ACTIONABILITY PENETRANCE SIGNIFICANCE/BURDEN OF DISEASE NEXT STEPS. YES ( 1 of above) YES (Proceed to Stage II)

Transcription

1 Stage I: Rule-Out Dashboard GENE/GENE PANEL: TNNT2, LMNA HGNC ID: 11949, 6636 ACTIONABILITY 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 Family Management Circumstances to Avoid ( 1 of above) 3. Is the result actionable in an undiagnosed adult with the genetic condition? OMIM: , PENETRANCE 4. Is there at least one known pathogenic variant with at least moderate penetrance ( 40%) or moderate relative risk ( 2) in any population? SIGNIFICANCE/BURDEN OF DISEASE 5. Is this condition an important health problem? NEXT STEPS 6. Are Actionability (Q2-3), Penetrance (Q4), and Significance (Q5) all? (Proceed to Stage II) (Consult Actionability Working Group) Exception granted, proceed to Stage II Exception not granted, STOP 1

2 Signif/Burden of Condition GENE/GENE PANEL: TNNT2, LMNA 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, it is likely the prevalence of DCM has been underestimated. However, further studies have not been published. Familial DCM (FDC) may account for 20-48% of DCM cases. (1-4) 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, parozysmal dyspnea) and/or reduced cardiac output (fatique, dyspnea on exertion)], arrhythmias and/or conduction system disease, and thromboembolic disease including stroke. Patients with DCM are at risk of premature death. (1;3) DCM may be asymptomatic for years. Presentation of clinical symptoms usually occurs late in the disease course. 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. FDC 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. (1-3) 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 left ventricular ejection fraction (LVEF) indicated that enalapril (ACE inhibitor) was associated with a significantly increased life expectancy (HR=0.90, 95% CI= , p=0.0003). In addition, a meta-analysis of randomized clinical trials indicated a 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) (5) (6;7) Patient Management Implantable cardiac device (ICD) therapy should be considered in patients with a familial cardiomyopathy associated with sudden cardiac death (SCD). Other indicators for ICD implantation include a left ventricular ejection fraction (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 nonischemic 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 nonischemic 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 mortaility in both groups. (Tier 2) Pregnant women with DCM seeking a first trimester induced abortion should be referred to a (8;9) 2

3 Surveillance Family Management Circumstances to Avoid hospital-based provider (with patient permission). (Tier 2) Management of FDC can include general measures (salt and fluid restriction, treatment of hypertension, limitation of alcohol intake, control of body weight, moderate exercise).(tier 4) Clinical screening for DCM is recommended in asymptomatic individuals known to carry a diseasecausing 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 symtoms, 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 FDC 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 FDC 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 symtoms, 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. (10) (1;3) (3) 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 GENE/GENE PANEL: TNNT2, LMNA Final Consensus Scores Gene(s) Outcome/intervention pair Severity Likelihood Effectiveness Nature of the Intervention TNNT2, LMNA Sudden cardiac death/surveillance and ICD Sudden cardiac death/surveilllance pharmacotherapy Delay heart failure/surveillance and ACE inhibitors Topic Narrative Description of Evidence Ref 3. What is the chance that this threat will materialize? Mode of Inheritance TNNT2- and LMNA- associated FDC is inherited in an autosomal dominant manner. (3) TNNT2 and LMNA are associated with 2.9% and 7.3% of FDC and 1.6% and 3.0% of sporadic Prevalence of Genetic Mutations DCM, respectively. (Tier 3) Information on the prevalence of genetic mutations associated with FDC in the general population was not available. Penetrance OR FDC 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) (2;3) Relative Risk (include high risk racial or ethnic subgroups) Specific penetrance estimates of DCM were not available for TNNT2-related DCM, however LMNA-related DCM has a penetrance of greater than 90-95% by the seventh decade. (Tier 4) Information in relative risk was not available. (11) Expressivity FDC has highly variable age of onset. (Tier 3) (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. Total Score 3 3C 2B 2 10CB 3 3C 2C 3 11CC 2 3C 2B 3 10CB To see the scoring key, please go to: Date of Search (MM.DD.YYYY): (updated ) Reference List 1. OrphaNet. Familial or idiopathic dilated cardiomyopathy 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 Oct;21(10). 4

5 3. 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 Nov;12(11): 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 Oct 15;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 May 31;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 May 7;41: 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 Jan 22;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 Jun;16(6):e Guiahi M, Davis A. First-trimester abortion in women with medical conditions: release date October 2012 SFP guideline # Contraception 2012 Dec;86(6): Hershberger RE, Morales A. LMNA-Related Dilated Cardiomyopathy. GeneReviews