Stage I: Rule-Out Dashboard Secondary Findings in Adults

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1 ACTIONABILITY Stage I: Rule-Out Dashboard GENE/GENE PANEL: MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL3, ACTC1, DISORDER: Familial Hypertrophic Cardiomyopathy (HCM) PRKAG2, MYL2, CSRP3 HGNC ID: 7551, 7577, 11949, 11947, 12010, 7584, 143, 9386, 7583, 2472 OMIM ID: , , , , , , , , , PENETRANCE 1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition? YES NO 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 YES ( 1 of above) NO 3. Is the result actionable in an undiagnosed adult with the genetic condition? YES NO 4. Is there at least one known pathogenic variant with at least moderate penetrance ( 40%) or moderate relative risk ( 2) in any population? YES NO UNKNOWN SIGNIFICANCE/BURDEN OF DISEASE 5. Is this condition an important health problem? YES NEXT STEPS NO 6. Are Actionability (Q2-3), Penetrance (Q4), and Significance (Q5) all YES? YES (Proceed to Stage II) NO (Consult Actionability Working Group) Exception granted, proceed to Stage II Exception not granted, STOP 1

2 Signif/Burden of Condition Stage II: Summary Report GENE/GENE PANEL: MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL3, ACTC1, PRKAG2, MYL2, CSRP3 DISORDER: Familial Hypertrophic Cardiomyopathy (HCM) 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) Hypertrophic cardiomyopathy (HCM) is a common genetic cardiovascular disease. The prevalence in the general population is estimated at 1:500, which is equivalent to at least 600,000 people affected in the United States. HCM is a primary cardiac disorder characterized by hypertrophy, usually left ventricle hypertrophy (LVH), in the absence of other loading conditions. Clinical manifestations of HCM range from asymptomatic LVH to progressive heart failure to sudden cardiac death (SCD). Progressive ventricular outflow obstruction may cause palpitation associated with arrhythmia, congestive heart failure, and sudden death. Other symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. Symptoms can be readily provoked by exercise. HCM is a heterogeneous cardiac disease with a diverse clinical presentation and course, presenting in all age groups from infancy to the very elderly; however, LVH often becomes apparent during adolescence or young adulthood. Although HCM was initially thought to be associated with high mortality, it is now recognized that most affected individuals will have a relatively mild course of disease and can achieve normal life expectancy without disability or the necessity for major therapeutic interventions. In some patients, HCM is associated with disease complications that may be profound with the potential to result in disease progression or premature death. An important minority of persons with HCM are at increased risk for SCD (most often occurring in adolescents or young adults) most likely related to ventricular tachycardia/ventricular fibrillation. Approximately 5-10% of individuals with HCM progress to end-stage disease. The annual mortality rate in individuals with end-stage disease is estimated at 11%. Community-based studies suggest an annual mortality rate in the range of 1%. HCM is the commonest structural cause of SCD in individuals less than 35 years, including competitive athletes. There are very few data on the natural histories of individuals who carry a pathogenic variant and have no phenotype, but recent studies suggest a benign clinical course for most clinically unaffected carriers. 2. How effective are interventions for preventing the harm? Information on the effectiveness of the recommendations below was not provided unless otherwise stated. No treatments currently exist to prevent or decrease disease development or to reverse established manifestations. (1-4) (1-5) (1-4, 6) (1) Patient Management In all cases of HCM, clinicians should consider evaluation of patients in centers with multidisciplinary teams, with expertise in diagnosis, genetics, risk stratification, and management of heart muscle disease. (Tier 2) All patients should undergo comprehensive SCD risk stratification at initial evaluation. Patients with multiple risk factors have a substantially increased risk of sudden death sufficient to ward consideration for prophylactic therapy. In a study of 268 patients with HCM, those with two or more risk factors had a lower six-year survival rate from sudden death than those with one or no risk factors (72% versus 94%). It is possible to identify most high-risk patients by noninvasive clinical markers, and only a small minority of those HCM patients who die suddenly (about 3%) are without any of the currently acknowledged risk markers. (Tier 1) SCD risk stratification is reasonable on a periodic basis (12 to 24 months) for patients with HCM who have not undergone ICD therapy. There are no randomized trials or statistically validated prospective prediction models that can be used to guide ICD implantation in patients with HCM. (2, 6) 2

3 Surveillance Stage II: Summary Report Recommendations are instead based on observational, retrospective cohort studies that have determined the relationship between clinical characteristics and prognosis. (Tier 2) It is reasonable to recommend an implantable cardioverter-defibrillator (ICD) for patients with one or more major risk factors for SCD (e.g., history of sudden death presumably due to HCM in a first-degree relative, abnormal blood pressure response during exercise, decreased leftventricular wall thickness). In an international multicenter registry of HCM patients with ICDs, patients with primary prevention ICDs placed on the basis of 1 or more of the conventional risk markers experienced appropriate ICD therapy at a rate of 4% per year. ICD therapy was effective in terminating VT/VF despite the complex HCM phenotype. (Tier 2) Within the Swedish ICD Registry, all-cause mortality in 342 HCM patients with an ICD was found to be larger than that of the age and sex-matched Swedish general population (standardized mortality ratio: 3.4 (95% CI: ; p<0.0001) over a mean follow up of 5.4 years. However, ICDs almost eliminated premature arrhythmic death in the population with only two patients dying suddenly (after having ICD turned off or removed). The main cause of death in individuals was still attributed to HCM primary due to heart failure. The genetic cause of HCM in the population was not reported. (Tier 5) Healthcare professionals should offer people with HCM clear and consistent information about the prevention of infective endocarditis, including the benefits and risks of antibiotic prophylaxis (including why prophylaxis is no longer routinely recommended), the importance of maintaining good oral health, education regarding the symptoms of infective endocarditis, and the risks of invasive procedures including non-medical procedures such as body piercing or tattooing. Any episodes of infection in people at risk for infective endocarditis should be investigated and treated promptly to reduce the risk of endocarditis developing.(tier 2) Pregnant women with HCM seeking pregnancy termination should be referred to a hospitalbased provider (with patient permission), with the procedure performed in-hospital after consultation with a cardiologist. (Tier 2) Patients with HCM may benefit from beta-blockers and calcium-channel blockers; however, the usefulness of these agents to alter clinical outcomes is not well established for the management of asymptomatic patients with HCM with or without obstruction.(tier 2) A pilot randomized controlled trial examined the use of diltiazem (a calcium channel blocker) in 38 individuals with a pathogenic or likely pathogenic variant in a sarcomere gene with no cardiovascular symptoms or concomitant illnesses. Participants had a mean age of 15.8 years (range: 5 to 39 years) and received a median of 756 days of treatment. This initial study found that while heart rate and blood pressure did not significantly differ between groups, improved early LV remodeling was improved in the diltiazem treatment group (p<0.001). Over the course of the study four participants developed overt HCM (two in each treatment group). (Tier 5) A diagnosis of HCM is not a contraindication for pregnancy, but female patients should be carefully evaluated in regard to the risk of pregnancy. Expert maternal/fetal medical care and pre-pregnancy risk counseling is advised. Scheduled (induced) vaginal delivery is recommended as the first choice in most patients.(tier 2) Counseling on safe and effective contraception is indicated in all women of fertile age.(tier 2) In individuals with pathogenic variants who do not express the HCM phenotype, it is recommended to perform serial electrocardiogram, transthoracic echocardiogram (TTE), and clinical assessment at periodic intervals (every 1 to 5 years in adults), based on the patient s age and change in clinical status. One study of 235 found that at first cardiac evaluation almost onequarter of asymptomatic carriers of MYBPC3 variants were clinically diagnosed with HCM. Risk factors for SCD were frequently present and 11% of carriers were at risk for SCD. A second study (2-4, 6-8) (9) (10) (6, 11) (2, 3, 6) (12) (2, 6) 3

4 more broadly addressing 76 individuals with HCM associated pathologic variants identified through DNA testing found clinical HCM in 41% of those examined. (Tier 1) Family Management Circumstances to Avoid 24-to-48-hour ambulatory (Holter) electrocardiographic monitoring is recommended for initial evaluation of patients with HCM to detect ventricular tachycardia (VT) and identify patients who may be candidates for ICD and upon development of palpations or lightheadedness. On routine ambulatory (Holter) 24-h ECG monitoring, non-sustained burst of ventricular tachycardia (often asymptomatic) are present in 20-30% of adult HCM patients. (Tier 1) A comprehensive evaluation of diastolic function is recommended to detect diastolic dysfunction and the assessment of LV filling pressures. (Tier 2) Routine laboratory testing aids the detection of extra-cardiac conditions that cause or exacerbate ventricular dysfunction (for example, thyroid disease, renal dysfunction and diabetes mellitus) and secondary organ dysfunction in patients with severe heart failure. First-line laboratory screening should include hematology, glucose, cardiac enzymes (creatine kinase, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase), renal and liver function tests, ph, electrolytes and uric acid. (Tier 2) Irrespective of symptoms, cardiopulmonary exercise testing with simultaneous measurement of respiratory gases (or standard treadmill or bicycle ergometry when unavailable) should be considered to assess the severity and mechanism of exercise intolerance and change in systolic blood pressure. (Tier 2) In pregnant women with HCM, increased surveillance for fetal bradycardia is warranted. (Tier 2) Cascade genetic screening after pre-test counselling, is recommended in first degree-adult relatives of patients with definite pathogenic variant. (Tier 1) First-degree relatives of an affected individual who have not undergone genetic testing, should be clinically screened for HCM. This involves physical examination by a cardiologist, an electrocardiogram, and a transthoracic echocardiogram (TTE). Screening may also include echocardiogram, CK-MM, Holter monitoring, exercise treadmill testing, and MRI. Intervals for screening vary by age (e.g. every 2-3 years until age 30), but should be individually tailored. (Tier 2) Children may be considered for genetic testing starting at age 10 or older. In children whose genetic status is unknown clinical assessment should be considered starting at age 10. Presence of hypertrophy frequently occurs in association with accelerated body growth during the fiveyear period of the adolescent years. It is common for young affected family members <13 years old to represent silent carriers. (Tier 2) Care should be taken to avoid high dose diuretics, venodilators, and arterial vasodilators to avoid vasodilation because these may exacerbate the degree of ventricular obstruction. (Tier 2) Participation in competitive athletics for asymptomatic, genotype-positive HCM patients without evidence of left ventricular hypertrophy is reasonable, particularly in the absence of a family history of HCM-related sudden death. Those who wish to participate should be advised on an individual basis, taking into account the local legal framework, the underlying variant, and the type of sporting activity. Athletes with a probable or unequivocal clinical expression and diagnosis of HCM (i.e., with the disease phenotype of left ventricular hypertrophy) should not participate in most competitive sports, with the exception of those of low intensity.(tier 2) (2, 6) (2, 3, 6, 13) (2, 6) (6, 14) 4

5 Avoid burst activities, like sprinting, as well as intense isometric exercise, such as heavy weight lifting; avoid exercise in extreme environmental conditions and maintain adequate hydration. (Tier 2) 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 5

6 GENE/GENE PANEL: MYBPC3, MYH7, TNNT2, TNNI3, DISORDER: Familial Hypertrophic Cardiomyopathy (HCM) TPM1, MYL3, ACTC1, PRKAG2, MYL2, CSRP3 (including CMH1, CMH2, CMH3, CMH6, CMH7, CMH8, CMH10, CMH11, CMH12) Topic Narrative Description of Evidence Ref 3. What is the chance that this threat will materialize? Mode of Inheritance Prevalence of Genetic Mutations Autosomal dominant In up to 60% of adolescents and adults with HCM, the disease is an autosomal dominant trait caused by pathogenic variants in cardiac sarcomere protein genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL3). Five to ten percent of adult cases are caused by other genetic disorders including 1% associated with PRKAG2. (Tier 3) Penetrance OR Relative Risk (include high risk racial or ethnic subgroups) Expressivity It is unknown how many cases of HCM are due to pathogenic variants in ACTC1 or CSRP3. (Tier 4) The association with specific genes and HCM prognosis remains controversial. (Tier 5) Penetrance of HCM is variable based on the underlying genotype and the age of patient at assessment. Multiple small studies of relatives of HCM probands have found that the penetrance of HCM (based on cardiac evaluation) is over 40% in at least one gene (MYBPC3). (Tier 5) One study of 653 HCM patients with an absence of SCD risk factors and no or mild symptoms (aged 10-75) found that over 10 years of follow up the cumulative sudden death risk was 5.9%. During the follow up ICDs were implanted in an additional 6% of patients based on the development of SCD risk factors. The underlying HCM genes were not reported. (Tier 5) A pooled evaluation of found 22.8% (95% CI: 17.3 to 28.2%) of HCM patients with pathogenic variants in sarcomere-encoding genes developed hypertension. (Tier 1) No information on relative risk was identified. HCM has variable expressivity; clinical manifestations vary from individual to individual even within the same family. 4. What is the nature of the intervention? Nature of Intervention Management of HCM includes regular invasive and non-invasive screening tests and the possible recommendation of ICD therapy, which confers appreciable risk. Reported rates of complications include approximately 25% of patients with HCM who experienced inappropriate ICD discharge; 6% to 13% who experienced lead complications (fracture, dislodgment, oversensing); 4% to 5% who developed a device-related infection; and approximately 2% to 3% who experienced bleeding or thrombosis complications. 5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care? Chance to Escape Clinical Detection General population screening recommendations are inadequate for individuals with HCM. SCD may be the first manifestation of disease. (1) (15) (16-21) (22) (23) (1) (1) 6

7 Final Consensus Scores Gene(s) Outcome/intervention pair Severity Likelihood Effectiveness Nature of the Intervention MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL3, ACTC1, PRKAG2, MYL2, CSRP3 Sudden cardiac death /ICD Implantation (ICD) Total Score 3 2E 3E 2 10EE To see the scoring key, please go to: Date of Search (MM.DD.YYYY): References 1. Cirino A, Ho C. GeneReview: Hypertrophic Cardiomyopathy Overview Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, et al ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124(24): The Cardiac Society of Australia New Zealand. Guidelines for the diagnosis and management of hypertrophic cardiomyopathy Epstein AE, DiMarco JP, Ellenbogen KA, Estes NAM, 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. Circulation. 2013;127(3):e283-e OMIM. CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1; CMH1[cited OMIM. 6. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, et al ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). European heart journal. 2014;35(39): National Institute for Health Care Excellence. Implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, et al. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with familial sudden cardiac death syndromes. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2010;12(8): Magnusson P, Gadler F, Liv P, Morner S. Causes of death and mortality in hypertrophic cardiomyopathy patients with implantable defibrillators in Sweden. Journal of cardiovascular medicine (Hagerstown, Md). 2016;17(7):

8 10. National Institute for Health Care Excellence. Prophylaxis against infective endocarditis: Antimicrobial prophylaxis against infective endocarditis in adults and children undergoing interventional procedures [Update] Guiahi M, Davis A, Society of Family Planning. First-trimester abortion in women with medical conditions. Contraception. 2012;86: Ho CY, Lakdawala NK, Cirino AL, Lipshultz SE, Sparks E, Abbasi SA, et al. Diltiazem treatment for pre-clinical hypertrophic cardiomyopathy sarcomere mutation carriers: a pilot randomized trial to modify disease expression. JACC Heart failure. 2015;3: 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:e Maron BJ, Udelson JE, Bonow RO, Nishimura RA, Ackerman MJ, Estes NA, 3rd, et al. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 3: Hypertrophic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy and Other Cardiomyopathies, and Myocarditis: A Scientific Statement From the American Heart Association and American College of Cardiology. Circulation. 2015;132(22):e Sabater-Molina M, Perez-Sanchez I, Hernandez Del Rincon JP, Gimeno JR. Genetics of hypertrophic cardiomyopathy: a review of current state. Clinical genetics Calore C, De BM, Romualdi C, Lorenzon A, Angelini A, Basso C, et al. A founder MYBPC3 mutation results in HCM with a high risk of sudden death after the fourth decade of life. J Med Genet Terauchi Y, Kubo T, Baba Y, Hirota T, Tanioka K, Yamasaki N, et al. Gender differences in the clinical features of hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations. J Cardiol Page SP, Kounas S, Syrris P, Christiansen M, Frank-Hansen R, Andersen PS, et al. Cardiac myosin binding protein-c mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome. Circulation Cardiovascular genetics. 2012;5: Oliva-Sandoval MJ, Ruiz-Espejo F, Monserrat L, Hermida-Prieto M, Sabater M, Garcia-Molina E, et al. Insights into genotype-phenotype correlation in hypertrophic cardiomyopathy. Findings from 18 Spanish families with a single mutation in MYBPC3. Heart (British Cardiac Society). 2010;96(24): Christiaans I, Birnie E, van Langen IM, van Spaendonck-Zwarts KY, van Tintelen JP, van den Berg MP, et al. The yield of risk stratification for sudden cardiac death in hypertrophic cardiomyopathy myosin-binding protein C gene mutation carriers: focus on predictive screening. European heart journal. 2010;31(7): Michels M, Soliman OI, Phefferkorn J, Hoedemaekers YM, Kofflard MJ, Dooijes D, et al. Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers. European heart journal. 2009;30(21): Spirito P, Autore C, Formisano F, Assenza GE, Biagini E, Haas TS, et al. Risk of sudden death and outcome in patients with hypertrophic cardiomyopathy with benign presentation and without risk factors. Am J Cardiol. 2014;113(9): Lopes LR, Rahman MS, Elliott PM. A systematic review and meta-analysis of genotype-phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations. Heart (British Cardiac Society). 2013;99(24):