Genetic Testing for Dilated Cardiomyopathy
At this time, there is no specific genomic sequencing panel CPT code for this indication. The codes above would be reported for the specific genes tested, and the unlisted molecular pathology code 81479 would be reported one time for the remaining genes in the panel that have not been codified by CPT.
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 predictive test in family members when familial DCM is present.
DCM is defined as the presence of left ventricular enlargement and dilatation in conjunction with significant systolic dysfunction. Dilated cardiomyopathy 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 decade.(2)
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, including(3):
Therefore, when a patient presents with DCM, a workup is performed to identify underlying causes, especially those that are treatable. In many cases, a definite underlying cause is not identified. 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 idiopathic DCM 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 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 (AICD). AICD 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 has been proposed as a newer classification that includes both familial dilated cardiomyopathy and some cases of sporadic idiopathic dilated cardiomyopathy. The percentage of patients with sporadic DCM that has a genetic basis is not well characterized. Most pathologic mutations are inherited in an autosomal dominant fashion, but some autosomal recessive, X-linked, and mitochondrial patterns of inheritance also are present..(4)
In general, genotype-phenotype correlations are either not present or not well characterized. There have been some purported correlations between certain genetic mutations and 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 mutations in LMNA, SCN5A, and DES.(1)
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 the development of 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 mutations, 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 who are referred for genetic testing will have a pathologic mutation identified. 4 Pathologic mutations associated with 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 four genes account for approximately 30% of pathologic mutations identified in cohorts of patients with DCM.(4) A high proportion of the identified mutations are rare, or novel, variants, thus creating challenges in assigning the pathogenicity of discovered variants.(2)
Genetic testing can be performed on any number of candidate genes individually or collectively. Because of the large number of potential mutations associated with DCM and the infrequent nature of most mutations, panel testing is frequently offered. examples of commercially available genetic panels for DCM are listed in Table 1.
Table 1. Commercially Available Genetic Panels for Dilated Cardiomyopathy
DCM: Dilated cardiomyopathy.
Some individuals with DCM will be found to have more than 1 pathologic DCM mutation.1 The frequency of multiple mutations is uncertain, as is the clinical significance.
No U.S. Food and Drug Administration-cleared genotyping tests were identified. The available commercial genetic tests for DCM are offered as laboratory-developed tests. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act.
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The evaluation of a genetic test focuses on 3 main principles: (1) analytic validity (technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent); (2) clinical validity (diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease); and (3) clinical utility (how results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes).
Commercially available genetic testing for dilated cardiomyopathy (DCM) involves a variety of methods such as chip-based oligonucleotide hybridization, direct sequencing of protein-coding portions and flanking regions of targeted exons, and next-generation sequencing. Analytic validity is highest for direct sequencing, approaching 100%. For other methods of genetic testing, analytic validity may be lower and less precisely defined. For genomic hybridization and next-generation sequencing, analytic sensitivity is in the range of 95% to 99%.
In the next-generation sequencing study described in the following, Haas et al (2014) achieved 50-fold coverage in 99.1% of 84 genes sequenced (ie, each gene was sequenced at least 50 times). (5) In a subsample of 25 gene segments containing at least 1 mutation by Sanger sequencing, sensitivity and specificity of next-generation sequencing was 96% and 100%, respectively.
Numerous studies have evaluated the proportion of patients with clinically diagnosed DCM who have pathologic mutations. These studies vary in the genes examined and methods used to detect mutations. The most common type of study describes the presence of 1 type of mutation in probands with DCM or family members of the proband. (6-11)
Fewer studies have evaluated cohorts of patients with DCM for the presence of any known DCM mutation. Hershberger et al (2008) examined a cohort of 313 patients with DCM, 183 with familial DCM and 130 with sporadic DCM. (12) a total of 31 unique variants were identified in 36 probands (11.5%). The 6 genes evaluated and the frequencies of mutations identified were MYH7 (4.2%), TNNT2 (2.9%), SCN5A (2.6%), TCAP (1.0%), LDB3 (1.0%), and CSRP3 (0.3%). However, only 11 of the 31 probands had variants that were judged to be probably pathologic. The remainder were judged to be possibly pathologic (n=21) or unlikely pathologic (n=4).
In 2011, Millat et al. examined a cohort of 105 unrelated patients with DCM. (13) Sixty-four individuals had familial DCM and 41 had sporadic DCM. All coding exons and intronic junctions of the MYH7, LMNA, TNNT2, TNNI3, and RBM20 genes were examined by high-resolution melting and direct sequencing. Pathologic mutations were found in 19% (20/105) of individuals. Ten mutations were novel variants and 9 were previously described variants.
In 2012, Lakdawala studied 264 unrelated adult and pediatric individuals with DCM, approximately half of whom had familial disease.(14) Ten genes (MYH7, TNNT2, TNNI3, TPM1, MYBPC3, ACTC, LMNA, PLN, TAZ, LDB3) were analyzed by direct sequence analysis. A total of 40 unique pathologic mutations were identified in 17.4% (46/264) individuals with DCM. Genes with the most frequent mutations were MYH7 (6.6%), LMNA (5.3%), and TNNT2 (3.7%). Variants of uncertain significance were identified in an additional 10.6% (28/264) of individuals.
Use of next-generation sequencing technology may lead to higher sensitivity for detecting mutations. (15-17) In 2014, Haas et al. reported on a gene sequencing study of the European INHERITANCE (INtegrated HEart Research In TrANslational genetics of dilated Cardiomyopathies in Europe) project. (5) Investigators aimed to characterize clinically relevant DCM genes, as well as genes causative for other inherited cardiomyopathies using next-generation sequencing. Patients with sporadic (51%) or familial (49%) DCM were enrolled in 8 clinical centers in Europe between 2009 and 2011 (total N=639). Secondary DCM was ruled out by excluding patients with hypertension, valve disease, and other loading conditions; coronary artery disease was ruled out by coronary angiography in 53% of patients. Next-generation sequencing was used to sequence 84 genes; pathogenicity of mutations was classified as known (included in the human genome mutation database for heart muscle diseases and channelopathies); likely (frameshift insertions/deletions, stop-gain/stop-loss variants, and splice-site mutations); potential (not common, non-synonymous variants associated with “disease” prediction according to online calculator, SNPs&GO18); or benign (identified in the SNP database19 with allele frequency ≥1%). DCM-causing mutations were found in 101 patients (16%), most commonly in PKP2, MYBPC3, and DSP. Additionally, 117 likely pathogenic variants were found in 26 genes in 147 patients (23%), most commonly in TTN, PKP2, MYBPC3, DSP, RYR2, DSC2, DSG2, and SCN5A. Eighty-two patients (13%) carried more than one DCM-causing mutation, and there was considerable overlap of identified disease-causing mutations with other cardiac diseases: 31% of patients had mutations associated with arrhythmogenic right ventricular cardiomyopathy (ARVC); 16% with hypertrophic cardiomyopathy; 6% with channelopathies; and 6% with other cardiac diseases. Although statistically significant associations were identified between mutations in certain genes (e.g., RBM20) and clinical status (e.g., implantable cardioverter-defibrillator use), these were considered exploratory, and correction for multiple comparisons was not made.
Herman et al. (2012) used next-generation sequencing to analyze TTN mutations in 312 individuals with a clinical diagnosis of DCM. (15) This study also included control groups of 231 individuals with hypertrophic cardiomyopathy and 249 individuals without heart disease. Next-generation sequencing techniques were used to identify variants on the TTN gene, and these variants were further characterized by polymerase chain reaction and dideoxy-sequencing; restriction digestion and gel electrophoresis; or RNA-sequencing.
Mutations in the TTN gene that were judged to be pathologic were identified in 67 of 312 (21.5%) individuals with DCM. There were 72 unique mutations identified, 25 nonsense, 23 frameshift, 23 splicing, and 1 large insertion. TTN mutations were found in 3 (1%) of 231 patients with hypertrophic cardiomyopathy and 7 (3%) of 249 patients without heart disease, which was a significantly lower frequency compared with patients with DCM (p<0.001).
Hirtle-Lewis et al. (2013) used Whole-exome sequencing of 4 genes as part of a strategy to identify and classify genetic variants associated with DCM. (20) The population comprised 96 patients with idiopathic DCM treated at a Canadian clinic. The 4 genes examined were LMNA, TNNT2, TCAP, and PLN, all of which had been previously examined by direct-sequence analysis without any pathologic variants identified. A total of 11 variants were identified, 7 of which were novel variants. Two variants were judged to have a high probability of causing disease, 4 were judged to be variants of unknown significance, and the remainder were considered benign variants.
Other studies have documented the range of diagnoses (i.e., lack of specificity) associated with DCM-causing mutations. In the Netherlands, the PLN (phospholamban) R14del mutation is a founder mutation present in 10% to 15% of patients diagnosed with DCM or arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). In a retrospective study of 295 symptomatic and asymptomatic PLN R14del mutation carriers, 21% of patients met diagnostic criteria for DCM.21 In a retrospective cohort of 41 symptomatic and asymptomatic LMNA mutation carriers, 32% were diagnosed with DCM. (22)
Clinical validity of genetic testing for DCM is relatively low. Clinical sensitivity is uncertain, but likely to be less than 40%. New mutations continue to be discovered, and next-generation sequencing methods may accelerate gene discovery. Clinical specificity also is uncertain; variants thought to be pathologic have been reported in some patients without cardiomyopathy. next-generation sequencing may decrease clinical specificity if it identifies more variants of uncertain significance.
Potential clinical utility of genetic testing for DCM includes confirmation of the diagnosis, evaluating whether there is a genetic cause in an individual with idiopathic DCM, and/or evaluating whether a close relative has inherited a disease-causing mutation that is known to be present in the family.
To demonstrate clinical utility, results of genetic testing should be associated with changes in management that lead to improved outcomes. Changes in management could include initiation of therapy in a patient in whom the diagnosis is confirmed, and/or changes in screening or surveillance for at-risk family members.
Confirming the diagnosis of DCM. Genetic testing could have utility if it was able to confirm the diagnosis of DCM when the diagnosis cannot be made clinically, or if it were used to confirm a diagnosis earlier than would otherwise be possible without genetic testing, and if earlier diagnosis led to management changes that improve outcomes.
The diagnosis of DCM is made on clinical grounds, requiring the presence of left ventricular enlargement and evidence of systolic dysfunction. The presence or absence of a genetic mutation will not alter the clinical diagnosis of DCM. Genetic testing may have an influence on the diagnostic workup for the underlying etiology of DCM. In patients with a likely familial component, genetic testing may improve the efficiency of workup by avoiding other tests for secondary causes of DCM that are likely to be negative. In patients with sporadic forms of DCM, testing for secondary causes will likely still precede genetic testing, so that genetic testing will not influence the diagnostic workup.
Current treatment for DCM does not vary according to whether a genetic mutation is present. While there is general agreement that early treatment for DCM is optimal, there are no trials that demonstrate improved outcomes with presymptomatic treatment compared with delaying treatment until the onset of symptoms, although such trials are in progress (see Ongoing and Unpublished Clinical Trials section). If early treatment is based primarily on genetic testing, then additional concerns of false -positive and false -negative test results need to be considered.
Although researchers have investigated pharmacogenetic associations in DCM, the absence of prospective, randomized trials to compare standard treatment versus genotype-guided treatment precludes assessment of clinical utility of the findings. Reddy et al. (2014) evaluated the impact of adrenergic receptor genotype on hemodynamic status in 2 cohorts of pediatric patients (age <22 years) who had DCM and stable (n=44) or advanced (i.e., listed for transplantation; n=91) heart failure. (23) Three adrenergic receptor mutations associated with heart failure in adults were genotyped: ADRA2C del322-325, ADRB1 Gly389Arg, and ADRB2 Gly16Arg. At mean (SD) follow-up of 2.2 (3.3) years, patients with stable or advanced heart disease who had at least 1 mutation showed greater response to ß-blocker treatment than patients who had no mutation (genotype x ß-blocker interaction p values ≤0.05 for several hemodynamic parameters). Wasielewski et al (2014) investigated whether familial DCM may predispose to anthracycline-associated cardiomyopathy (AACM). (24) Genotyping of 48 cardiomyopathy-associated genes in patients with DCM who also had AACM (n=5) and in patients with AACM who met criteria for familial DCM based on family history (n=6) identified 2 known pathogenic variants and 9 variants of unknown significance. Because the intent of the study was descriptive, statistical significance of these results was not determined.
Predictive testing. In family members of patients with DCM, genetic testing can be used to determine if a known pathologic mutation has been inherited. There are several issues in predictive testing for DCM that create challenges in establishing clinical utility.
This first requires confidence that the mutation identified in the proband is causative of DCM. If this is not the case, then genetic testing may provide misleading information. Because of the high number of novel mutations and variants of unknown significance identified in DCM, the confidence that a mutation is causative of the disorder is less than for some other conditions.
Uncertain penetrance and variable clinical expression also needs to be considered in determining the utility of predictive testing. Because of heterogeneity in clinical expression, it may not be possible to adequately counsel an asymptomatic patient on the likelihood of developing DCM even when an inherited mutation has been identified.
Predictive testing may lead to changes in screening and surveillance, particularly for patients who test negative in whom surveillance might be discontinued. However, it is uncertain whether this approach will lead to improved outcomes. For example, a proband may be identified with a variant that is possibly pathogenic. A close family member may test negative for that variant and be falsely reassured that they are not at risk for DCM when they still may harbor another undiscovered mutation.
Clinical utility of genetic testing for DCM has not been established. Genetic testing is not likely to alter the diagnosis of DCM, which is based on clinical factors. For some patients with likely familial disease, the diagnostic workup may be altered, but extent of change and impact on outcomes is unclear. Studies of pharmacogenetic associations to guide treatment selection in DCM are preliminary. Predictive testing may have some role in testing at-risk family members but is currently limited by low clinical validity of testing and heterogeneity in penetrance and clinical expression of disease.
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov found two Phase III trials and one Phase II trial in patients with or at risk for developing DCM.
Summary of Evidence
Dilated cardiomyopathy (DCM) is a disorder of cardiac muscle that leads to progressive left ventricular enlargement, heart failure, and/or cardiac arrhythmias. A subset of DCM is caused by genetic mutations. Genetic forms of DCM are heterogeneous in types of genetic mutations, clinical expression, and hereditability.
Many genetic mutations on more than 40 different genes have been associated with DCM. This remains an active area of research, and it is likely that many more mutations will be identified in the future. Analytic validity of genetic testing for DCM is expected to be high when testing is performed by direct sequencing or next-generation sequencing. In contrast, clinical validity is not high. The percentage of patients with idiopathic DCM who have a genetic mutation (clinical sensitivity) is relatively low, in the range of 30% to 40%. Clinical specificity of DCM-associated mutations is unknown, but DCM-associated mutations in the same genes have been reported in 1% to 3% of patients without DCM.
Clinical utility of genetic testing for DCM is uncertain. For a patient who is diagnosed with idiopathic DCM, the presence of a genetic mutation will not change treatment or prognosis. For an individual at risk due to genetic DCM in the family, genetic testing can identify whether the mutation has been inherited. However, it is uncertain how knowledge of a mutation will improve outcomes for an asymptomatic individual. Early treatment based on a genetic diagnosis is unproven. Uncertain accuracy of predictive testing makes it uncertain whether changes in management will improve outcomes.
Because of low clinical validity and uncertain clinical utility, genetic testing for dilated cardiomyopathy is considered investigational in all situations.
Practice Guidelines and Position Statements
The Heart Rhythm Society and European Hearth Rhythm Association issued joint guidelines in 2011 on genetic testing for cardiac channelopathies and cardiomyopathies. (26) These guidelines contained the following recommendations on genetic testing for DCM:
Class I recommendations
Class IIa recommendations
The 2011 American College of Cardiology Foundation and American Heart Association joint guideline for the diagnosis and treatment of hypertrophic cardiomyopathy (HCM)27 makes the following class I recommendations for genetic screening:
The Heart Failure Society of America published a practice guideline in 2009 on the Genetic Evaluation of Cardiomyopathy. (28) The following recommendations for genetic testing for cardiomyopathy (including DCM) were made:
U.S. Preventive Services Task Force Recommendations
No U.S. Preventive Services Task Force recommendations for cardiomyopathy have been identified.
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.
Molecular pathology procedure, Level 4 (e.g., 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)
Molecular pathology procedure, Level 5 (e.g., 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)
Molecular pathology procedure, Level 7 (e.g., analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia)
Molecular pathology procedure, Level 8 (e.g., analysis of 26-50 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of >50 exons, sequence analysis of multiple genes on one platform)
New Policy. New policy developed with literature review through December 15, 2013. Genetic testing for dilated cardiomyopathy is considered investigational for all indications.
Update Related Policies. Remove 12.04.91.
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. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).