Download Cardiomyopathy

Cardiomyopathy
Genetic Testing
A Comprehensive Guide
A cardiomyopathy is defined as a disease of the heart muscle, and
can be characterized by the muscle becoming enlarged (dilated),
thick (hypertrophied), or rigid. These changes to the cardiac muscle
cause the heart to work less efficiently because of a reduced
ability to pump blood and/or maintain a normal rhythm. Ultimately,
cardiomyopathies can lead to heart failure, arrhythmias, and/or
sudden death.
Cardiomyopathy can develop in patients due to a variety of
reasons, including but not limited to: long-term high-blood pressure,
coronary artery disease, uncontrolled heart rhythm, infection,
metabolic disorders, and/or nutritional deficiencies. However, in
some instances individuals are born with a genetic predisposition to
develop cardiomyopathy over their lifetime. These heritable forms
of cardiomyopathy are generally caused by pathogenic variants
in genes that code for proteins that play important roles in the
contraction of the heart. Genetic testing can help determine if an
individual carries a disease-causing variant in a gene that has been
associated with a heritable risk to develop cardiomyopathy, as well
as potentially provide valuable information to the patient and their
family about future medical management.
Clinical Presentation
Cardiomyopathy 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
complications of a cardiomyopathy are heart failure and sudden
death. However, more common signs and symptoms of
cardiomyopathies may include:
• Chest Pain
• Fatigue
• Cough
• Palpitations or arrhythmias
• Syncope
• Swelling in the ankles and feet
• Dyspnea
GUIDE FOR CARDIOMYOPATHY
1
CLINICAL INFORMATION
Heritable Cardiomyopathies
CLINICAL INFORMATION
Several different forms of cardiomyopathy conditions have been
characterized, each of which can be caused by certain genetic
factors. Although each of the conditions affect the cardiac muscle
and the heart’s ability to pump blood efficiently, each condition has
distinct features, some of which are summarized in Table 1.1-5
Phenotype
Description
Dilated
Cardiomypathy
(DCM)
DCM is characterized by the enlargement,
and often impaired contraction, of one or
both ventricles.
Hypertrophic
Cardiomyopathy
(HCM)
HCM is characterized by a thickened wall
of the left ventricle in the absence of other
systemic disease.
Restrictive
Cardiomyopathy
(RCM)
RCM is characterized by a rigid cardiac
muscle that is unable to relax and fill with
blood properly.
Arrhythmogenic
Right Ventricular
Cardiomyopathy
(ARVC)
ARVC is characterized by the replacement of
normal heart cells with fat or fibrotic tissue,
predominantly in the right ventricle. The left
ventricle may also be affected over time.
Left Ventricular
Non-Compaction
(LVNC)
LVNC is characterized by prominent and
excessive trabeculations in the left ventricle.
Table 1: Description of cardiomyopathy phenotypes.
2
Diagnosis
The diagnosis of an inherited cardiomyopathy might be considered
in an individual and/or family for a number of reasons, including a
combination of personal health history, family health history, and/or
cardiac testing. Other known causes of cardiomyopathy, including
systemic disease, structural cardiac conditions, and alcohol/drug
abuse should be ruled out before considering genetic testing
for a cardiomyopathy. Table 2 discusses important evaluations
that should be investigated by a physician when considering the
diagnosis of a heritable cardiomyopathy.
Things to
Consider
History, Presence of, or Abnormal Results
Medical
History
Co-morbid conditions, nutritional deficiencies,
and/or alcohol or drug abuse
Family
History
Information
Cardiomyopathy, enlarged heart, heart failure and/
or sudden death
Physical
Examination
Elevated jugular venous pressure, rales, gallop,
heart murmur and/or edema
Non-Invasive
ECG, echocardiogram, and/or cardiac MRI
Testing
Invasive
Testing
Blood tests, cardiac catheterization, coronary
angiography, electrophysiology study (EPS),
implanted cardiac loop recorder, and/or
endomyocardial biopsy
Table 2: Medical history information to consider before undergoing genetic testing
for a possible inherited cardiomyopathy.
Information gathered from the evaluations listed in Table 2 can
provide valuable insight to determine when genetic testing for a
cardiomyopathy would be appropriate.
GUIDE FOR CARDIOMYOPATHY
3
Factors Influencing Clinical Presentation
Many of the genes associated with heritable cardiomyopathies
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 cardiomyopathy phenotypes
and clinical presentations, but there may be overlap between the
conditions. Nearly all forms of heritable cardiomyopathies 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). Additionally, in some
cases cardiomyopathy may only be one of the many features in a
multi-systemic disorder with a complex phenotype. This genetic
and phenotypic crossover among heritable cardiomyopathies can
make genetic testing challenging in some individuals and families.
For this reason, in certain circumstances a more comprehensive
panel test could be considered.
Normal
4
DCM
HCM
Cardiomyopathy Panel
ALPK3 MURC
FKRP* MYLK2
HCN4 MYOZ2
NKX2-5
PDLIM3
Hypertrophic
Cardiomyopathy
(HCM)
CAV3
FHL1
GLA
JPH2
Arrhythmogenic Right
Ventricular Cardiomyopathy
(ARVC)
MTTG*
MYL2
MYL3
PRKAG2
ACTC1
ACTN2
CSRP3
LAMP2
MTTI*
MTTK*
MTTQ*
MYBPC3
ABCC9
ALMS1
ANKRD1
BAG3
CHRM2
CRYAB
DMD
JUP
PKP2
RYR2
PLN
MYH7
TCAP
TNNC1
TNNI3
TNNT2
TPM1
TTR
VCL
DES
DSC2
DSG2
DSP
LMNA
SCN5A
TTN
MIB1
MTND1*
MTND5*
MTND6*
MTTD*
MTTH*
MTTL1*
MTTL2*
DOLK
DTNA
EMD^
FKTN
GATAD1
ILK
LAMA4
LDB3
TGFB3
TMEM43
MTTM*
MTTS1*
MTTS2*
MYH6
MYPN
NEBL
NEXN
PRDM16
RBM20
SGCD
TAZ^
TMPO
TXNRD2
Dilated
Cardiomyopathy
(DCM)
RAF1
BRAF
HRAS*
KRAS
MAP2K1
A2ML1*
ACTB*
ACTG1*
CBL*
MAP2K2
NRAS
PTPN11
RIT1
SOS1
KAT6B*
LZTR1*
SHOC2*
SOS2*
SPRED1*
Noonan Syndrome
& RASopathies†
* Del/Dup analysis not offered
^ Gene level resolution; may not detect exon level events
† When the Noonan Syndrome and Rasopathies Panel is ordered as a stand-alone
test, deletion/duplication analysis is not included for any of the 19 genes.
GUIDE FOR CARDIOMYOPATHY
5
6
Identification of Patients at Risk for
Heritable Cardiomyopathies1-8
Patients or families with one or more of the following “red flags”
may benefit from genetic testing:
• Cardiomyopathy or enlarged heart
• ICD/Pacemaker placement at <50 years of age
• Heart failure and/or transplant
• Exercise intolerance
• Unexplained cardiac arrest(s) or sudden death
• Unexplained accidents such as downing and single car
accidents
Summary of Recent Consensus Genetic Testing
Guidelines for Cardiomyopathies7,8
Disorder
Asymptomatic
Individuals with a Clinical
Relatives (Familial
Diagnosis
Mutation Testing)
DCM
Class IIa
Class I
DCM (w/ cardiac
conduction
disease)
Class I
Class I
HCM
Class I
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 CARDIOMYOPATHY
7
TEST INFORMATION
• Unexplained syncope and/or syncope with exercise or
emotional distress
TEST INFORMATION
Cardiomyopathy Testing Options
Test
Offerings
Genes
Turn
Around
Time
Cardiomyopathy
Panel
ABCC9, ACTC1, ACTN2, ALMS1, ALPK3, ANKRD1, BAG3, BRAF,
CAV3, CHRM2, CRYAB, CSRP3, DES, DMD, DOLK, DSC2, DSG2, DSP,
DTNA, EMD^, FHL1, FKRP*, FKTN, GATAD1, GLA, HCN4, HRAS*, ILK,
JPH2, JUP, 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,RBM20, RIT1, RYR2, SCN5A, SGCD, SOS1, TAZ^,
TCAP, TGFB3, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN,
TTR, TXNRD2, VCL
4 weeks
Phenotype-Specific Panels
4 weeks
HCM
ACTC1, ACTN2, CAV3, CSRP3, FHL1, GLA, JPH2, LAMP2, MTTG*, MTTI*, MTTK*, MTTQ*,
MYBPC3, MYH7, MYL2, MYL3, PLN, PRKAG2, TCAP, TNNC1, TNNI3, TNNT2, TPM1, TTR, VCL
DCM/LVNC
ABCC9, ACTC1, ACTN2, ALMS1, ANKRD1, BAG3, CHRM2, CRYAB, CSRP3, DES, DMD,
DOLK, DSC2, DSG2, DSP, DTNA, EMD^, FKTN, GATAD1, ILK, LAMA4, LAMP2, LDB3,
LMNA, MIB1, MTND1*, MTND5*, MTND6*, MTTD*, MTTH*, MTTI*, MTTK*, MTTL1*,
MTTL2*, MTTM*, MTTQ*, MTTS1*, MTTS2*, MYH6, MYH7, MYBPC3, MYPN, NEBL, NEXN,
PLN, PRDM16, RAF1, RBM20, SCN5A, SGCD, TAZ^, TCAP, TMPO, TNNC1, TNNI3, TNNT2,
TPM1, TTN, TTR, TXNRD2, VCL
ARVC
DES, DSC2, DSG2, DSP, JUP, LMNA, PKP2, PLN, RYR2, SCN5A, TGFB3, TMEM43, TTN
Other Testing Options
Combined Panel
4 weeks
ABCC9, ACTC1, 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*, FKTN, 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, TAZ^, 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:
Cardiology Test Requisition Form
www.genedx.com/forms
Patient Information
Sample Information
First name
Last name
Gender ❒ Male ❒ Female
Date of birth (mm/dd/yyyy) ________________
Date of death (if applicable) (mm/dd/yyyy) _______________________________
Ancestry ❒ Caucasian ❒ Eastern European ❒ Central/South American
❒ Western European ❒ Native American ❒ Middle Eastern ❒ Hispanic
❒ African American ❒ Asian
❒ Pacific Islander ❒ Caribbean
❒ Ashkenazi Jewish ❒ Northern European ❒ Other: _________________
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]
Medical record #
City
State
Zip code
Home phone
Work phone
Email
Patient's primary language if not English
Date sample obtained (mm/dd/yy)
Statement of Medical Necessity
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 Physician is authorized by law to order the tests(s) requested herein. I confirm
that I have provided genetic testing information to the patient and they have consented
to genetic testing.
Ordering Account Information
Acct #
Account Name
Reporting Preference*. ❒ Care Evolve ❒ Fax ❒ Email
*If unmarked, we will use the account's default preferences or fax to new clients.
Physician
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)
Patient has had a blood transfusion ❒ Yes ❒ No Date of last transfusion __/__/__
(2-4 weeks of wait time is required for some testing) Specimens are not accepted
for patients who have had allogeneic bone marrow transplants.
Clinical Diagnosis: _________________________ ICD-10 Codes: ________
Age at Initial Presentation: __________
Mailing address
NPI #
Medical Professional Signature (required)
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
clinical information to be used in de-identified studies at GeneDx to improve genetic
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 or my health care provider in the future
about research opportunities, including treatments for the condition in my family.
❒ Check this box if you wish to opt out of being contacted for research studies.
❒ 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.
Street address 2
City
State
Zip code
Phone
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 #
Payment Options
Insurance Bill PATIENT STATUS – ONE MUST BE CHECKED ❒ Hospital Inpatient ❒ Hospital Outpatient ❒ Not a Hospital Patient
Insurance Carrier
Policy Name
Insurance ID #
Group #
Secondary Insurance
Carrier Name
Date
Patient Consent (sign here or on the consent document)
Street address 1
❒ Hold sample for Benefit Investigation (only if OOP cost is >$100)
Name of Insured
Insurance ID#
Group #
Date of Birth
Name of Insured
Date
Referral/Prior Authorization # ________________
Please attach copy of Referral/authorization
GeneDx Benefit Investigation #
Insurance Address
Date of Birth
City
State Zip
Relationship to Insured ❒ Child ❒ Spouse ❒ Self ❒ Other _______
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 an assessment of your possible eligibility for GeneDx’s financial assistance program (FAP), please provide the number of your household members _____ and the annual income of your
household $________. GeneDx may require additional information from you to complete an application for GeneDx’s financial assistance program.
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 provided
by my health care provider necessary for reimbursement. I authorize GeneDx to inform my Plan of my test result only if test results are required for preauthorization of or payment for reflex/additional testing. I authorize Plan benefits
to be payable to GeneDx. I understand that GeneDx will attempt to contact me if my out-of-pocket responsibility will be greater than $100 per test (for any reason, including co-insurance and deductible, or non-covered services). If
GeneDx is unsuccessful in its attempts to contact me, I understand that it will be my responsibility to contact GeneDx to determine my out-of-pocket cost and to pay my out-of-pocket responsibility. I will cooperate fully with GeneDx
by providing all necessary documents needed for Plan billing and appeals. I understand that I am responsible for sending GeneDx any and all of the money that I receive directly from my Plan in payment for this test. Reasonable collection
and/or attorney’s fees, including filing and service fees, shall be assessed if the account is sent to collection but said fees shall not exceed those permitted by state law. I permit a copy of this authorization to be used in place of the original.
Patient Signature (required)____________________________________________________________________________________ Date _____________________________
Institutional Bill
Patient Bill
GeneDx Account #
Please bill my credit card (all major cards accepted)
❒ MasterCard
❒ Visa
❒ Discover
❒ American Express
Amount _______________
I understand that my credit card will be charged the full amount for the testing.
Hospital/Lab Name
Name as it appears on card
Contact Name
Address
City
Phone
© GeneDx 11/16
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 CARDIOMYOPATHY
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
t
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
gy Genet
ics Repor
Cardiology Genetics Report
Card
GeneD
x
-
207 Perry
Parkway
-
Gaithersburg
, MD 20877
-
Tel (301)
519-2100
-
Fax (201)
421-2010
-
com
www.genedx.
-
2100
-
Fax (201
) 421-
2010
-
www
.gene
dx.co
m
- Page
iology
Genet
ics Re
port
3 of 7
GUIDE FOR CARDIOMYOPATHY
11
RESULTS / MANAGEMENT
Pat ien
t Na
me :
Da te
of Bir
th:Accession No:
Spe cim
GeneDx
en
Sub mit
Date Typ
Specimen
Obtained:
e:
ter
Or der Dates ID
Specimen Received:
ed By: No :
Ge neD
RAF1 Date Test(s) Started:
x Acc
Sum
Date
Da te
ess ion
mary:of Report:
Spe cim
No :
Da te
Spe cim en Ob tain
Nam e:
The MYBPC3 gene encodes cardiac myosin binding proteinPatChog
in enic
the sarcomere A-band and binds
Pati ent
ed:
en Rec
Date
syndrowhich
variant
myosin heavy chain and titin in the thick and elastic filaments,
involved
Test(s)
Birt h:
eiv ed:
me and are
s in the in muscle
Date of
Da te
Starte
lentin
Panel
have gene
et al., 2010). Pathogenic variants
MYBPC3
have
RAF1been reported
iginthe
Typ e:
of Rep
d:
ication contraction (Hershberger
es (for
M2,
been
imen
gen
Dupl
pathoge
ort :
Spec
rep
e
tion/
mer cardiomyopathy
in up F,
toCAV
40%3,ofCHR
patients with autosomal dominant familial
hypertrophic
(HCM)
and
s ID No:
nic var ly called orted less have been
g and Dele
3, BRA been reported
FKTN, 2-4% of patients with autosomal(DC
reporte
dominant
cardiomyopathy
iants dilatedLEO
Subm itter
M) (Dh familial
2K1,
y Sequencin
1, FKRP, A, in
RD1, BAG have
PARD frequently
have
d
MAP
opath
By:
FHL
in
ANK
,
and
been in MYBPC3
iomy
as man
(Cirino and Ho, 2014; Hershberger and Morales, 2013). Pathogenic
havein asso
apany variants
A, EMD(DCM)
ALPK3,
Ord ered
reporte syndrome)
LDB3, LMNK, MTTL1,
ciat
y as 17%
ensive Card
et al., (LVNC)
Noo
P2,been
ALMS1,
DSP, DTN
also
in association with left
ventricular
(Probst
et(Allans ion wit
nan syn noncompaction
2014). d in
Compreh
MTT infrequently
A4, LAM
ACTN2, DSC2, DSG2,
associat
I,reported
of pati
h Noo
3,
on
C1),
LAM
MTT
:
feat
dro
S,
MYL
and
H,
K,
ents
nan
2, et al., 2009).
al., 2011; Dellefave
ested
ion wit
me
ure
ACTC (ACT , DMD, DOL JPH2, JUP, KRA MTTG, MTT
7, MYL
h chil Roberts, 201 syndrome with Noo
,
Approx s, cardiac is a develop
Test(s) Requ
D,
ABCC9,
DES
6, MYH
dhooddefects
S, ILK,
1). Add with mu nan
, PRDM16
mental
CSRP3,
D6, MTT
MYBPC3
p.Glu542Gln
(GAA>CAA): c.1624 G>C exp
in exon ima
of the MYBPC3
PC3, MYH
onset
, and gene (NM_000256.3)
uated:
diso
CRYAB, GLA, HCN4, HRAMTND5, MTN
PKP2, PLN(E542Q)
ecte 17 tely
80%
C, MYB
dilated itionally, ltiple
dev
P, TGFB3,
,
Genes Eval
syndro d to develo of individ elopmen rder charact
S2, MUR NRAS, PDLIM3, 1, TAZ, TCA
cardiom RAF1
MTTp.E542Q:
GATAD1 MIB1, MTND1,
tal dela
me wit
uals
p
erized
yopathy
,
MTTS1,
NKX2.5, 5A, SGCD, SOS RD2, VCL
abn
h mu hypertr
y (Ta
by
h Noo times
MTTQ,
ophic wit
MAP2K2
NEXN,
variant
geneorm
has
alitpreviously
TXNE542Q pathogenicRA
F1 p.Rin the MYBPC3 sen
,The
2, SCN
nan syn in rtaglia et short stat
le lentreported
NEBL,
MTTM,
ies, ocu ltipbeen
carmultiple
diomyGarcia-Castro
ure, dys
41L
MYPN,
TTN, TTR association with HCM (Carrier
RIT1, RYR
MTTL2,
et
al.,
etneu
al.,ral2003;
Van
Driestigin
etesal.,
lar hyp
: 1997; Richardsori
opathy drome due al., 2002;
morph
is a2004;
MYOZ2,
RBM20, TNNT2, TPM1,
ion
1,
erte
dea
K2,
diso
All
ificat
(HC
to
RAF
ic faci
fne
lorism, Helms
ans
MYL
et al., 2009; Rodriguez-Garcia
et al., 2010; Marsiglia
Bos
al., 2014).
rdeet
RAF1
p.Arg4 et al., 2013; ss
Class
M)
r whi
TNNI3,
(Geetlbal., 2014;
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Page 1 (301) 519Patient Name:
Date of Birth:
No:
Acce ssion
Specimen
Type:ined :
Gen eDx
Obta
:
Spec imen ID No:
Date Submitters
Rece ived
Spec imenBy:
DateOrdered
Started:
Test(s)
Date
MYBPC3 Summary:
Repo rt:
Date of
Likely Pathogenic Variant Result
A likely pathogenic result indicates the presence of a 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.
Variant of Uncertain Significance (VUS) Result
RESULTS / MANAGEMENT
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 CARDIOMYOPATHY
13
Medical Management Based on Genetic
Test Results
There are a variety of screening and management strategies
available to patients with heritable cardiomyopathies. A specific
patient’s management plan should be personalized and based on
his or her genetic test result (type of cardiomyopathy 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 cardiomyopathies, but is not meant to be all inclusive.
Recommendation
General Recommendations
Category
Lifestyle Modification
• Patients should avoid tobacco use and maintain a normal
blood pressure and a healthy weight and diet. Moderate
physical exercise is often appropriate, however, patients
should consult their health care provider about specific
exercise recommendations.9
Screening
• Affected patients should receive follow-up care as
recommended by their doctor. At-risk family members
should consider cardiac screening, which typically involves
electrocardiogram (ECG) and echocardiogram (echo),
but may also include a cardiac MRI and/or Holter monitor
evaluation. 10,11
Medications
• A variety of medications can be used to control symptoms
and prevent progression of heart failure and irregular
heart rhythms, depending on the type of cardiomyopathy.
Patients should consult their health care provider about
specific medication recommendations.
Procedures/Surgery
• In patients with HCM, septal myectomy or alcohol septal
ablation may be recommended if symptoms or blood flow
obstruction is severe.
• If cardiomyopathy leads to advanced heart failure, a heart
transplant may be recommended.
Implanted Devices
• Guidelines exist for pacemaker/ICD implantation for
patients with cardiomyopathy.10,11 Left ventricular assist
devices may be considered in patients with end stage
heart failure and are usually reserved for those with DCM.
Family Planning/
Pregnancy
• Patients should discuss family planning decisions with
their doctor prior to attempting a pregnancy. In certain
cases, pregnancy may not be safe for women with a
cardiomyopathy and advanced heart failure. In cases of
pregnancy, affected women should be seen by providers
who are experts in the care of pregnant women with
cardiovascular disease.
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.
The majority of genes associated with heritable cardiomyopathies
follow an autosomal dominant inheritance pattern, which means
that only one pathogenic variant is required to cause disease.
Individuals with a disease-causing variant for an autosomal
dominant condition have a 50% chance of passing on that variant
and the associated risk to each child. Other first degree relatives
(parents, siblings) may also be at risk, depending upon whether
the variant arose de novo or was inherited from a parent. 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. It is important to remember that for most
of these genes, not all people who inherit a pathogenic or likely
pathogenic variant will develop cardiomyopathy.
In some cases, certain genes known to cause cardiomyopathy
have been associated with other types of inheritance, including:
autosomal recessive, X-linked, or mitochondrial. Table 3
summarizes these inheritance patterns below.
Description
Autosomal
Recessive
• Two pathogenic variants are required to cause disease, one in
each copy of the gene. Each parent is usually carrier of one of the
variants.
X-linked
• The pathogenic variant is located on the X-chromosome. Males are
more likely to express the associated condition (and features) since
they carry only one X chromosome. Females may express the
phenotype in some instances, usually in a milder form.
Mitochondrial
• The pathogenic variant is located in the mitochondrial DNA
(mtDNA) as opposed to the nuclear DNA (nDNA). Inheritance of the
pathogenic variant is passed on by mothers (but NOT fathers) to
their offspring.
Table 3: Other inheritance patterns seen with inherited cardiomyopathies.
Please refer to the GeneDx genetic test report for additional
information regarding the specific inheritance pattern for any
variants found during testing.
GUIDE FOR CARDIOMYOPATHY
15
KEY INFORMATION
Inheritance
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 CARDIOMYOPATHY
17
Resources for Patients
GeneReviews
ARVC:
www.ncbi.nlm.nih.gov/books/NBK1131
DCM:
www.ncbi.nlm.nih.gov/books/NBK1309
HCM: www.ncbi.nlm.nih.gov/books/NBK1768
National Institutes of Health Genetics Home Reference
(NIH/GHR)
ARVC: ghr.nlm.nih.gov/condition/arrhythmogenic-rightventricular-cardiomyopathy
RCM: ghr.nlm.nih.gov/condition/familial-restrictivecardiomyopathy
National Heart, Lung, and Blood Institute
www.nhlbi.nih.gov
Patient Support Organizations
Cardiomyopathy UK: the heart muscle charity:
www.cardiomyopathy.org
Johns Hopkins ARVC/D Registry:
www.hopkinsmedicine.org/heart_vascular_institute/clinical_
services/centers_excellence/arvd/patient_resources/registry.html
Hypertrophic Cardiomyopathy Association:
www.4hcm.org
Children’s Cardiomyopathy Foundation:
www.childrenscardiomyopathy.org
18
References
1. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss
AJ, Seidman CE, Young JB; Contemporary definitions and classification of the
cardiomyopathies: an American Heart Association Scientific Statement from the
Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality
of Care and Outcomes Research and Functional Genomics and Translational Biology
Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
Circulation. 2006 Apr 11;113(14):1807-16. Epub 2006 Mar 27.
2. McNally E, MacLeod H, and Dellefave L. Arrhythmogenic right ventricular dysplasia/
cardiomypathy, autosomal dominant. In: Pagon RA, Bird TD, Dolan CR, Stephens
K, Adam MP, editors. SourceGeneReviews ™ [Internet]. Seattle (WA): University of
Washington, Seattle; 1993-. 2005 Apr 18 [updated 2014 Jan 9].
3. Thiene G, Corrado D, Basso C. Arrhythmogenic right ventricular cardiomyopathy/
dysplasia. Orphanet J Rare Dis. 2007 Nov 14; 2:45.
4. Hershberger RE, Kushner JD, Parks SB. Dilated cardiomyopathy overview. In:
Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. SourceGeneReviews
™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. 2007 Jul 27
[updated 2015 Sept 24].
5. Marian AJ, Roberts R. Molecular genetics of hypertrophic cardiomyopathy. Annu Rev
Med. 1995; 46:213-22..
6. NSGC Cardiovasular SIG Pocket Guide “Indications for Referral to cardiovascular
genetics.” http:// www.nsgc.org/CardioGuide..
7. HRS/EHRA expert consensus statement on the state of genetic testing for the
channelopathies and cardiomyopathies. Heart Rhythm 2011 8(8):1308-1339.
8. Eliott et al. 2014 ESC Guidelins on diagnosis and management of hypertrophic
cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic
Cardiomyopathy of the European Sociaety of Cardiology (ESC). Eur HeartJ. 2014 Oct
14;35(39):2733-79.
9. 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):280716. Review
10.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.
11.American College of Cardiology Foundation Task Force on Expert Consensus
Documents, Hundley WG, Bluemke DA, Finn JP, Flamm SD, Fogel MA, Friedrich MG,
Ho VB, Jerosch-Herold M, Kramer CM, Manning WJ, Patel M, Pohost GM, Stillman
AE, White RD, Woodard PK. ACCF/ACR/AHA/NASCI/SCMR 2010 expert consensus
document on cardiovascular magnetic resonance: a report of the American College
of Cardiology Foundation Task Force on Expert Consensus Documents. J Am Coll
Cardiol. 2010 Jun 8;55(23):2614-62. doi: 10.1016/j.jacc.2009.11.011.
GUIDE FOR CARDIOMYOPATHY
19
Notes
20
Notes
GUIDE FOR CARDIOMYOPATHY
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
E [email protected] • www.genedx.com
© 2016 GeneDx. All rights reserved. 40235 V1 11/16
Information current as of 11/16