Genetic Testing for Dilated Cardiomyopathy. Description

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1 Subject: Genetic Testing for Dilated Cardiomyopathy Page: 1 of 12 Last Review Status/Date: March 2015 Genetic Testing for Dilated Cardiomyopathy 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, which include genetic and non-genetic 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. Background Dilated cardiomyopathy (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 US. (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) The 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 may also lead to electrical instability and arrhythmias. Symptoms of arrhythmias may include light-headedness, syncope or sudden cardiac arrest. There are many underlying conditions that can cause DCM, including: (3) Ischemic coronary artery disease Toxins Metabolic conditions Endocrine disorders Inflammatory and infectious diseases Infiltrative disorders Tachycardia-mediated cardiomyopathy Therefore, when a patient presents with DCM, a work-up is performed to identify underlying causes, especially those that are treatable. In many cases, a definite underlying cause is not identified. Approximately 35-40% 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).

2 Subject: Genetic Testing for Dilated Cardiomyopathy Page: 2 of 12 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 two 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 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 may also be treated with anti-arrhythmic medications, pacemaker 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. DCM that is end-stage can be treated with cardiac transplantation. Genetic DCM Genetic DCM has been proposed as a newer classification that includes both familial dilated cardiomyopathy and some cases of sporadic idiopathic dilated cardiomyopathy. The percent of patients with sporadic DCM that have a genetic basis is not well characterized. The majority of pathologic mutations are inherited in an autosomal dominant fashion, but some autosomal recessive, X-linked, and mitochondrial patterns of inheritance are also 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 the 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 has also 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%-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 over 40 genes of various types and locations. The most common genes involved are genes that code for titin (TTN), myosin heavy chain (MYH7), troponin T (TNNT2), and alpha-tropomysin (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 of a number of candidate genes individually or collectively. Because of the large number of potential mutations associated with DCM and the infrequent nature of

3 Subject: Genetic Testing for Dilated Cardiomyopathy Page: 3 of 12 most mutations, panel testing is frequently offered. Examples of commercially available genetic panels for DCM are listed in Table 1. Table. Commercially Available Genetic Panels for Dilated Cardiomyopathy Laboratory Panel name Number of Testing method genes tested Ambry Genetics DCM panel 37 Next-gen sequencing GeneDX DCM sequencing panel Cardiomyopathies Del/Dup Panel Next-gen sequencing CGH Transgenomic DCM panel Conduction disease-dcm Panel 13 2 Sanger sequencing Sanger sequencing Partners Healthcare DCM panel 27 Next-gen sequencing Baylor COM DCM panel 8 Sanger sequencing Some individuals with DCM will be found to have more than one pathologic DCM mutation. (1) The frequency of multiple mutations is not certain, as is the clinical significance. Regulatory Status No U.S. Food and Drug Administration (FDA)-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. Related Policies Genetic Testing for Cardiac Ion Channelopathies Policy *This policy statement applies to clinical review performed for pre-service (Prior Approval, Precertification, Advanced Benefit Determination, etc.) and/or post-service claims. Genetic testing for dilated cardiomyopathy is considered investigational in all situations. Rationale 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 (the diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease); and 3) clinical utility (how the 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).

4 Subject: Genetic Testing for Dilated Cardiomyopathy Page: 4 of 12 Analytic Validity 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, the analytic validity may be lower and less precisely defined. For genomic hybridization and next generation sequencing, the 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. Clinical Validity Numerous studies have evaluated the percentage 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 one 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 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 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, and LDB3) were analyzed by direct sequence analysis. A total of 40 unique pathologic mutations were identified in 17.4% (46/264) of 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 Subject: Genetic Testing for Dilated Cardiomyopathy Page: 5 of 12 (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&GO (18)); or benign (identified in the SNP database (19) 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 (eg, RBM20) and clinical status (eg, 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 67/312 (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 (ie, lack of specificity) associated with DCMcausing 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

6 Subject: Genetic Testing for Dilated Cardiomyopathy Page: 6 of 12 cohort of 41 symptomatic and asymptomatic LMNA mutation carriers, 32% were diagnosed with DCM. (22) Section Summary Clinical validity of genetic testing for DCM is relatively low. The 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. The clinical specificity is also uncertain, but variants thought to pathologic have been reported in some patients without cardiomyopathy. The use of next-generation sequencing may decrease clinical specificity if it identifies more variants of uncertain significance. Clinical Utility 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, the results of genetic testing should be associated with some 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 LV 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 work-up for the underlying etiology of DCM. In patients with a likely familial component, genetic testing may improve the efficiency of work-up 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 work-up. 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. If early treatment is based primarily on genetic testing, then the additional concerns of false positive and false negative tests 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)

7 Subject: Genetic Testing for Dilated Cardiomyopathy Page: 7 of 12 who had DCM and stable (n=44) or advanced (ie, listed for transplantation; n=91) heart failure. (23) Three adrenergic receptor mutations associated with heart failure in adults were genotyped: ADRA2C del , 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 beta-blocker treatment than patients who had no mutation (genotype x beta-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 the 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 not certain that 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. Section Summary 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 work-up may be altered, but extent of change and the 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 the low clinical validity of testing, and heterogeneity in penetrance and clinical expression of disease. Ongoing and Unpublished Clinical Trials A search of online site, ClinicalTrials.gov, found 2 phase 3 trials and 1 phase 2 trial in patients with or at risk for developing DCM.

8 Subject: Genetic Testing for Dilated Cardiomyopathy Page: 8 of 12 NCT : The PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors (PRECARDIA) trial is a 3-year European phase 3 trial. Treatment with perindopril, an ACE (angiotensin-converting enzyme) inhibitor, will be compared with no treatment in unaffected carries of a familial, disease-causing genetic mutation associated with DCM. Estimated enrollment is 200, and expected completion is December This study is part of the European INHERITANCE research program. (25) NCT : The PHOspholamban RElated CArdiomyopathy STudy - Intervention (i- PHORECAST) trial is a 3-year phase 3 trial in the Netherlands. Treatment with eplerenone, an aldosterone antagonist and antifibrotic agent, will be compared with no treatment in asymptomatic PLN R14del mutation carriers. Estimated enrollment is 150, and expected completion is May NCT : A Study of ARRY in Patients With LMNA-Related Dilated Cardiomyopathy is a 1-year, multicenter, phase 2 trial in the U.S. Two doses of the investigational study drug, ARRY , will be compared in patients with symptomatic genetic DCM due to a mutation in LMNA. Estimated enrollment is 12, and expected completion is June Practice Guidelines and Position Statements The Heart Rhythm Society (HRS) and the 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 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 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 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 highest risk of arrhythmia and syndromic features, to facilitate cascade screening within the family, and to help with family planning. 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: Evaluation of familial inheritance and genetic counseling is recommended as part of the assessment of patients with HCM. (Level of Evidence B).

9 Subject: Genetic Testing for Dilated Cardiomyopathy Page: 9 of 12 Patients who undergo genetic testing also should undergo counseling by someone knowledgeable in the genetics of cardiovascular disease so that results and their clinical significance can be appropriately reviewed with the patient. (Level of Evidence B). Screening (clinical, with or without genetic testing) is recommended in first-degree relatives of patients with HCM. (Level of Evidence B). Genetic testing for HCM and other genetic causes of unexplained cardiac hypertrophy is recommended in patients with an atypical clinical presentation of HCM or when another genetic condition is suspected to be the cause. (Level of Evidence B). The Heart Failure Society of America (HFSA) 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: 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. Summary 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 the 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, the clinical validity is not high. The percent of patients with idiopathic DCM who have a genetic mutation (clinical sensitivity) is relatively low, in the range of 30-40%. The clinical specificity of DCM-associated mutations is not known, but DCM-associated mutations in the some 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

10 Subject: Genetic Testing for Dilated Cardiomyopathy Page: 10 of 12 asymptomatic individual. Early treatment based on a genetic diagnosis is unproven. The uncertain accuracy of predictive testing makes it uncertain whether changes in management will improve outcomes. Because of the low clinical validity and uncertain clinical utility, genetic testing for dilated cardiomyopathy is considered investigational in all situations. Medicare National Coverage There is no national coverage determination (NCD). References 1. Hersheberger RE M, A. Dilated Cardiomyopathy Overview. GeneReviews Last accessed February 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 ; 60(4): PMID Hershberger RE, Morales A, Siegfried JD. Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals. Genet Med. Nov 2010; 12(11): PMID Lakdawala NK, Winterfield JR, Funke BH. Dilated cardiomyopathy. Circ Arrhythm Electrophysiol. Feb 2013; 6(1): PMID Haas J, Frese KS, Peil B, et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J. Aug PMID Brodsky GL, Muntoni F, Miocic S, et al. Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement. Circulation. Feb 82000; 101(5): PMID MacLeod HM, Culley MR, Huber JM, et al. Lamin A/C truncation in dilated cardiomyopathy with conduction disease. BMC Med Genet. Jul ; 4:4. PMID Olson TM, Michels VV, Thibodeau SN, et al. Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. Science. May ; 280(5364): PMID Sylvius N, Duboscq-Bidot L, Bouchier C, et al. Mutational analysis of the beta- and deltasarcoglycan genes in a large number of patients with familial and sporadic dilated cardiomyopathy. Am J Med Genet A. Jul ; 120A(1):8-12. PMID Taylor MR, Slavov D, Ku L, et al. Prevalence of desmin mutations in dilated cardiomyopathy. Circulation. Mar ; 115(10): PMID 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): PMID 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): PMID

11 Subject: Genetic Testing for Dilated Cardiomyopathy Page: 11 of 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):e PMID Lakdawala NK, Funke BH, Baxter S, et al. Genetic testing for dilated cardiomyopathy in clinical practice. J Card Fail. Apr 2012; 18(4): PMID Herman DS, Lam L, Taylor MR, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. Feb ; 366(7): PMID 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. May ; 88(3): PMID 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): PMID University of Bologna. Web server SNPs & gene ontology (ws-snps&go). Accessed February, National Center for Biotechnology Infomation. dbsnp: short genetic variations, build uild_id=137. Accessed February, 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): PMID 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): PMID 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): PMID Reddy 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. Nov PMID Wasielewski M, van Spaendonck-Zwarts KY, Westerink ND, et al. Potential genetic predisposition for anthracycline-associated cardiomyopathy in families with dilated cardiomyopathy. Open Heart. 2014; 1(1):e PMID Inheritance Project. Accessed February, 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): PMID American College of Cardiology Foundation and American Heart Association (ACCF/AHA). Guideline for the diagnosis and treatment of hypertrophic cardiomyopathy. 2011; Accessed February, 2015.

12 Subject: Genetic Testing for Dilated Cardiomyopathy Page: 12 of 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): PMID Policy History Date Action Reason March 2014 New Policy March 2015 Update Policy Policy updated with literature review; references 5, 18-19, and added. Policy statement unchanged. Keywords Genetic Testing, Dilated Cardiomyopathy This policy was approved by the FEP Pharmacy and Medical Policy Committee on March 20, 2015 and is effective April 15, Signature on file Deborah M. Smith, MD, MPH