNext (left ventricular
non-compaction)
•CMNext (cardiomyopathy)
•CardioNext
•ARVDNext
(arrhythmogenic
right ventricular dysplasia)
•CardioNext
other cardiovascular testing
•Familial hypercholesterolemia
aortic aneurysms/dissections
•TAADNext (thoracic aortic
aneurysms/dissections)
•Marfan syndrome
•Ehlers-Danlos syndrome, vascular
type
•Hereditary hemorrhagic
telangiectasia
•Transthyretin amyloidosis
•Other syndromic testing
Inherited Arrhythmias and Associated Genes
INHERITED
ARRHYTHMIA
DESCRIPTION
ASSOCIATED GENES
Arrhythmogenic
right ventricular
dysplasia (ARVD)*
Progressive fibrofatty replacement of the
myocardium in the right ventricle
DSC2, DSG2, DSP, JUP,
PKP2, RYR2, TGFB3,
TMEM43
Brugada syndrome (BrS) Characterized by right precordial ST wave CACNA1C, CACNA2D1,
elevation on an EKG, causing potential for CACNB2, GPD1L, HCN4,
sudden cardiac arrest
KCND3, KCNE3, KCNJ8,
SCN1B, SCN3B, SCN5A,
TRPM4
Catecholaminergic
polymorphic
ventricular tachycardia
(CPVT)
Bidirectional or polymorphic ventricular
tachycardia causing syncope and sudden
cardiac arrest during exercise or stress
ANK2, CALM1, CASQ2,
KCNJ2, RYR2, TRDN
Long QT syndrome
(LQTS)
Prolonged QT and T-wave abnormalities
on an EKG, ventricular tachycardia and
syncope
AKAP2, CAV3, KCNE1,
KCNE2, KCNH2, KCNQ1,
SCN4B, SNTA1, SCN5A
Short QT syndrome
(SQTS)
Characterized by an extremely short QT
CACNA1C, CACNB2,
wave interval, T-wave abnormalities, atrial KCNH2, KCNJ2, KCNQ1
fibrillation and syncope
*Also known as ARVC: arrhythmogenic right ventricular cardiomyopathy
Ambry Genetics Testing Options for Inherited Arrhythmia
RhythmFirst
• First-tier test for long QT syndrome, Brugada syndrome, and short QT
syndrome
• KCNH2, KNCQ1, and SCN5A
CPVTNext
• 6 genes for catecholaminergic polymorphic ventricular tachycardia
ARVDNext
• 8 genes for arrhythmogenic right ventricular dysplasia
RhythmNext
• 34 genes for inherited arrhythmias
CardioNext
• 84 genes for hereditary cardiovascular disorders
• Clinicians may choose whether to include TTN gene
RhythmFirst
A next generation sequencing and deletion/duplication panel of the 3 genes that are
most commonly associated with inherited arrhythmias: SCN5A, KCNQ1, and KCNH2.
Mutations in SCN5A may cause long QT or Brugada syndromes; mutations in KCNQ1
or KCNH2 may cause long QT or short QT syndromes.
target population for rhythmfirst
RhythmFirst is indicated in the following:
• Patients with a strong clinical suspicion for long QT syndrome, based on clinical and
family history and prolonged QT interval on EKG defined as QTc>480 ms
(adolescents) or >500 ms (adults).
• Asymptomatic patients with QT prolongation in the absence of other clinical
conditions that might prolong the QT interval
• Patients with a strong clinical suspicion for Brugada syndrome or short QT syndrome,
based on clinical/family history and EKG pattern
• Patients with personal or family history of unexplained sudden cardiac arrest/death,
with structurally normal heart and normal physical exam/autopsy
genetic testing for long qt syndrome and brugada syndrome
100%
RhythmFirst
90%
RhythmNext
80%
Unknown Causes
70%
60%
50%
40%
30%
20%
10%
0%
Brugada syndrome
Long QT syndrome
RhythmFirst will identify an inherited mutation in 75% of patients with a diagnosis of LQTS, which
represents over 95% of known genetic causes. RhythmFirst will identify an inherited mutation in about
15-30% of patients with a diagnosis of BrS, which represents over 80% of known genetic causes.
Long QT syndrome (LQTS)
LQTS occurs in approximately 1 in 2,500 individuals worldwide and is characterized
by a prolonged QT interval and T-wave abnormalities on an EKG, ventricular
tachycardia, syncope, and risk for sudden cardiac death. Age of onset for LQTS
usually ranges from childhood to early adulthood. The genes associated with LQTS
are included in RhythmFirst , RhythmNext, and the comprehensive cardiovascular
genetics panel (CardioNext). RhythmFirst will identify an inherited mutation in 75%
of patients with a diagnosis of LQTS, which represents over 95% of known genetic
causes. Patients who test negative may benefit from more comprehensive genetic
testing, such as RhythmNext.
genes implicated in long qt syndrome
Other
SCN5A
KCNQ1
Unknown
Mutations in 9 genes have been identified in LQTS.
KCNH2, KCNQ1, and SCN5A account for over 95% of
known genetic causes. “Other” includes the
additional 31 genes included in RhythmNext.
KCNH2
genetic testing guidelines from heart rhythm
society (hrs) and european heart rhythm
association (ehra)
Genetic testing is a Class I recommendation for all
patients with a suspicion of LQTS or asymptomatic
patients with a prolonged QT interval (QTc>480ms for
adolescents or >500ms for adults).
Adapted from Ackerman MJ, et al. Heart Rhythm. 2011 Aug;8(8):1308-39.
Brugada syndrome (BrS)
BrS occurs in approximately 1 in 5-10,000 individuals worldwide and is characterized by
right precordial ST wave elevation on an EKG. Onset is typically during adulthood. A
positive family history for sudden premature death and potentially lethal arrhythmias are
also common. BrS may be responsible for more than 4% of all sudden deaths and 20% of
sudden deaths in patients with structurally normal hearts. The genes associated with BrS
are included in RhythmFirst, RhythmNext, and the comprehensive cardiovascular
genetics panel (CardioNext). As 80% of BrS mutations occur in SCN5A, RhythmFirst is an
excellent first-tier option. Patients who test negative may benefit from more
comprehensive genetic testing, such as RhythmNext.
genes implicated in brugada syndrome
Other
SCN5A
Mutations in 12 genes have been identified in BrS.
SCN5A accounts for 15-30% of known genetic
causes. “Other” includes the additional 33 genes
included in RhythmNext.
Unknown
Short QT Syndrome (SQTS)
SQTS is a rare inherited arrhythmia that is characterized by an extremely short QT wave
interval, T-wave abnormalities, atrial fibrillation and syncope. There are five genes
currently associated with SQTS; two (KCNH2 and KCNQ1) are included on RhythmFirst.
Patients who test negative may benefit from more comprehensive genetic testing, such as
RhythmNext, which includes an additional 3 genes that are very rare causes of SQTS. The
SQTS genes are also included in the comprehensive cardiovascular genetics panel
(CardioNext).
Arrhythmogenic right ventricular dysplasia (ARVD)
ARVDNext
A next generation sequencing and deletion/duplication panel of 8 genes that
predispose to arrhythmogenic right ventricular dysplasia (ARVD): DSG2, DSP, DSC2,
JUP, PKP2, RYR2, TGFB3, and TMEM43.
ARVD occurs in approximately 1 in 1,000 individuals worldwide and is characterized
by progressive fibrofatty replacement of the myocardium in the right ventricle. Age of
onset is typically in early adulthood. It is a leading cause of ventricular arrhythmia and
sudden cardiac death in people under 35 years. Because ARVD can frequently
present as a cardiomyopathy or can present as arrhythmia, these genes are included
in the comprehensive cardiomyopathy (CMNext), arrhythmia (RhythmNext) and the
comprehensive cardiovascular genetics (CardioNext) panels.
genes implicated in arrhythmogenic right ventriicular dysplasia
Other
DSC2
PKP2
DSP
DSG2
Unknown
DSG2
Mutations in one of 8 known genes have been
identified in 50-60% of patients with ARVD. “Other”
includes the 4 additional genes included in
ARVDNext.
Unknown
target population for arvdnext
ARVDNext is indicated in the following:
• Patients with a definite, borderline or possible diagnosis of ARVD
• Patients with a first-degree relative with a definite diagnosis of ARVD
• Patients with a first-degree relative with ARVD confirmed pathologically at autopsy or
during surgery
• Patients with a first-degree relative with borderline/possible ARVD and a family
history of sudden death before 35 years of age
Catecholaminergic polymorphic ventricular tachycardia (CPVT)
CPVTNext
A next generation sequencing and deletion/duplication panel of 6 genes that predispose
to catecholaminergic polymorphic ventricular tachycardia (CPVT): ANK2, CALM1, CASQ2,
KCNJ2, RYR2, and TRDN.
CPVT occurs in approximately 1 in 10,000 individuals worldwide and is characterized by
syncope, often occurring during exercise or acute emotion. These episodes are caused by
bidirectional or polymorphic ventricular tachycardia. These arrhythmias may
spontaneously resolve, or progress and lead to sudden cardiac arrest. Age of onset in
CPVT is typically in childhood, and there is up to a 30% lifetime risk for cardiac arrest, if
untreated. An exercise stress test is usually necessary for diagnosis, as it is needed to
evoke the typical CPVT arrhythmia on EKG. These genes are also included in the
RhythmNext panel and the comprehensive cardiovascular genetics panel (CardioNext).
Patients with negative genetic testing may not have CPVT, or they may have a mutation in
a gene(s) that is not currently associated with CPVT.
genes implicated in catecholaminergic polymorphic ventricular
tachycardia
Other
CASQ2
Unknown
RYR2
Mutations in 6 genes have been identified in CPVT.
RYR2 accounts for over 80% of known genetic
causes. “Other” includes the additional 4 genes
included in CPVTNext.
genetic testing guidelines from heart rhythm
society (hrs) and european heart rhythm
association (ehra)
CPVT genetic testing is a Class I recommendation for all
patients with a suspicion of CPVT.
Adapted from Ackerman MJ, et al. Heart Rhythm. 2011 Aug;8(8):1308-39.
RhythmNext
A next generation sequencing and deletion/duplication panel of 34 genes that predispose
to arrhythmogenic right ventricular dysplasia (ARVD), Brugada syndrome,
catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome
(LQTS), short QT syndrome (SQTS), other arrhythmias/channelopathies, as well as
sudden cardiac arrest. RhythmNext includes AKAP9, ANK2, CACNA1C, CACNA2D1,
CACNB2, CALM1, CASQ2, CAV3, DSC2, DSG2, DSP, GPD1L, HCN4, JUP, KCND3, KCNE1,
KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ8, KCNQ1, LMNA, PKP2, RYR2, SCN1B, SCN3B, SCN4B,
SCN5A, SNTA1, TGFB3, TMEM43, TRDN, and TRPM4. These genes are also included in the
comprehensive cardiovascular genetics panel (CardioNext).
Both the features of these diseases and the associated genes overlap, making a
confirmatory diagnosis difficult to obtain. By utilizing a comprehensive panel that includes
relevant arrhythmia genes, the likelihood of identifying a causative and informative
genetic mutation is maximized.
genes implicated in inherited arrhythmias
brugada
syndrome
arrhythmia
long qt
syndrome
AKAP9
CAV3
KCNE1
KCNE2
KCNH2
KCNQ1
SCN4B
SNTA1
arrhythmogenic
right ventricular
dysplasia
CACNA2D1
GPD1L
HCN4
KCND3
KCNE3
KCNJ8
SCN1B
SCN3B
TRPM4
LMNA
DSC2 JUP
DSG2 PKP2
DSP TGFB3
TMEM43
RYR2
SCN5A
KCNH2
KCNQ1
ANK2
CALM1
CASQ2
TRDN
CACNA1C
CACNB2
KCNJ2
short qt
syndrome
catecholaminergic
polymorphic
ventricular
tachycardia
CardioNext
Multiple genes are implicated in inherited cardiomyopathy, inherited arrhythmias, and
other inherited cardiovascular conditions. Mutations in many of these are associated
with several types of cardiovascular conditions. Given the overlap in genetic causes
and the variability in clinical symptoms and presentation within a patient or family, a
clinician may consider one comprehensive inherited cardiovascular test to genetically
confirm a diagnosis in an efficient manner.
CardioNext includes 84 genes that have been implicated in inherited cardiomyopathy,
inherited arrhythmias, and other inherited cardiovascular conditions. This panel
includes genes involved in hypertrophic cardiomyopathy, dilated cardiomyopathy,
arrhythmogenic right ventricular dysplasia, left ventricular non-compaction, long QT
syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular
tachycardia, and short QT syndrome. This panel also includes genes that cause
cardiomyopathy, associated with inherited muscular dystrophies, as well as some
genes associated with congenital heart defects.
Clinicians may also include the TTN gene in this panel. TTN mutations account for up
to 20% of all familial DCM. However, the role of TTN in other forms of
cardiomyopathy remains unclear. TTN is a very large gene; therefore, TTN testing is
more likely than other genes to identify variants of uncertain significance (VUS),
which may or may not contribute to the cardiomyopathy in a patient.
genes included in cardionext
cardionext
GATA4 NKX2.5 TBX1
JAG1
SCN2B TBX5
KCNJ5 TAZ
TBX20
rhythmnext
AKAP9
ANK2
CACNA1C
CACNA2D1
CACNB2
CALM1
CASQ2
CAV3
GPD1L
HCN4
KCND3
KCNE1
KCNE2
KCNE3
KCNH2
KCNJ2
KCNJ8
KCNQ1
SCN1B
SCN3B
SCN4B
SNTA1
TRDN
TRPM4
DSG2
DSP
DSC2
JUP
LMNA
PKP2
RYR2
SCN2B
SCN5A
TGFB3
TMEM43
cmnext
ABCC9
ACTC1
ACTN2
ANKRD1
BAG3
CRYAB
CSRP3
DES
EMD
EYE4
FKTN
FXN
GATAD1
GLA
JPH2
LAMA4
LAMP2
LDB3/ZASP
MYBPC3
MYH6
MYH7
MYL2
MYL3
MYOZ2
MYPN
NEXN
PLN
PTPN11
RAF1
RBM20
TCAP
TMPO
TNNC1
TNNI3
TNNT2
TPM1
TTN
TTR
TNNI3
TXNRD2
VCL
Genetic Test Results Explained
A patient undergoing genetic testing will receive one of three possible results: positive,
negative, or inconclusive (i.e. variant of unknown significance or VUS).
RESULTS
EXPLANATION
Positive
• A mutation was found in one of the genes tested
• Increased risk for arrhythmia and other medical issues specific to the gene
mutation
• Screening and recommendations specific to the gene
• Testing at-risk relatives for specific mutation may be recommended
Negative
• No clinically significant genetic changes identified in any of the genes tested
• Risk for arrhythmia and other medical issues is based on personal and family
history
• Screening and recommendations based on personal and family history
• Genetic testing not indicated for family members
Inconclusive • A genetic change was identified, but current knowledge cannot predict if the
change is disease-causing or benign
• Risk for arrhythmia and other medical issues is based on personal and family
history
• Screening and recommendations based on personal and family history
• Family research studies may be indicated
Benefits of Testing
Early diagnosis of an inherited arrhythmia can direct medical management. For
example:
• Reduce or avoid physical isometric/dynamic activities such as competitive sports
• Increased cardiovascular screening such as electrocardiogram (EKG), Holter monitor,
echocardiogram, or exercise stress tests
• Medications may be recommended or avoided to help control heart rhythm
• Surgical intervention such as an implantable cardioverter defibrillator (ICD)
• Additional clinical management and prevention options specific to the gene mutation
and syndrome may be indicated
• Identifying at-risk family members with targeted genetic testing for an identified
family mutation
• Assist couples when discussing reproductive concerns
VUS Rates and Family Studies Program
Variants of unknown significance (VUS) are more common in cardiovascular panels
because they analyze multiple genes simultaneously. As information is accumulated,
updated VUS rates will be made readily available. The possibility of inconclusive
results warrants careful discussion in pre- and post-test counseling sessions. Detailed
interpretation of any VUS identified is included in the test report.
Ambry Genetics is committed to careful analysis and timely reclassification of VUS. If
a VUS is identified, complimentary testing of informative relatives may be offered
through Ambry’s family studies program. Familial tracking (segregation studies) can
assist in clarifying the nature of a VUS. When enough evidence has been accumulated
to reclassify the VUS as either disease-causing or benign, clinicians will be
automatically notified.
Ambry has invested heavily in both research and clinical collaborations to ensure the
quality and accuracy of our variant analyses and interpretations.
For more information, please visit:
www.ambrygen.com/variantclassification
Specimen Requirements
Blood: Collect 6-10cc (adult) or at least 5cc (children) in purple top EDTA tube
(preferred) or yellow top citric acetate tube. Storage: 2-8°C and do not freeze.
Shipment: Room temperature for two-day delivery.
Blood Spot: Blood spots are not accepted.
Saliva: Fill 2 tubes with saliva up to black line (1cc of saliva) in Oragene Self Collection
container. After tube is closed, 1cc of buffer will mix with saliva for a total volume of
2cc. Store at room temperature in sterile bag. Shipment: Room temperature for
two-day delivery.
DNA: 20 μg of DNA in TE (10mM Tris-Cl pH 8.0, 1mM EDTA); preferred 200 μl at
~100 ng/μl. Please provide DNA OD 260-280 ratio (preferred 1.7-1.9) and send
agarose picture with high mw genomic DNA, if available. Store at -20°C. Ship frozen
on dry ice (preferred) or ice. It is recommended if DNA has undergone multiple
freeze/thaw cycles that it not be submitted.
Cultured Cells: We accept cultured cells from fibroblasts. Prefer two T25 cell flasks
(one flask is acceptable) or suitable alternative at 80% confluence. Store at 2-8°C in
tissue culture incubator up to 72 hours. Do not freeze. Please call ahead when
sending prenatal samples.
Ambry Expertise
support
Board-certified genetic counselors, laboratory directors, and medical directors are
readily available to assist with test selection, case reviews, and result interpretation.
insurance
Ambry is contracted with the majority of commercial insurances and Medicare. All
out-of-network patients are treated as in-network to minimize out-of-pocket costs.
Insurance, Medicare, and Medicaid coverage varies. Preverification is recommended.
patient protection plan
If patient out-of-pocket financial responsibility is potentially greater than $100,
Ambry will contact the patient for verbal approval prior to initiating the test. We
remain committed to working with you and your patients to make the genetic testing
process as simple and cost-effective as possible.
about ambry genetics
Since 2001, Ambry has performed hundreds of thousands of genetic tests and
identified more than 45,000 mutations in greater than 500 different genes.
Ambry Genetics offers a full menu of diagnostic solutions and is the worldwide leader
in hereditary cancer testing. Our comprehensive menu of over 40 individual cancer
genes is the largest available in the U.S.
To order your free sample submission kits, please contact:
Ambry Genetics
15 Argonaut
Aliso Viejo, CA 92656
(866) 262-7943
[email protected]
For more details about these tests, visit ambrygen.com
References used to develop clinical content are available at ambrygen.com
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