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Arrhythmia
Genetic Testing
A Comprehensive Guide
A cardiac arrhythmia is defined as an irregular heart rhythm caused
by abnormal electrical activity. The abnormal electrical activity
can cause the heart to beat too rapidly, too slowly, or erratically,
and may interfere with the heart’s ability to efficiently pump blood
throughout the body. Many arrhythmias are harmless and resolve
quickly; however, a prolonged arrhythmia event can be serious and
even life-threatening.
The risk for arrhythmias can be influenced by a number of common
factors including heart disease, high blood pressure, stress,
caffeine, smoking, alcohol use, and certain medications. However,
in some instances, individuals are born with a genetic predisposition
to develop severe cardiac arrhythmias over their lifetime. In many
cases, these genetic predispositions to arrhythmias are caused by
a harmful change (pathogenic variant) in one of the genes encoding
the ion channel proteins that regulate the electrical activity of the
heart. Pathogenic variants in these ion channel genes, as well
as pathogenic variants in genes that encode channel-interacting
proteins, can cause inherited cardiac arrhythmias. Collectively,
these disorders are referred to as channelopathies. Genetic testing
can determine if a person carries a pathogenic variant in a gene
that has been associated with an inherited arrhythmia syndrome.
Testing may also provide valuable information about medical
management to patients and their family members.
Clinical Presentation/Course
Arrhythmias can affect individuals of all ages and ethnicities.
They may present at differing ages and with variable symptoms,
even among members of the same family. The most serious
complication of an arrhythmia is sudden death. However, more
common signs and symptoms of arrhythmias may include:
• Palpitations
• A slow or irregular heart rate
• Dizziness
• Near-syncope or syncope (fainting)
• Chest pain
GUIDE FOR INHERITED ARRHYTHMIA
1
CLINICAL INFORMATION
Inherited Arrhythmias
CLINICAL INFORMATION
Numerous inherited arrhythmia conditions have been
characterized. Although all of the conditions affect the electrical
activity of the heart resulting in an abnormal heart rhythm, each
condition is also characterized by unique features, some of which
are summarized in Table 1.
Phenotype
Description
ARVC is characterized by the replacement of normal heart cells with
Arrhythmogenic Right
Ventricular Cardiomyopathy fat or fibrotic tissue, predominantly in the right ventricle. The left
ventricle may also be affected over time.1,2
(ARVC)
Atrial Fibrillation
(AF) (Familial)
Characteristics suggestive of familial atrial fibrillation include lack
of obvious cause or risk factors (idiopathic), young age and family
history of multiple family members with AF.3,4
Brugada Syndrome (BrS)
Brugada syndrome is characterized by one of several ECG patterns
that include ST-segment elevation in the precordial leads, especially
the type I pattern with a “coved morphology”. This diagnosis may be
suspected due to a personal or family history of unexplained syncope
or a unexplained sudden cardiac arrest/death in the absence of
structural heart disease.5
Progressive Cardiac
Conduction Disease
(CCD)
Cardiac conduction disorders (CCDs) are typically associated with a
delay in electrical impulse conduction at the atrial, nodal and ventricular
levels. In an electrocardiogram (ECG), CCDs are characterized by a
prolonged P-wave duration as well as PQ interval and QRS widening
with axis deviation in the absence of structural heart disease. Not
all ECG changes may be present initially, but they can progressively
develop associated with age-dependent penetrance.6,7
Catecholaminergic
Polymorphic Ventricular
Tachycardia
(CPVT)
CPVT is characterized by polymorphic ventricular tachycardia in the
presence of adrenergic stimulation, particularly in individuals less
than 20 years of age. Diagnosis is supported by absence of structural
heart disease and induction of bidirectional VT or polymorphic VT by
exercise test or by infusion of adrenergic agonist.8
Long QT Syndrome
(LQTS)
LQTS is characterized by a prolonged QTc interval on ECG or Holter
monitor in the absence of an acquired cause of prolonged QT. A
prolonged QTc interval is defined as of >450 msec in adult males
and >470 msec in adult females, although it is important to note that
up to 25% of individuals with a confirmed diagnosis of LQTS have
a normal QTc interval. A personal and/or family history of syncope,
cardiac arrest, or sudden death in a child or young adult can also
lead to suspicion of LQTS.9-13
Short QT Syndrome
(SQTS)
The characteristic sign for SQTS is the presence of a very short
QT interval on ECG. Although a diagnostic value for a short QTc
interval has not yet been clearly defined, previous patients have
demonstrated mean QTc intervals of approximately 350 ms in males
and 365 ms in females.14-16
Table 1: Description of inherited arrhythmia conditions.
2
Diagnosis
The diagnosis of an inherited arrhythmia may be considered in an
individual and/or family for a number of different reasons, including
a combination of personal health history, family health history,
and cardiac testing. Other known causes of arrhythmia, including
systemic disease, structural cardiac conditions, medications and
electrolyte disturbances, should be ruled out before considering
genetic testing for an inherited arrhythmia syndrome. Table 2
discusses important evaluations that should be investigated by a
physician when considering the diagnosis of an inherited disorder.
Things to
Consider
History, Presence of, or Abnormal Results
Family History
Information
Syncope, seizures, young or unexplained sudden death, drownings, and
unexplained single car accidents
Physical
Examination
Rales, edema, heart murmur, or fast or irregular pulse
Non-Invasive
Testing
Chest x-ray, exercise stress test, ECG, Holter or event monitor, signal-averaged
ECG (SAECG), tilt table test or echocardiogram
Invasive Testing
Cardiac catheterization, coronary angiography, electrophysiology study (EPS) or
implanted cardiac loop recorder
Table 2: Medical history information to consider before undergoing genetic testing
for inherited arrhythmia conditions.
Information gathered from the evaluations listed in Table 2 can
provide valuable insight to determine when genetic testing for an
inherited arrhythmia may be appropriate.
GUIDE FOR INHERITED ARRHYTHMIA
3
Factors Influencing Clinical Presentation
Many of the genes associated with inherited arrhythmias have
been shown to have both reduced penetrance and variable
expressivity. In other words, patients found to have pathogenic or
likely pathogenic variants may or may not experience any cardiac
complications over their lifetime (reduced penetrance), or may
exhibit different clinical presentations (variable expressivity). This
information can help explain why different patients, even members
of the same family that carry the identical genetic variant, may
have vastly different clinical symptoms and presentations over
their lifetimes.
Factors to Consider when Ordering Genetic
Testing
There are several specific recognizable arrhythmia phenotypes and
clinical presentations, but there is overlap between the conditions.
Nearly all forms of inherited arrhythmia have been associated with
more than one gene (genetic heterogeneity), while certain genes
have also been associated with more than one specific phenotype
(phenotypic heterogeneity). This genetic and phenotypic crossover
among inherited arrhythmia conditions can make genetic testing
challenging in some individuals and families. For this reason, in
certain circumstances a more comprehensive panel could be
considered.
Characteristic ECG Findings in Select Arrhythmia Conditions
Normal
LQTS
BrS
CPVT
4
Arrhythmia
CACNA2D1
HCN4
KCNE1L^
CACNB2
Short QT
Syndrome
(SQTS)
NKX2-5
RANGRF
ABCC9
GPD1L
KCND3
CACNA1C
Brugada
Syndrome
(BrS)
KCNE3
KCNJ8
SCN10A
SCN1B^
SCN2B
SCN3B
TRPM4
KCNH2
KCNQ1
Long QT Syndrome
(LQTS)
AKAP9
ANK2
CAV3
KCNE1
KCNJ2
PKP2
SCN5A
KCNE2
KCNJ5
SCN4B
SNTA1
PLN
TGFB3
TMEM43
TTN
CALM1*
CALM2
CALM3
TRDN
Catecholaminergic
Polymorphic
Ventricular
Tachycardia
(CPVT)
DSP
JUP
LMNA
DES
DSC2
DSG2
CASQ2
RYR2
Arrhythmogenic
Right Ventricular
Cardiomyopathy
(ARVC)
* Del/Dup analysis not offered
^ Gene level resolution; may not detect exon level events
GUIDE FOR INHERITED ARRHYTHMIA
5
6
Identification of Patients at Risk for
Inherited Arrhythmias
Patients or families with one or more of the following may benefit
from genetic testing:17-19
• Arrhythmias or “Irregular heartbeat”
• Implantable cardioverter defibrillator (ICD) or pacemaker
placement at <50 years of age
• Unexplained cardiac arrest(s) or sudden death
• Sudden infant death syndrome (SIDS)
TEST INFORMATION
• Unexplained syncope and/or syncope with exercise or
emotional distress
• Unexplained seizures or seizures with a normal neurological
evaluation
• Unexplained accidents such as drowning and single car
accidents
Heart Rhythm Society (HRS) and European
Heart Rhythm Association (EHRA) Consensus
Guidelines on Genetic Testing for
Channelopathies19
Disorder
Individuals with a Clinical
Diagnosis
Asymptomatic
Relatives (Familial
Mutation Testing)
LQTS
Class I
Class I
CPVT
Class I
Class I
BrS
Class IIa
Class I
SQTS
Class IIb
Class I
ARVC
Class IIa
(For patients meeting the ARVC task
force diagnostice criteria)
Class I
Recommendation Classes
Class I: Genetic testing is recommended. Test result impacts diagnosis and/or
management recommendations.
Class IIa: Genetic testing can be useful for patients with a clinical diagnosis.
Class IIb:Genetic testing may be considered as part of the diagnostic evaluation.
Class III: Genetic testing is not recommended.
GUIDE FOR INHERITED ARRHYTHMIA
7
Arrhythmia Testing Options
Test
Genes
Offerings
Arrhythmia
Panel
ABCC9, AKAP9, ANK2, CACNA1C, CACNA2D1, CACNB2,
CALM1*, CALM2, CALM3, CASQ2, CAV3, DES, DSC2, DSG2,
DSP, GPD1L, HCN4, JUP, KCND3, KCNE1, KCNE2, KCNE3,
KCNE1L^, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNQ1, LMNA,
NKX2-5, PKP2, PLN, RANGRF, RYR2, SCN10A, SCN1B^, SCN2B,
SCN3B, SCN4B, SCN5A, SNTA1, TGFB3, TMEM43, TRDN,
TRPM4, TTN
TEST INFORMATION
Phenotype-Specific Panels
Turn Around
Time
4 weeks
4 weeks
LQTS
AKAP9, ANK2, CACNA1C, CALM1*, CALM2, CALM3, CAV3, KCNE1, KCNE2,
KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, SNTA1, TRDN
BrS
ABCC9, CACNA1C, CACNB2, GPD1L, KCND3, KCNE3, KCNJ8, PKP2, SCN10A,
SCN1B^, SCN2B, SCN3B, SCN5A, TRPM4
CPVT
CALM1*, CALM2, CALM3, CASQ2, KCNJ2, RYR2, TRDN
SQTS
CACNA1C, CACNB2, KCNH2, KCNJ2, KCNQ1
ARVC
DES, DSC2, DSG2, DSP, JUP, LMNA, PKP2, PLN, RYR2, SCN5A, TGFB3, TMEM43, TTN
Other Testing Options
Combined
Panel
4 weeks
ABCC9, ACTC 1, ACTN2, AKAP9, ALMS1, ALPK3, ANK2, ANKRD1, BAG3, BRAF, CACNA1C, CACNA2D1, CACNB2, CALM1*, CALM2, CALM3, CASQ2, CAV3, CHRM2, CRYAB, CSRP3, DES, DMD, DOLK, DSC2, DSG2, DSP, DTNA, EMD^, FHL1, FKRP*, FTKN,
GATAD1, GLA, GPD1L, HCN4, HRAS*, ILK, JPH2, JUP, KCND3, KCNE1, KCNE2, KCNE3,
KCNE1L, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNQ1,KRAS, LAMA4, LAMP2, LDB3, LMNA,
MAP2K1, MAP2K2, MIB1, MTND1*, MTND5*, MTND6*, MTTD*, MTTG*, MTTH*, MTTI*,
MTTK*, MTTL1*, MTTL2*, MTTM*, MTTQ*, MTTS1*, MTTS2*, MURC, MYBPC3, MYH6,
MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL, NEXN, NKX2.5*, NRAS, PDLIM3,
PKP2, PLN, PRDM16, PRKAG2, PTPN11, RAF1, RANGRF, RBM20, RIT1, RYR2, SCN10A,
SCN1B^, SCN2B, SCN3B, SCN4B, SCN5A, SGCD, SNTA1, SOS1, TTAZ^, TCAP, TGFB3,
TMEM43,TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRDN, TRPM4, TTN, TTR, TXNRD2, VCL
* Del/Dup analysis not offered
^ Gene level resolution; may not detect exon level events
Additional testing options are available, including targeted variant
testing for a previously identified variant(s). Appropriate test
selection depends on the specific clinical history of a patient,
including family and personal health histories as well as familial test
results. Testing for most genes includes sequencing and deletion/
duplication analysis via next-generation sequencing and array CGH
with exon level resolution, respectively.
8
Sample Submission
Genetic testing can be performed on blood, oral rinse, or extracted
DNA samples. GeneDx test kits are available to ordering providers,
and include sample collection items (such as mouthwash for oral
rinse and collection tubes), the necessary sample submission
paperwork, and a self-addressed return shipping label.
Additionally, all test requisition forms are available for download
from the GeneDx website:
www.genedx.com/forms
Please note that all testing must
be performed under the guidance
of a health care provider. For more
information on the sample submission
process, please visit our website:
www.genedx.com/supplies or email
us at: [email protected]
Cardiology Test Requisition Form
Patient Information
Sample Information
First name
Last name
Gender ❒ Male ❒ Female Date of birth (mm/dd/yy) _______________________
Ancestry ❒ Caucasian
❒ Eastern European ❒ Northern European
❒ Western European ❒ Native American ❒ Middle Eastern
❒ African American ❒ Asian
❒ Pacific Islander
❒ Caribbean
❒ Central/South American
❒ Ashkenazi-Jewish ❒ Hispanic
❒ Other: ______________
Medical record #
City
State
Zip code
Work phone
Statement of Medical Necessity
Patient's primary language if not English
This test is medically necessary for the diagnosis or detection of a disease, illness,
impairment, symptom, syndrome or disorder. The results will determine my
patient's medical management and treatment decisions. The person listed as the
Ordering Account Information
Acct #
Account Name
Reporting Preference*. ❒ Care Evolve ❒ Fax ❒ Email
that I have provided genetic testing information to the patient and they have consented
to genetic testing.
*If unmarked, we will use the account's default preferences or fax to new clients.
Physician
Date sample obtained (mm/dd/yy)
Patient has had a bone marrow transplant/transfusion
❒ Yes ❒ No
Date of last transfusion __/__/__ (must be at least 2 weeks prior to blood draw for testing)
Clinical Diagnosis: _____________________ ICD-10 Codes: ______
Age at Initial Presentation:
_______
Mailing address
Home phone
Specimen ID
❒ Blood in EDTA (5-6 mL in lavender top tube)
❒ DNA (>20 ug): Tissue source ______ concentration ___ (ug/ml) Vol ___(ul)
❒ Oral Rinse (At least 30 mL of Scope oral rinse in a 50 mL centrifuge tube)
❒ Dried Blood Spots (2 cards) - Not accepted for any testing with a del/dup component
❒ Other __________________________(Call lab)
NPI #
Medical Professional Signature (required)
Date
Patient Consent (sign here or on the consent document)
Genetic Counselor
I have read the Informed Consent document and I give permission to GeneDx to
perform genetic testing as described. I also give permission for my specimen and
Street address 1
Street address 2
City
State
Phone
testing and for publication, if appropriate. My name or other personal identifying
information will not be used in or linked to the results of any studies and publications. I also give GeneDx permission to inform me in the future about research
opportunities, including treatments for the condition in my family.
❒ Check this box if you wish to opt out of any research studies.
❒ Check this box if you do not wish to be contacted.
❒ Check this box if you are a New York state resident, and give permission for GeneDx to
retain any remaining sample longer than 60 days after the completion of testing.
Zip code
Fax (important)
Email
Beeper
Send Additional Report Copies To:
Physician or GC/Acct #
Fax#/Email/CE #
Physician or GC/Acct #
Patient/Guardian Signature
Fax#/Email/CE #
Date
Payment Options
Insurance Bill
Referral/Prior Authorization # ____________________
Insurance Carrier
Policy Name
Insurance ID #
Group #
Secondary Insurance
GeneDx Benefit Investigation #
Name of Insured
Insurance ID#
Group #
Date of Birth
Name of Insured
Please attach copy of Referral/authorization
Insurance Address
Date of Birth
City
State Zip
Relationship to Insured ❒ Child ❒ Spouse ❒ Self ❒ Other _______
Carrier Name
Relationship to Insured ❒ Child ❒ Spouse ❒ Self ❒ Other _______
Please include a copy of the front and back of the patient’s insurance card (include secondary when applicable)
If you would like to expedite the eligibility requirements for consideration of Financial Assistance, please provide number of
Household Members _______ and Annual Adjusted Gross Income ______________.
I represent that I am covered by insurance and authorize GeneDx, Inc. to give my designated insurance carrier, health plan, or third party administrator (collectively "Plan") the information on this form and other information
I will cooperate fully with GeneDx by providing all necessary documents needed for insurance billing and appeals. I understand that I am responsible for sending GeneDx any and all of the money that I receive directly from my
law. I permit a copy of this authorization to be used in place of the original.
Patient Signature (required)____________________________________________________________________________________ Date _____________________________
Institutional Bill
Patient Bill
Amount _______________
I understand that my credit card will be charged the full amount for the testing.
Please bill my credit card (all major cards accepted)
❒ Visa
❒ Discover
❒ American Express
GeneDx Account #
❒ MasterCard
Hospital/Lab Name
Name as it appears on card
Contact Name
Address
City
Phone
© GeneDx 02/16
State
Zip Code
Account Number
Expiration date
Signature
Date
CVC
For GeneDx Use Only
Fax
207 Perry Parkway, Gaithersburg, MD 20877 • T: (888) 729-1206 (Toll-Free), (301) 519-2100 • F: (201) 421-2010 • www.genedx.com
GUIDE FOR INHERITED ARRHYTHMIA
9
Page 1 of 7
10
Genetic Test Results
Nearly all test results fall into one of four categories:
1. Positive Result (pathogenic variant(s))
2. Likely Pathogenic Variant Result
3. Variant of Uncertain Significance (VUS) Result
4. Negative Result (no variants of clinical significance)
GeneDx test reports contain detailed information about a specific
genetic result and, if available, medical management options.
Genetic counseling is recommended prior to genetic testing to
understand the benefits and limitations of testing and after genetic
testing to discuss the implications of the genetic test results.
Genetic counseling services across the country can be found at
www.nsgc.org
Positive Result
A positive result indicates
a pathogenic (diseasecausing) genetic variant
(change) was identified in
a specific disease gene.
This finding confirms an
underlying genetic cause
for the patient’s symptoms
and provides a diagnosis of
a specific genetic disorder,
or indicates an increased
risk for developing a genetic
disorder. Knowledge of the specific pathogenic variant(s) provides
valuable information to the patients, their health care providers
and family members because it helps to determine the recurrence
risk and to develop an appropriate medical management plan.
A medical management plan may include lifestyle modifications,
ongoing screening, preventative medications and measures, and/
or surgical/medical device interventions. Furthermore, a positive
genetic test result allows targeted testing of at-risk relatives to
determine if any of them carry the pathogenic variant(s) as well as
to address the recurrence risk of the disorder in future offspring.
Cardiolo
Nam e:
Pati ent
Birt h:
Dat e of
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Spe cim
No:
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Sub mitt
By:
Ord ered
:
Requested
Test(s)
uated:
Genes Eval
Result:
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Interpreta
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No:
Patient Name:eDx Acc essi on
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Gen
Obt aine
Date of Birth:e Spe cim en
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Dat
Rec eive
cim en
Specimen Type:
Dat e Spe
ted:
(s) Star
Submitters ID No:
Date Test
Ordered By: e of Rep ort:
Dat
rt
Cardiology Genetics Report
GeneDx Accession No:
Date Specimen Obtained:
Pat ien
t Na
me
Da te Date
Specimen Received:
of Bir :
th:
Spe cimDate
en TypTest(s) Started:
Sub mit
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Date
of
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Or der
No :
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Card
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Genet
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Gene Dx
-
207 Perry
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GeneDx 207 Perry
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Tel (301
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GUIDE FOR INHERITED ARRHYTHMIA
3 of 6
11
port
RESULTS / MANAGEMENT
CAVbeen reported in approximately 25-35% of patients with autosomal
Q2,
KCNH2 Summary:
Pathogenic
gene
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tion/Dupl dominant longCAL
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and, CAL
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:
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Gen
Likely Pathogenic Variant Result
A likely pathogenic result indicates the presence of genetic
variant(s) in a specific gene for which there is significant, but not
conclusive, evidence that the variant(s) causes a genetic disorder,
or poses an increased risk for developing other diseases. With this
type of result, medical management options and testing of family
members are often similar to as previously described for a positive
result.
RESULTS / MANAGEMENT
Variant of Uncertain Significance (VUS) Result
A variant of uncertain significance (VUS) result indicates an
inconclusive outcome of a genetic test. A VUS is a change in a
gene for which the association with disease cannot be clearly
established. The available information for the variant is either
insufficient or conflicting, and it cannot be determined at this time
whether the variant is associated with a specific genetic disorder
or if the variant is an unrelated (benign) variant unrelated to the
patient’s disorder.
In the case of a VUS test result, all medical management
recommendations should be based on clinical symptoms, and
past personal and family history. Predictive genetic testing of
family members for a VUS is not indicated. Nevertheless, in some
circumstances, it can be useful to test other family members
through our Variant Testing Program to gain more evidence about
the variant itself and its possible association with disease. Over
time, additional clinical evidence may be collected about certain
VUS, which could ultimately lead to the reclassification of the
variant and test result.
12
Negative Result
A negative result indicates that the genetic test did not identify
reportable, medically relevant variant(s) in any of the genes tested.
Therefore, the cause for the patient’s disorder or family history
remains unknown. Although the patient’s disorder may be caused
by non-genetic factors, a negative genetic test result does not
completely rule out an underlying genetic cause. For example, the
patient’s disorder may be due to unidentified genetic changes in
gene regions or genes not included in the initial test. Depending on
the patient’s personal and family health history, additional genetic
testing may be indicated for the patient or another family member.
A genetic specialist or other health care providers can determine if
further genetic testing is appropriate.
In case of a negative genetic test result, all medical management
recommendations should be based on clinical symptoms in
addition to past personal and family history. Predictive genetic
testing of family members is not available.
When an individual tests negative for a familial pathogenic variant
that was previously identified in another affected family member,
this is considered a ‘true’ negative test result. In most cases, this
means that the individual has no greater risk for developing the
specific genetic disorder that runs in the family than anyone in the
general population.
GUIDE FOR INHERITED ARRHYTHMIA
13
Medical Management Based on Genetic
Test Results
There are a variety of screening and management strategies
available to patients with inherited arrhythmias. A specific patient’s
management plan should be personalized and based on his or her
genetic test result (type of arrhythmia and in some cases, specific
genotype), as well as their personal and family health histories. The
table below gives a general overview of some types of medical
management and surveillance options available to patients with
inherited arrhythmias, but is not meant to be all inclusive.
Recommendation
General Recommendations
Category
Lifestyle
Modification
• Depending on diagnosis, avoidance of competitive sports may be
recommended.20 Additional known arrhythmogenic triggers, such
as exercise (especially in LQT1 patients) and alarm clocks (in LQT2
patients) should be avoided.
• Affected patients should undergo follow-up as recommended by
their doctor.19-21
Screening
Medications
• At-risk family members should undergo screening, which typically
involves an ECG and Holter monitor evaluation and may also
include echocardiogram, stress testing and cardiac MRI. 21-24
• A variety of medications can be used to control symptoms and
prevent arrhythmias depending on the specific diagnosis. These
medications include: beta- blockers, calcium channel blockers,
digoxin, verapamil, diuretics and anti-arrhythmics.
• Certain medications should also be avoided, depending on
diagnosis.
• Brugada Drugs to Avoid: www.brugadadrugs.org
• Long QT Drugs to Avoid: crediblemeds.org
Procedures/Surgery
• Ablation or cardioversion may be considered.
Implanted Devices
• Published guidelines exist discussing ICD/pacemaker placement for
patients with arrhythmia.
Family Planning/
Pregnancy
• Patients should discuss family planning decisions with their doctor
prior to attempting a pregnancy. In those cases where pregnancy
is desired, a careful review of medications prior to pregnancy for
potential teratogenic effects, recurrence risk and determination of
how a patient will be followed during pregnancy is recommended.
14
Implications for Family Members
Regardless of the result, patients should share their test report
with their blood relatives, who can then discuss the results with
their health care providers. Sharing a copy of the test result with
family members and health care providers will help to determine if
additional testing is necessary and will ensure that the proper test
is ordered for relatives, if indicated.
Most of the genes associated with inherited arrhythmias are
associated with autosomal dominant inheritance, which means
that only one pathogenic variant is required to cause disease. With
positive or likely pathogenic test results in genes associated with
autosomal dominant inheritance, first-degree relatives (including
parents, siblings, and children) have a 50% chance to have the
same variant. The risk for other family members to carry the variant
depends on how closely related they are to the person with a
positive or likely pathogenic test result. However, it is important
to remember that for most of these genes, not all people who
inherit a pathogenic or likely pathogenic variant will experience
arrhythmia-related cardiac events due to reduced penetrance.
In rare instances, some types of inherited arrhythmias are
associated with autosomal recessive inheritance, such as with the
CASQ2 and TRDN genes. With autosomal recessive inheritance,
two pathogenic variants are required to cause disease, where one
pathogenic variant is almost always inherited from each parent.
The recurrence risk for two carriers of an autosomal recessive
condition to have an affected child is 25%.
KEY INFORMATION
GUIDE FOR INHERITED ARRHYTHMIA
15
Genetic Counseling
Prior to genetic testing, patients should speak with their health
care provider and/or a genetics specialist about their personal
and family health history. Health care providers should discuss
the benefits and limitations of testing, as well as possible test
results. These conversations help to determine if the patient is
an appropriate candidate for testing, facilitate the ordering of
appropriate test(s) and ensure that the patient has agreed to the
proposed genetic testing (written informed consent).
If pathogenic variant(s) have already been identified in a family
member, testing of the specific variant(s) is appropriate. If no
pathogenic variant(s) are known in a family with a specific genetic
disorder, an affected family member with the highest likelihood
of a positive test outcome (an individual manifesting associated
clinical symptoms) is ideally the best person for initial testing
within a family. In instances when an affected family member is
not available, testing of an unaffected family member may be
considered, although a negative test result will not guarantee
that the unaffected individual does not have an increased risk to
develop the clinical symptoms that are present in the family.
KEY INFORMATION
Once a patient makes the decision to undergo genetic testing,
post-test genetic counseling is recommended to understand
the implications of the results, including a discussion of the
appropriate medical management based on both the test results
and the patient’s medical and family history. Genetic counseling
services across the country can be found at www.nsgc.org
16
Insurance Coverage and Cost for Genetic
Testing
GeneDx accepts all commercial insurance plans and is a Medicare
provider. Additionally, GeneDx is a registered provider with several
Medicaid plans. If a patient does not have health insurance coverage
or cannot afford to pay the cost of testing, GeneDx offers a financial
assistance program to help ensure that all patients have access to
medically necessary genetic testing.
For more information on the paperwork that is required by some
insurance carriers, as well as additional details on patient billing and
our financial assistance program, please visit our website:
www.genedx.com/billing
Genetic Information Nondiscrimation Act
The Genetic Information Nondiscrimination Act of 2008, also
referred to as GINA, is a federal law that protects Americans from
discrimination by health insurance companies and employers
based on their genetic information. However, this law does
not cover life insurance, disability insurance, or long-term care
insurance. GINA’s employment protections do not extend to
individuals in the U.S. military, federal employees, Veterans
Health Administration and Indian Health Service. Some of these
organizations may have internal policies to address genetic
discrimination. For more information, please visit:
http://genome.gov/10002328
GUIDE FOR INHERITED ARRHYTHMIA
17
Resources for Patients
GeneReviews
ARVC:
www.ncbi.nlm.nih.gov/books/NBK1131/
Brugada: www.ncbi.nlm.nih.gov/books/NBK1517/
CPVT: www.ncbi.nlm.nih.gov/books/NBK1289/
Long QT: www.ncbi.nlm.nih.gov/books/NBK1129/
National Institutes of Health Genetics Home Reference
(NIH/GHR)
ARVC: ghr.nlm.nih.gov/condition/arrhythmogenic-rightventricular-cardiomyopathy
Brugada: ghr.nlm.nih.gov/condition/brugada-syndrome
CPVT: ghr.nlm.nih.gov/condition/catecholaminergicpolymorphic-ventricular-tachycardia
Long QT: ghr.nlm.nih.gov/condition/romano-ward-syndrome
Short QT: ghr.nlm.nih.gov/condition/short-qt-syndrome
National Heart Lung and Blood Association:
www.nhlbi.nih.gov/health/health-topics/topics/arr
Patient Support Organizations
Sudden Arrhythmia Death Syndrome (SADS) Foundation:
www.sads.org
The Canadian Sudden Arrhythmia Death Syndromes (SADS)
Foundation: www.sads.ca
Sudden Cardiac Arrest Association:
www.suddencardiacarrest.org
Ramon Brugada Senior Foundation: www.brugada.org
18
References
1. 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 Society and Federation of Cardiology. Br Heart J.
1994: 71: 215-8 (PubMed: 8142187).
2. Marcus FI et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia:
Proposed modification of the Task Force Criteria. Eur Heart J. 31:806-814, 2010 (PubMed:
20172912).
3. Lubitz SA, Yin X, Fontes JD, et al. Association between familial atrial fibrillation and risk of
new-onset atrial fibrillation. JAMA 2010;304:2263–2269.
4. Arnar DO, Thorvaldsson S, Manolio TA, et al. Familial aggregation of atrial fibrillation in
Iceland. Eur Heart J 2006;27:708 –712.
5. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome. Report of the Second
Consensus Conference. Heart Rhythm 2005;2:429–440.
6. Probst V, Kyndt F, Potet F, et al. Haploinsufficiency in combination with aging causes
SCN5A-linked hereditary Lenegre disease. J Am Coll Cardiol 2003;41:643–652.
7. Brink AJ, Torrington M. Progressive familial heart block—two types. S Afr Med J
1977;52:53–59.
8. Krahn AD, Gollob M, Yee R, Gula LJ, Skanes AC, Walker BD, Klein GJ. Diagnosis of
unexplained cardiac arrest: role of adrenaline and procainamide infusion. Circulation. 2005
Oct 11;112(15):2228-34. Epub 2005 Oct 3.
9. Vyas H, Hejlik J, Ackerman MJ. Epinephrine QT stress testing in the evaluationof congenital
long-QT syndrome: diagnostic accuracy of the paradoxical QT response. Circulation
2006;113:1385–1392
10.Takenaka K, Ai T, Shimizu W, et al. Exercise stress test amplifies genotype phenotype
correlation in the LQT1 and LQT2 forms of the long-QT syndrome. Circulation
2003;107:838–844.
11.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
–283.
12.Krahn AD, Gollob M, Yee R, et al. Diagnosis of unexplained cardiac arrest: role of adrenaline
and procainamide infusion. Circulation 2005;112:2228 –2234.
13.Viskin S, Postema PG, Bhuiyan ZA, et al. The response of the QT interval to the brief
tachycardia provoked by standing: a bedside test for diagnosing long QT syndrome. J Am
Coll Cardiol 2010;55:1955–1961.
14.Funada A, Hayashi K, Hidekazu I, et al. Assessment of QT-intervals and prevalence of Short
QT syndrome in Japan. Clin Cardiol 2008;31:270 –2749
15.Mason JW, Ramseth DJ, Chanter DO, et al. Electrocardiographic reference ranges derived
from 79,743 ambulatory subjects. J Electrocardiol 2007;40:228–234.
16.Kobza R, Roos M, Niggli B, et al. Prevalence of long and short QT in a young population of
41,767 predominantly male Swiss conscripts. Heart Rhythm 2009; 6:652– 657.
17.Wilde, A. A. M. & Behr, E. R. Genetic testing for inherited cardiac disease. Nat Rev Cardiol.
2013 Oct; 10(10): 571–83.
GUIDE FOR INHERITED ARRHYTHMIA
19
18.NSGC Cardiovasular SIG Pocket Guide “Indications for referral to cardiovascular
genetics.” http://www.nsgc.org/CardioGuide
19.HRS/EHRA expert consensus statement on the state of genetic testing for the
channelopathies and cardiomyopathies. Heart Rhythm 2011 8(8):1308-1339.
20.Maron BJ, Chaitman BR, Ackerman MJ, Bayés de Luna A, Corrado D, Crosson JE, Deal
BJ, Driscoll DJ, Estes NA 3rd, Araújo CG, Liang DH, Mitten MJ, Myerburg RJ, Pelliccia
A, Thompson PD, Towbin JA, Van Camp SP; Working Groups of the American Heart
Association Committee on Exercise, Cardiac Rehabilitation, and Prevention; Councils
on Clinical Cardiology and Cardiovascular Disease in the Young. Recommendations for
physical activity and recreational sports participation for young patients with genetic
cardiovascular diseases. Circulation. 2004 Jun 8;109(22):2807-16. Review.
21.Hershberger R, Lindenfeld J, Mestroni L, et al. Genetic evaluation of cardiomyopathy—a
Heart Failure Society of America practice guideline. J Card Fail. 2009 Mar; 15(2):83-97.
22.Oe et al. Prevalence and clinical course of the juveniles with Brugada-type ECG in
Japanese population. Pacing Clin Electrophysiol. 2005 Jun;28(6):549-54.
23.Napolitano C, Priori SG and Bloise R. Catecholaminergic polymorphic ventricular
tachycardia. GeneReviews. NCBI/NIH. Initial posting 2004, last update 2013.
24.24. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular
Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American
College of Cardiology/American Heart Association Task Force and the European
Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop
Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention
of Sudden Cardiac Death) J. Am. Coll. Cardiol 2006; 48:e247-e346.
20
Notes
GUIDE FOR INHERITED ARRHYTHMIA
21
About GeneDx
GeneDx was founded in 2000 by two scientists from the National Institutes
of Health (NIH) to address the needs of patients diagnosed with rare
disorders and the clinicians treating these conditions. Today, GeneDx has
grown into a global industry leader in genomics, having provided testing to
patients and their families in over 55 countries. Led by its world-renowned
whole exome sequencing program, and an unparalleled comprehensive
genetic testing menu, GeneDx has a continued expertise in rare and
ultra-rare disorders. Additionally, GeneDx also offers a number of other
genetic testing services, including: diagnostic testing for hereditary cancers,
cardiac, mitochondrial, and neurological disorders, prenatal diagnostics,
and targeted variant testing. At GeneDx, our technical services are backed
by our unmatched scientific expertise and our superior customer support.
Our growing staff includes more than 30 geneticists and 100 genetic
counselors specializing in clinical genetics, molecular genetics, metabolic
genetics, and cytogenetics who are just a phone call or email away to
assist you with your questions and testing needs. We invite you to visit our
website: www.genedx.com to learn more about us.
207 Perry Parkway
Gaithersburg, MD 20877
T 1 888 729 1206 (Toll-free), 1 301 519 2100 • F 1 201 421 2010
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Information current as of 11/16