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MEDICAL POLICY 12.04.114
Genetic Testing for Dilated Cardiomyopathy
BCBSA Ref. Policy: 2.04.114
Effective Date: May 1, 2018
Last Revised: April 3, 2018
Replaces: 2.04.114
RELATED MEDICAL POLICIES:
12.04.28 Genetic Testing for Predisposition to Inherited Hypertrophic
Cardiomyopathy
12.04.43 Genetic Testing for Cardiac Ion Channelopathies
Select a hyperlink below to be directed to that section.
POLICY CRITERIA | CODING | RELATED INFORMATION
EVIDENCE REVIEW | REFERENCES | HISTORY
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Introduction
Dilated cardiomyopathy is a condition in which the left ventricle (the main pumping chamber of
the heart) becomes enlarged and can no longer pump effectively. This can lead to heart failure,
as well as cause an abnormal rhythm of the heart. It has been found that sometimes dilated
cardiomyopathy seems to run in families, and in these cases it may be caused by a genetic
problem. Doing genetic tests to see if a genetic problem has caused a persons dilated
cardiomyopathy is still investigational. Testing people who do not have any known heart
problems to see if they are at risk for developing dilated cardiomyopathy is also investigational.
Medical studies have not shown that this type of testing helps to manage the care of patients.
For this reason, genetic testing for dilated cardiomyopathy is still considered to be unproven
(investigational).
Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The
rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for
providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can
be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a
service may be covered.
Policy Coverage Criteria
https://www.lifewisewa.com/medicalpolicies/12.04.28.pdfhttps://www.lifewisewa.com/medicalpolicies/12.04.28.pdfhttps://www.lifewisewa.com/medicalpolicies/12.04.43.pdf
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Testing Investigational Genetic testing for dilated
cardiomyopathy
Genetic testing for dilated cardiomyopathy is considered
investigational in all situations.
Coding
There are several listings of genetic tests performed for dilated cardiomyopathy in the CPT Tier 2
molecular pathology codes listed below.
Code Description
CPT 81403 Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence
analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent
reactions, mutation scanning or duplication/deletion variants of 2-5 exons)
Includes: PLN (phospholamban) (eg, dilated cardiomyopathy, hypertrophic
cardiomyopathy), full gene sequence
81405 Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence
analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or
characterization of a dynamic mutation disorder/triplet repeat by Southern blot
analysis)
Includes: ANKRD1 (ankyrin repeat domain 1) (eg, dilated cardiomyopathy), full gene
sequence; TPM1 (tropomyosin 1 [alpha]) (eg, familial hypertrophic cardiomyopathy),
full gene sequence; TNNC1 (troponin C type 1 [slow]) (eg, hypertrophic
cardiomyopathy or dilated cardiomyopathy), full gene sequence
81406 Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence
analysis, mutation scanning or duplication/deletion variants of 26-50 exons,
cytogenomic array analysis for neoplasia)
Includes: LDB3 (LIM domain binding 3) (eg, familial dilated cardiomyopathy,
myofibrillar myopathy), full gene sequence; LMNA (lamin A/C) (eg, Emery-Dreifuss
muscular dystrophy; [EDMD1, 2 and 3] limb-girdle muscular dystrophy; [LGMD] type
1B, dilated cardiomyopathy; [CMD1A], familial partial lipodystrophy; [FPLD2]), full gene
sequence; TNNT2 (troponin T, type 2 [cardiac]) (eg, familial hypertrophic
cardiomyopathy), full gene sequence
81407 Molecular pathology procedure, Level 8 (eg, analysis of 26-50 exons by DNA sequence
analysis, mutation scanning or duplication/deletion variants of >50 exons, sequence
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Code Description
analysis of multiple genes on one platform)
Includes: MYH6 (myosin, heavy chain 6, cardiac muscle, alpha) (eg, familial dilated
cardiomyopathy), full gene sequence; MYH7 (myosin, heavy chain 7, cardiac muscle,
beta) (eg, familial hypertrophic cardiomyopathy, Liang distal myopathy), full gene
sequence; SCN5A (sodium channel, voltage-gated, type V, alpha subunit) (eg, familial
dilated cardiomyopathy), full gene sequence
81439 Inherited cardiomyopathy (eg, hypertrophic cardiomyopathy, dilated cardiomyopathy,
arrhythmogenic right ventricular cardiomyopathy) genomic sequence analysis panel,
must include sequencing of at least 5 genes, including DSG2, MYBPC3, MYH7, PKP2,
and TTN
Note: CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). HCPCS
codes, descriptions and materials are copyrighted by Centers for Medicare Services (CMS).
If a genetic sequencing panel (GSP) is performed that does not meet the criteria in code 81439,
the relevant tier 2 codes above would be reported for the specific genes tested, and the unlisted
molecular pathology code would be reported 1 time for the remaining genes in the panel that
lack a specific CPT.
Related Information
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants
found in DNA and serves as an international standard in DNA diagnostics (see Table 1). The
Societys nomenclature is recommended by the Human Variome Project, the Human Genome
Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular
Pathology standards and guidelines for interpretation of sequence variants represent expert
opinion from both organizations, in addition to the College of American Pathologists. These
recommendations primarily apply to genetic tests used in clinical laboratories, including
genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended
standard terminologypathogenic, likely pathogenic, uncertain significance, likely
benign, and benignto describe variants identified that cause Mendelian disorders.
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Table 1. Nomenclature to Report on Variants Found in DNA
Previous Updated Definition
Mutation Disease-associated variant Disease-associated change in the DNA sequence
Variant Change in the DNA sequence
Familial variant Disease-associated variant identified in a proband for use in subsequent
targeted genetic testing in first-degree relatives
Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology
Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited
disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and
understanding risk factors can be difficult for some patients; genetic counseling helps
individuals understand the impact of genetic testing, including the possible effects the test
results could have on the individual or their family members. It should be noted that genetic
counseling may alter the utilization of genetic testing substantially and may reduce
inappropriate testing; further, genetic counseling should be performed by an individual with
experience and expertise in genetic medicine and genetic testing methods.
Evidence Review
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Description
Dilated cardiomyopathy (DCM) is characterized by progressive left ventricular enlargement and
systolic dysfunction, leading to clinical manifestations of heart failure. There are a variety of
causes of DCM, including genetic and nongenetic conditions. Genetic forms of DCM are
heterogeneous in their molecular basis and clinical expression. Genetic testing for DCM has
potential utility in confirming a diagnosis of genetic DCM, and as a prognostic test in family
members when familial DCM is present.
Background
Dilated Cardiomyopathy
Dilated cardiomyopathy (DCM) is defined as the presence of left ventricular enlargement and
dilatation in conjunction with significant systolic dysfunction. DCM has an estimated prevalence
of 1 in 2700 in the United States.1 The age of onset for DCM is variable, ranging from infancy to
the eighth decade, with most individuals developing symptoms in the fourth through sixth
decades.2
Diagnosis
Primary clinical manifestations of DCM are heart failure and arrhythmias. Symptoms of heart
failure, such as dyspnea on exertion and peripheral edema, are the most common presentation
of DCM. These symptoms are generally gradual in onset and slowly progressive over time.
Progressive myocardial dysfunction also may lead to electrical instability and arrhythmias.
Symptoms of arrhythmias may include light-headedness, syncope, or sudden cardiac arrest.
Many underlying conditions can cause DCM, including3:
Ischemic coronary artery disease
Toxins
Metabolic conditions
Endocrine disorders
Inflammatory and infectious diseases
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Infiltrative disorders
Tachycardia-mediated cardiomyopathy
Therefore, when a patient presents with DCM, a workup is performed to identify underlying
causes, especially those treatable. The standard workup consists of clinical exam, blood pressure
monitoring, electrocardiography, echocardiography, and workup for coronary artery disease as
warranted by risk factors. Extensive workup including cardiac magnetic resonance imaging,
exercise testing, right-sided catheterization with biopsy, and 24-hour ECG monitoring will
uncover only a small number of additional etiologies for DCM.4 Approximately 35% to 40% of
DCM cases are thus determined to be idiopathic after a negative workup for secondary causes.3
This has traditionally been termed idiopathic dilated cardiomyopathy (IDC).
Clustering of IDC within families has been reported, leading to the conclusion that at least some
cases of DCM have a genetic basis. Familial DCM is diagnosed when 2 closely related family
members have IDC in the absence of underlying causes. Penetrance of familial DCM is variable
and age-dependent, often leading to lack of appreciation of the familial component.
Treatment
Treatment of DCM is similar to that for other causes of heart failure. This includes medications to
reduce fluid overload and relieve strain on the heart, and lifestyle modifications such as salt
restriction. Patients with clinically significant arrhythmias also may be treated with
antiarrhythmic medications, pacemaker implantation, and/or an automatic implantable cardiac
defibrillator. Automatic implantable cardiac defibrillator placement for primary prevention also
may be performed if criteria for low ejection fraction and/or other clinical symptoms are present.
End-stage DCM can be treated with cardiac transplantation.
Genetic DCM
Genetic DCM has been proposed as a newer classification that includes both familial DCM and
some cases of sporadic IDC. The percentage of patients with sporadic DCM that has a genetic
basis is not well characterized. Most disease-associated variants are inherited in an autosomal
dominant fashion, but some autosomal recessive, X-linked, and mitochondrial patterns of
inheritance also are present.5
In general, genotype-phenotype correlations are either not present or not well-characterized.
There have been some purported correlations between certain disease-associated variants and
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the presence of arrhythmias. For example, patients with conduction system disease and/or a
family history of sudden cardiac death may be more likely to have disease-associated variants in
the LMNA, SCN5A, and DES genes.1 Kayvanpour et al (2017) performed a meta-analysis of
genotype-phenotype associations in DCM.6 The analysis included 48 studies (total N=8097
patients) and found a higher prevalence of sudden cardiac death, cardiac transplantation, and
ventricular arrhythmias in LMNA and PLN disease-associated variant carriers and increasing
penetrance with age of DCM phenotype in subjects with TTN-truncating variants.
There may be interactions between genetic and environmental factors that lead to the clinical
manifestations of DCM. A genetic variant may not in itself be sufficient to cause DCM, but may
predispose to developing DCM in the presence of environmental factors such as nutritional
deficiencies or viral infections.2 It also has been suggested that DCM genetics may be more
complex than simply single-gene variants, with low-penetrance variants that are common in the
population contributing to a cumulative risk of DCM that includes both genetic and
environmental factors.
Genetic Testing for DCM
Approximately 30% to 40% of patients referred for genetic testing will have a disease-associated
variant identified.5 Disease-associated variants linked to DCM have been identified in more than
40 genes of various types and locations. The most common genes involved are those that code
for titin (TTN), myosin heavy chain (MYH7), troponin T (TNNT2), and alpha-tropomyosin (TPM1).
These 4 genes account for approximately 30% of disease-associated variants identified in
cohorts of patients with DCM.5 A high proportion of the identified disease-associated variants
are rare, or novel, variants, thus creating challenges in assigning the pathogenicity of discovered
variants.2 Some individuals with DCM will have more than 1 DCM-associated variant.1 The
frequency of multiple disease-associated variants is uncertain, as is the clinical significance.
Summary of Evidence
For individuals who have signs and/or symptoms of dilated cardiomyopathy (DCM) who receive
comprehensive genetic testing, the evidence includes case series reporting clinical validity.
Relevant outcomes are overall survival, test accuracy and validity, symptoms, change in disease
status, functional outcomes, quality of life, and treatment-related morbidity. There is a large
degree of uncertainty with clinical validity. The percentage of patients with idiopathic DCM who
have a genetic variant (clinical sensitivity) is relatively low, in the range of 10% to 50%. Clinical
specificity of DCM-associated variants is unknown, but DCM-associated variants in the same
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genes have been reported in 1% to 3% of patients without DCM. Because of the suboptimal
clinical validity, the accuracy of assigning variants as disease-associated or benign may also be
suboptimal. The clinical usefulness of genetic testing for diagnosing DCM has not been
demonstrated. For a patient who is diagnosed with idiopathic DCM, the presence of a DCM-
associated variant will not change treatment or prognosis. The evidence is insufficient to
determine the effect of the technology on health outcomes.
For individuals who are asymptomatic with a first-degree relative who has DCM and a known
familial variant who receive targeted genetic testing for a known familial variant, the evidence
includes case series reporting test accuracy and clinical value. Relevant outcomes are test
accuracy and validity, symptoms, morbid events, functional outcomes, quality of life, and
treatment-related morbidity. For an individual at risk due to genetic DCM in the family, genetic
testing can identify whether a familial variant has been inherited. However, it is uncertain how
knowledge of a familial variant improves outcomes for an asymptomatic individual. The
uncertain clinical validity of predictive testing makes it unclear whether actions taken as a result
of testing will improve outcomes. Early treatment based on a genetic diagnosis is unproven. The
evidence is insufficient to determine the effect of the technology on health outcomes.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this policy are listed below.
Table 3. Summary of Key Trials
NCT No. Trial Name Planned
Enrollment
Completion
Date
Ongoing
NCT02148926 Clinical and Genetic Examinations of Dilated
Cardiomyopathy
480 Sep 2017
(ongoing)
NCT01736566 The MedSeq Project Pilot Study: Integrating Whole Genome
Sequencing Into the Practice of Clinical Medicine
220 Aug 2017
(ongoing)
NCT01857856 PHOspholamban RElated CArdiomyopathy STudy -
Intervention (Efficacy Study of Eplerenone in
Presymptomatic PLN-R14del Carriers)
150 Apr 2020
Unpublished
NCT02057341a A Study of ARRY-371797 in Patients With LMNA-Related 12 May 2016
https://www.clinicaltrials.gov/ct2/show/NCT02148926?term=NCT02148926&rank=1https://www.clinicaltrials.gov/ct2/show/NCT01736566?term=NCT01736566&rank=1https://www.clinicaltrials.gov/ct2/show/NCT01857856?term=NCT01857856&rank=1https://www.clinicaltrials.gov/ct2/show/NCT02057341?term=NCT02057341&rank=1
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NCT No. Trial Name Planned
Enrollment
Completion
Date
Dilated Cardiomyopathy (completed)
NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial.
Practice Guidelines and Position Statements
British Society of Echocardiography
Guidelines from the British Society of Echocardiography (2017) have presented diagnostic
criteria for assessing dilated cardiomyopathy (DCM) with echocardiography, recommending that
caregivers regularly administer echocardiograms to individuals with potential genetic risk,
particularly those related to an individual with idiopathic DCM.53 The guidelines did not address
the use of genetic testing in cases of DCM.
Cardiac Society of Australia and New Zealand
The Cardiac Society of Australia and New Zealand published a 2017 position statement on the
appropriate assessment of and treatment for familial DCM.54 The statement addressed the
growing number of potentially pathogenic novel variants, recommending that any genetic tests
be evaluated by experts in molecular cardiology to prevent unnecessary or inaccurate reporting
to family members should the variant in question not be disease-causing. The authors
recommended genetic testing for individuals related to patients with familial DCM, especially
relatives of young patients. In general, individuals with increased risk of familial DCM (eg,
women of child-bearing age, families with a history of conduction system disease) should be
counseled on lifestyle modification and followed at regular intervals.
Heart Rhythm Society and European Hearth Rhythm Association
The Heart Rhythm Society and European Hearth Rhythm Association issued joint guidelines
(2011) on genetic testing for cardiac channelopathies and cardiomyopathies.55 These guidelines
contained the following recommendations on genetic testing for DCM:
Class I recommendations
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Comprehensive or targeted (LMNA and SCN5A) DCM genetic testing is recommended for
patients with DCM and significant cardiac conduction disease (ie, first-, second-, or third-
degree heart block) and/or with a family history of premature unexpected sudden death.
Mutation-specific testing is recommended for family members and appropriate relatives
following the identification of a DCM-causative mutation [variant] in the index case.
Class IIa recommendations
Genetic testing can be useful for patients with familial DCM to confirm the diagnosis, to
recognize those who are at highest risk of arrhythmia and syndromic features, to facilitate
cascade screening within the family, and to help with family planning.
The Heart Rhythm Society and European Heart Rhythm Association (2011) consensus statement
also noted that prophylactic implantable cardioverter defibrillator can be considered in patients
with known arrhythmia and/or conduction system disease (LMNA or Desmin [DES]).55
Heart Failure Society of America
The Heart Failure Society of America published practice guidelines (2009) on the genetic
evaluation of cardiomyopathy.52 The following recommendations for genetic testing for
cardiomyopathy (including DCM) were made:
Evaluation, genetic counseling, and genetic testing of cardiomyopathy patients are complex
processes. Referral to centers expert in genetic evaluation and family-based management
should be considered (Level of Evidence B).
Genetic testing should be considered for the one most clearly affected person in a family to
facilitate screening and management.
Genetic and family counseling is recommended for all patients and families with
cardiomyopathy (Level of Evidence A).
U.S. Preventive Services Task Force Recommendations
No U.S. Preventive Services Task Force recommendations for cardiomyopathy have been
identified.
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Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage
decisions are left to the discretion of local Medicare carriers.
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory
service; laboratory-developed tests must meet the general regulatory standards of the Clinical
Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must
be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing.
To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review
of this test.
References
1. Hersheberger RE, Morales A. Dilated Cardiomyopathy Overview. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews.
Seattle, WA: University of Washington; 2015.
2. Piran S, Liu P, Morales A, et al. Where genome meets phenome: rationale for integrating genetic and protein biomarkers in the
diagnosis and management of dilated cardiomyopathy and heart failure. J Am Coll Cardiol. Jul 24 2012;60(4):283-289. PMID
22813604
3. Hershberger RE, Morales A, Siegfried JD. Clinical and genetic issues in dilated cardiomyopathy: a review for genetics
professionals. Genet Med. Nov 2010;12(11):655-667. PMID 20864896
4. Broch K, Andreassen AK, Hopp E, et al. Results of comprehensive diagnostic work-up in 'idiopathic' dilated cardiomyopathy.
Open Heart. oct 2015;2(1):e000271. PMID 26468400
5. Lakdawala NK, Winterfield JR, Funke BH. Dilated cardiomyopathy. Circ Arrhythm Electrophysiol. Feb 2013;6(1):228-237. PMID
23022708
6. Kayvanpour E, Sedaghat-Hamedani F, Amr A, et al. Genotype-phenotype associations in dilated cardiomyopathy: meta-analysis
on more than 8000 individuals. Clin Res Cardiol. Feb 2017;106(2):127-139. PMID 27576561
7. National Center for Biotechnology Infomation. GTR: Genetic Testing Registry. n.d.; https://www.ncbi.nlm.nih.gov/gtr/.
Accessed April 2018.
8. National Center for Biotechnology Information. Genetic Testing Registry. https://www.ncbi.nlm.nih.gov/gtr/. Accessed April
2018.
9. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.
N Engl J Med. May 20 2004;350(21):2151-2158. PMID 15152060
10. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J
Med. Jan 20 2005;352(3):225-237. PMID 15659722
https://www.ncbi.nlm.nih.gov/gtr/https://www.ncbi.nlm.nih.gov/gtr/
Page | 12 of 15
11. Brodsky GL, Muntoni F, Miocic S, et al. Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal
muscle involvement. Circulation. Feb 8 2000;101(5):473-476. PMID 10662742
12. MacLeod HM, Culley MR, Huber JM, et al. Lamin A/C truncation in dilated cardiomyopathy with conduction disease. BMC Med
Genet. Jul 10 2003;4:4. PMID 12854972
13. Olson TM, Michels VV, Thibodeau SN, et al. Actin mutations in dilated cardiomyopathy, a heritable form of heart failure.
Science. May 1 1998;280(5364):750-752. PMID 9563954
14. Sylvius N, Duboscq-Bidot L, Bouchier C, et al. Mutational analysis of the beta- and delta-sarcoglycan genes in a large number of
patients with familial and sporadic dilated cardiomyopathy. Am J Med Genet A. Jul 1 2003;120A(1):8-12. PMID 12794684
15. Taylor MR, Slavov D, Ku L, et al. Prevalence of desmin mutations in dilated cardiomyopathy. Circulation. Mar 13
2007;115(10):1244-1251. PMID 17325244
16. Villard E, Duboscq-Bidot L, Charron P, et al. Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin
heavy chain gene. Eur Heart J. Apr 2005;26(8):794-803. PMID 15769782
17. Dhandapany PS, Razzaque MA, Muthusami U, et al. RAF1 mutations in childhood-onset dilated cardiomyopathy. Nat Genet. Jun
2014;46(6):635-639. PMID 24777450
18. McNair WP, Sinagra G, Taylor MR, et al. SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly
localize to the voltage-sensing mechanism. J Am Coll Cardiol. May 24 2011;57(21):2160-2168. PMID 21596231
19. van Rijsingen IA, Nannenberg EA, Arbustini E, et al. Gender-specific differences in major cardiac events and mortality in lamin
A/C mutation carriers. Eur J Heart Fail. Apr 2013;15(4):376-384. PMID 23183350
20. Herman DS, Lam L, Taylor MR, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. Feb 16 2012;366(7):619-
628. PMID 22335739
21. Norton N, Li D, Rieder MJ, et al. Genome-wide studies of copy number variation and exome sequencing identify rare variants in
BAG3 as a cause of dilated cardiomyopathy. Am J Hum Genet. Mar 11 2011;88(3):273-282. PMID 21353195
22. 22. Theis JL, Sharpe KM, Matsumoto ME, et al. Homozygosity mapping and exome sequencing reveal GATAD1 mutation in
autosomal recessive dilated cardiomyopathy. Circ Cardiovasc Genet. Dec 2011;4(6):585-594. PMID 21965549
23. Haas J, Frese KS, Peil B, et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J. May 7
2015;36(18):1123-1135a. PMID 25163546
24. Dalin MG, Engstrom PG, Ivarsson EG, et al. Massive parallel sequencing questions the pathogenic role of missense variants in
dilated cardiomyopathy. Int J Cardiol. Feb 01 2017;228:742-748. PMID 27886618
25. Pugh TJ, Kelly MA, Gowrisankar S, et al. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical
DNA sequencing. Genet Med. Aug 2014;16(8):601-608. PMID 24503780
26. University of Bologna. ws-SNPs&GO. n.d.; http://snps.biofold.org/snps-and-go//index.html. Accessed April 2018.
27. National Center for Biotechnology Infomation. dbSNP: short genetic variations, build 137. n.d.;
http://www.ncbi.nlm.nih.gov/projects/SNP/snp_summary.cgi?view+summary=view+summary&build_id=137. Accessed
April 2018.
28. Hirtle-Lewis M, Desbiens K, Ruel I, et al. The genetics of dilated cardiomyopathy: a prioritized candidate gene study of LMNA,
TNNT2, TCAP, and PLN. Clin Cardiol. Oct 2013;36(10):628-633. PMID 24037902
29. van der Linde IHM, Hiemstra YL, Bokenkamp R, et al. A Dutch MYH7 founder mutation, p.(Asn1918Lys), is associated with early
onset cardiomyopathy and congenital heart defects. Neth Heart J. Dec 2017;25(12):675-681. PMID 28864942
30. Hershberger RE, Parks SB, Kushner JD, et al. Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and
TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy. Clin Transl Sci. May 2008;1(1):21-26. PMID 19412328
31. Millat G, Bouvagnet P, Chevalier P, et al. Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated
cardiomyopathy. Eur J Med Genet. Nov-Dec 2011;54(6):e570-575. PMID 21846512
http://snps.biofold.org/snps-and-go/index.htmlhttp://www.ncbi.nlm.nih.gov/projects/SNP/snp_summary.cgi?view+summary=view+summary&build_id=137
Page | 13 of 15
32. Lakdawala NK, Funke BH, Baxter S, et al. Genetic testing for dilated cardiomyopathy in clinical practice. J Card Fail. Apr
2012;18(4):296-303. PMID 22464770
33. Hasselberg NE, Haland TF, Saberniak J, et al. Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for
heart transplantation. Eur Heart J. Oct 31 2017. PMID 29095976
34. Priganc M, Zigova M, Boronova I, et al. Analysis of SCN5A gene variants in East Slovak patients with cardiomyopathy. J Clin Lab
Anal. Mar 2017;31(2). PMID 27554632
35. van Rijsingen IA, van der Zwaag PA, Groeneweg JA, et al. Outcome in phospholamban R14del carriers: results of a large
multicentre cohort study. Circ Cardiovasc Genet. Aug 2014;7(4):455-465. PMID 24909667
36. Hasselberg NE, Edvardsen T, Petri H, et al. Risk prediction of ventricular arrhythmias and myocardial function in Lamin A/C
mutation positive subjects. Europace. Apr 2014;16(4):563-571. PMID 24058181
37. Posafalvi A, Herkert JC, Sinke RJ, et al. Clinical utility gene card for: dilated cardiomyopathy (CMD). Eur J Hum Genet. Oct
2013;21(10). PMID 23249954
38. 3Reddy S, Fung A, Manlhiot C, et al. Adrenergic receptor genotype influences heart failure severity and beta-blocker response
in children with dilated cardiomyopathy. Pediatr Res. Feb 2015;77(2):363-369. PMID 25406899
39. Wasielewski M, van Spaendonck-Zwarts KY, Westerink ND, et al. Potential genetic predisposition for anthracycline-associated
cardiomyopathy in families with dilated cardiomyopathy. Open Heart. Oct 2014;1(1):e000116. PMID 25332820
40. Michels VV, Moll PP, Miller FA, et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic
dilated cardiomyopathy. N Engl J Med. Jan 09 1992;326(2):77-82. PMID 1727235
41. Grunig E, Tasman JA, Kucherer H, et al. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol. Jan
1998;31(1):186-194. PMID 9426039
42. Baig MK, Goldman JH, Caforio AL, et al. Familial dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic
relatives and may represent early disease. J Am Coll Cardiol. Jan 1998;31(1):195-201. PMID 9426040
43. Mahon NG, Murphy RT, MacRae CA, et al. Echocardiographic evaluation in asymptomatic relatives of patients with dilated
cardiomyopathy reveals preclinical disease. Ann Intern Med. Jul 19 2005;143(2):108-115. PMID 16027452
44. Brodt C, Siegfried JD, Hofmeyer M, et al. Temporal relationship of conduction system disease and ventricular dysfunction in
LMNA cardiomyopathy. J Card Fail. Apr 2013;19(4):233-239. PMID 23582089
45. Fernlund E, Osterberg AW, Kuchinskaya E, et al. Novel genetic variants in BAG3 and TNNT2 in a Swedish family with a history of
dilated cardiomyopathy and sudden cardiac death. Pediatr Cardiol. Aug 2017;38(6):1262-1268. PMID 28669108
46. Asadi M, Foo R, Salehi AR, et al. Mutation in delta-Sg gene in familial dilated cardiomyopathy. Adv Biomed Res. 2017;6:32. PMID
28401079
47. Bodian DL, Vilboux T, Hourigan SK, et al. Genomic analysis of an infant with intractable diarrhea and dilated cardiomyopathy.
Cold Spring Harb Mol Case Stud. Nov 2017;3(6). PMID 28701297
48. Yuan HX, Yan K, Hou DY, et al. Whole exome sequencing identifies a KCNJ12 mutation as a cause of familial dilated
cardiomyopathy. Medicine (Baltimore). Aug 2017;96(33):e7727. PMID 28816949
49. Petropoulou E, Soltani M, Firoozabadi AD, et al. Digenic inheritance of mutations in the cardiac troponin (TNNT2) and cardiac
beta myosin heavy chain (MYH7) as the cause of severe dilated cardiomyopathy. Eur J Med Genet. Sep 2017;60(9):485-488.
PMID 28642161
50. Rafiq MA, Chaudhry A, Care M, et al. Whole exome sequencing identified 1 base pair novel deletion in BCL2-associated
athanogene 3 (BAG3) gene associated with severe dilated cardiomyopathy (DCM) requiring heart transplant in multiple family
members. Am J Med Genet A. Mar 2017;173(3):699-705. PMID 28211974
51. Liu JS, Fan LL, Zhang H, et al. Whole-exome sequencing identifies two novel TTN mutations in Chinese families with dilated
cardiomyopathy. Cardiology. 2017;136(1):10-14. PMID 27544385
Page | 14 of 15
52. Hershberger RE, Lindenfeld J, Mestroni L, et al. Genetic evaluation of cardiomyopathy--a Heart Failure Society of America
practice guideline. J Card Fail. Mar 2009;15(2):83-97. PMID 19254666
53. Mathew T, Williams L, Navaratnam G, et al. Diagnosis and assessment of dilated cardiomyopathy: a guideline protocol from the
British Society of Echocardiography. Echo Res Pract. Jun 2017;4(2):G1-G13. PMID 28592613
54. Fatkin D, Johnson R, McGaughran J, et al. Position statement on the diagnosis and management of familial dilated
cardiomyopathy. Heart Lung Circ. Nov 2017;26(11):1127-1132. PMID 28655534
55. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the
channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society
(HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. Aug 2011;8(8):1308-1339. PMID 21787999
History
Date Comments 03/10/14 New Policy. New policy developed with literature review through December 15, 2013.
Genetic testing for dilated cardiomyopathy is considered investigational for all
indications.
07/24/14 Update Related Policies. Remove 12.04.91.
03/10/15 Annual Review. Policy updated with literature review through December 23, 2014;
references 5, 18-19, and 21-25 added. Policy statement unchanged.
04/01/16 Annual Review, approved March 8, 2016. Policy updated with literature review through
November 17, 2015; reference 1 updated; references 4 and 24 added. Policy statement
unchanged.
01/01/17 Coding update; added new CPT code 81439 effective 1/1/17.
05/01/17 Annual review, approved April 11, 2017. Policy updated with literature review through
December 21, 2016; references 6-10, 18-21, 26-27, and 39-43 added. The policy is
revised with updated genetics nomenclature mutation changed to variant when
applicable. Policy statement unchanged.
09/22/17 Policy moved to new format, no changes to policy statement.
05/01/18 Annual Review, approved April 3, 2018. Policy updated with literature review through
December 2017; references 29, 33-34, and 46-54 added. Policy statement unchanged.
Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The
Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and
local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review
and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit
booklet or contact a member service representative to determine coverage for a specific medical service or supply.
Page | 15 of 15
CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). 2018 Premera
All Rights Reserved.
Scope: Medical policies are systematically developed guidelines that serve as a resource for Company staff when
determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to
the limits and conditions of the member benefit plan. Members and their providers should consult the member
benefit booklet or contact a customer service representative to determine whether there are any benefit limitations
applicable to this service or supply. This medical policy does not apply to Medicare Advantage.
037336 (07-2016)
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