YES NO UNKNOWN. Stage I: Rule-Out Dashboard Secondary Findings in Adults ACTIONABILITY PENETRANCE SIGNIFICANCE/BURDEN OF DISEASE NEXT STEPS

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1 Stage I: Rule-Out Dashboard HGNC ID: 11949, 6636, 2928 OMIM ID: , , ACTIONABILITY PENETRANCE 1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition? 2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways? Yes No Patient Management Surveillance or Screening 4. Is there at least one known pathogenic variant with at least moderate penetrance ( 40%) or moderate relative risk ( 2) in any population? UNKWN SIGNIFICANCE/BURDEN OF DISEASE 5. Is this condition an important health problem? Family Management Circumstances to Avoid ( 1 of above) NEXT STEPS 6. Are Actionability (Q2-3), Penetrance (Q4), and Significance (Q5) all? 3. Is the result actionable in an undiagnosed adult with the genetic condition? (Proceed to Stage II) (Consult Actionability Working Group) Exception granted, proceed to Stage II Exception not granted, STOP 1

2 Signif/Burden of Condition Topic Narrative Description of Evidence Ref 1. What is the nature of the threat to health for an individual carrying a deleterious allele? Prevalence of the genetic disorder Clinical Features (Signs/symptoms) Natural History (Important subgroups & survival/recovery) Little data is available for the prevalence of idiopathic dilated cardiomyopathy (DCM). Only one formal prevalence study has been conducted, which took place in Minnesota in the 1980s. The prevalence of DCM was estimated as 1/2500 to 1/2700. This estimate was twice the prevalence of hypertrophic cardiomyopathy (HCM), estimated in the same study as ~1/5000. Given more recent epidemiologic studies have shown an HCM prevalence of approximately 1:500 and experts estimate that DCM is at least as common as HCM. The prevalence of DCM has likely been underestimated due to the fact that individuals may remain asymptomatic until marked ventricular dysfunction has occurred. However, further studies have not been published. It is not clear how many DCM cases are due to genetic pathogenic variants in LMNA, TNNT2, and DMD. DCM is a heart muscle disease characterized by left ventricular dilation and systolic dysfunction. DCM typically presents with heart failure [with symptoms of congestion (edema, orthopnea, paroxysmal nocturnal dyspnea) and/or reduced cardiac output (fatigue, dyspnea on exertion)], arrhythmias and/or conduction system disease, and thromboembolic disease including stroke. Patients with DCM are at risk of premature death. DCM may be asymptomatic with only mild ventricular dilation and dysfunction for years. Presentation of clinical symptoms usually occurs late in the disease course. Usually, by the time of the diagnosis individuals have severe impairment of the left ventricular ejection function (LVEF) and are in New York Heart Association (NYHA) functional class III-IV. Patients with severe heart failure, severe reduction of the functional capacity and depressed left ventricular ejection fraction have a low survival rate and may require heart transplant. DCM has a highly variable age of onset, from infancy to late adulthood with 10% of cases diagnosed prior to age 20 and 60% diagnosed by age 40. DCM due to pathogenic variants in LMNA presents with mild dilation and severe dysfunction of the left ventricle, conduction defects, supraventricular arrhythmias, variable skeletal muscle involvement and variable serum creatine kinase (CK) levels. The prognosis for many of these patients is not favorable. DCM due to pathogenic variants in DMD has a less severe prognosis and presents with increased CK, muscular abnormalities, and the typical signs of dystrophinopathy at the skeletal muscle biopsy. A meta-analysis of DCM cases, estimated that patients with LMNA pathogenic variants had a mean age of onset of 40 years (95% CI: 35-45), while patients with TNNT2 pathogenic variants had an earlier mean age of onset at 35 years (95% CI: 23-47). Among patients included in the meta-analysis, the rate of heart transplantation was 27% for LMNA and 17% for TNNT2. 2. How effective are interventions for preventing the harm? Information on the effectiveness of the recommendations below was not provided unless otherwise stated. ACE inhibitors and beta-blockers are recommended in patients with a reduced ejection fraction to prevent heart failure. (Tier 2) There was no evidence specifically for pharmacotherapy and sudden cardiac death. However, there was evidence for pharmacotherapy and all-cause mortality. One follow-up study among 6797 patients with reduced LVEF indicated that enalapril (ACE inhibitor) was associated with a significantly increased life expectancy (HR=0.90, 95% Patient CI= , p=0.0003). In addition, a meta-analysis of randomized clinical trials indicated a Management reduction mortality in patients with reduced LVEF associated with beta-blockers (RR in men=0.66, 95% CI= ; RR in women=0.63, 95% CI= ). However, the heart failure mortality benefit of ACE inhibitors was detected in men (RR=0.82, 95% CI= ) but not women (RR=0.92, 95% CI= ). (Tier 5) Implantable cardiac device (ICD) therapy should be considered in patients with a familial (1-4) (1, 2) (1, 2, 4, 5) (6) (7, 8) 2

3 Surveillance Family Management Circumstances to Avoid cardiomyopathy associated with sudden cardiac death (SCD). Other indicators for ICD implantation include a LVEF 35%, LVEF >35% and a family history of SCD, or LMNA mutations. Multiple randomized trials now supplement observational studies that have reported the role of ICD in primary prevention of SCD in patients with non-ischemic DCM. Specifically for patients with LMNA mutations, one prospective cohort study of 19 patients with an LMNA mutation and an ICD showed that 42% (N=8) received appropriate ICD therapy in response to ventricular tachycardia (N=2) and ventricular fibrillation (N=6) across a 34 month period. While not specific to DCM, a meta-analysis of randomized control trials of patients with non-ischemic cardiomyopathy reported an overall reduction in mortality with ICD therapy (RR=0.69, 95% CI= ; p=0.002). Two randomized controlled trials assessed mortality in patients with DCM with and without an ICD, but were discontinued due to lack of statistical power associated with low rates of all-cause mortality in both groups. (Tier 2) Pregnant women with DCM seeking a first trimester induced abortion should be referred to a hospital-based provider (with patient permission). (Tier 2) Clinical screening for DCM is recommended in asymptomatic individuals known to carry a disease-causing mutation. This screening should occur at any time that signs or symptoms appear or every 1 to 3 years. Screening should include: family history (with special attention to heart failure symptoms, arrhythmias, presyncope, and syncope), physical exam (with special attention to the cardiac and skeletal muscle systems), electrocardiogram (ECG), echocardiogram, and CK-MM (initial evaluation only). The basis of these extensive clinical screening recommendations is that cardiomyopathy can be treated in almost all cases, improving survival and/or quality of life. Echocardiograms and ECGs are important for risk assessment as patients with DCM often do not manifest symptoms of heart failure or arrhythmias until late in the disease process, usually with moderate or severe LVEF and systolic dysfunction. (Tier 2) Pregnancy is contraindicated in DCM, and is associated with a risk of peripartum cardiomyopathy and pregnancy-associated cardiomyopathy. Thus pregnant women with DCM should be followed by a high risk obstetrician. (Tier 4) Clinical screening for DCM is recommended in asymptomatic first-degree relatives in individuals with DCM who have not had genetic testing or when a disease-causing mutation was not identified. This screening should occur at any time that signs or symptoms appear or every 3-5 years. Screening should include: family history (with special attention to heart failure symptoms, arrhythmias, presyncope, and syncope), physical exam (with special attention to the cardiac and skeletal muscle systems), electrocardiogram, echocardiogram, and creatinine kinase MM isoenzyme (initial evaluation only). (Tier 2) Genetic and family counseling is recommended for families with a history of cardiomyopathy. Referral to centers expert in genetic evaluation and family-based management should be considered. (Tier 2) Information on circumstances to avoid was not available. (9, 10) (11) Description of sources of evidence: Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources Tier 5: Evidence from a non-systematically identified source 3

4 Topic Narrative Description of Evidence Ref 3. What is the chance that this threat will materialize? Mode of Inheritance Prevalence of Genetic Mutations TNNT2- and LMNA- associated DCM is inherited in an autosomal dominant manner. DMDassociated DCM is inherited in an X-linked manner. A meta-analysis reported that pathogenic variants in LMNA had a pooled frequency of 5% (95% CI: 3-7%) among familial and sporadic DCM cases, and TNNT2 had a pooled frequency of 2% (95% CI: 1-3%). (Tier 1) It is unknown how many cases of DCM are associated with DMD. (Tier 4) Information on the prevalence of pathogenic variants associated with DCM in the general population was not available. Overall, DCM has age-related penetrance of DCM: 10% by age <20 years, 34% by age 30, 60% by age 40, and 90% for more advanced ages (>40). (Tier 3) (5) (2, 4) Penetrance OR Relative Risk (include high risk racial or ethnic subgroups) A meta-analysis reported rates of heart transplantation of 27% for LMNA and 17% for TNNT2. Additional penetrance estimates specific to LMNA-related DCM were also reported (Tier 1): DCM or left ventricle dysfunction = 45% Conduction system disorders (included sinus dysfunction, atrioventricular conduction blocks, bundle branch blocks, or hemiblocks) =52% (74% in those with DCM, 40% in those without DCM) Supraventricular tachycardia (included atrial fibrillation, atrial flutter, or ectopy) = 43% (62% in those with DCM, 13% in those without DCM) Ventricular arrhythmia = 29% (50% in those with DCM, 5% in those without DCM) SCD = 6% (19% in those with DCM, 3% in those without DCM) Skeletal muscle affection: 26% (46% in those with DCM, 26% in those without DCM) (5) Specific penetrance estimates of DCM were not available for TNNT2- or DMD- related DCM. Information in relative risk was not available. Expressivity DCM has highly variable age of onset. (Tier 3) 4. What is the nature of the intervention? Nature of Intervention Identified interventions include non-invasive surveillance, pharmacotherapy, and possible ICD implantation, which could be associated with moderate risk. 5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care? Chance to Escape Clinical Detection DCM is typically an adult-onset disorder, with many asymptomatic years. DCM may be detected in an asymptomatic individual during a medical evaluation for another reason, but patients often present with heart failure. Final Consensus Scores Gene(s) Outcome/intervention pair Severity Likelihood Effectiveness Nature of the Intervention Total Score LMNA, Sudden cardiac death/surveillance and 3 2B 2B 2 9BB TNNT2 DMD ICD Sudden cardiac death/surveilllance 3 2B 2E 3 10BE pharmacotherapy Delay heart failure/surveillance and ACE inhibitors 2 3B 2E 3 10BE To see the scoring key, please go to: 4

5 Date of Search (MM.DD.YYYY): (updated , , ) References 1. Taylor MR, Carniel E, Mestroni L. Cardiomyopathy, familial dilated. Orphanet J Rare Dis. 2006;1: Hershberger RE, Morales A. Dilated Cardiomyopathy Overview. GeneReviews Hershberger RE, Morales A, Siegfried JD. Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals. Genet Med. 2010;12(11): Posafalvi A, Herkert JC, Sinke RJ, van den Berg MP, Mogensen J, Jongbloed JD, et al. Clinical utility gene card for: dilated cardiomyopathy (CMD). Eur J Hum Genet. 2013; Kayvanpour E, Sedaghat-Hamedani F, Amr A, Lai A, Haas J, Holzer DB, et al. Genotype-phenotype associations in dilated cardiomyopathy: meta-analysis on more than 8000 individuals. Clin Res Cardiol. 2017;106: Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Drazner MH, et al ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-e Jong P, Yusuf S, Rousseau MF, Ahn SA, Bangdiwala SI. Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study. Lancet. 2003;361(9372): Shekelle PG, Rich MW, Morton SC, Atkinson CS, Tu W, Maglione M, et al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials. J Am Coll Cardiol. 2003;41(9): Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA, III, Freedman RA, Gettes LS, et al ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2013;61(3):e Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2010;16(6):e Guiahi M, Davis A. First-trimester abortion in women with medical conditions: release date October 2012 SFP guideline # Contraception. 2012;86(6):