Stage I: Binning Dashboard

Transcription

1 ACTIONABILITY 1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition? Stage I: Binning Dashboard GENE/GENE PANEL: MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL3, ACTC1, DISORDER: Familial Hypertrophic Cardiomyopathy (HCM) PRKAG2, MYL2 HGNC ID: 7551, 7577, 11949, 11947, 12010, 7584, 143, 9386, 7583 OMIM ID: 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 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? Family Management Circumstances to Avoid ( 1 of above) 3. Is the result actionable in an undiagnosed adult with the genetic condition? 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 GENE/GENE PANEL: MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL3, ACTC1, PRKAG2, MYL2 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 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 of the left ventricle, 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. (1-5) (1-6) Significance/Burden Natural History 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, left ventricular hypertrophy (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. (1;2) 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%. (1;5) HCM is the commonest structural cause of SCD in individuals less than 35 years, including competitive athletes. (3) 2. How effective are interventions for preventing the harm? Information on the effectiveness of the recommendations below was not provided unless otherwise stated. Patient Management No treatments currently exist to prevent or decrease disease development or to reverse established manifestations 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. (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 (1) (2;3;5;7;8) 2

3 in terminating VT/VF despite the complex HCM phenotype. (Tier 2) Healthcare professionals should offer people with HCM clear and consistent information about the prevention of infective endocarditis, including 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. (Tier 2) Pregnant women with HCM seeking a first trimester induced abortion should be referred to a hospital-based provider (with patient permission). (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) (9) (10)(2;3) Surveillance Family Management Circumstances to Avoid 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 is advised. (Tier 2) In individuals with pathogenic mutations who do not express the HCM phenotype, it is recommended to perform serial electrocardiogram, transthoracic echocardiogram (TTE), and clinical assessment at periodic intervals (every 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 mutations were clinically diagnosed with HCM. Risk factors for SCD were frequently present and 11% of carriers were at risk for SCD. A second study more broadly addressing 76 HCM mutation carriers with various mutations identified through DNA testing found clinical HCM in 41% of those examined. (Tier 1) 24-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) In pregnant women with HCM, increased surveillance for fetal bradycardia is warranted. (Tier 2) First-degree relatives of an affected individual 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) Genetic and family counseling is recommended for all patients and families with HCM. (Tier 2) Children of patients with HCM should undergo periodic TTE screening starting by age 12 years. Presence of hypertrophy frequently occurs in association with accelerated body growth during the five-year pear 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) Competitive sports should be avoided in all patients with HCM. Recreational sports in which participation is intense should also be avoided. A number of large cohort studies from the United States indicate that HCM is the most common cardiovascular cause of SCD in young athletes accounting for about one third of these events. Individuals with HCM are disqualified from sanctioned high school and college sports. (Tier 2) (2;3;11) (2;11) (2;3) 3

4 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 GENE/GENE PANEL: MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL3, ACTC1, PRKAG2, MYL2 DISORDER: Familial Hypertrophic Cardiomyopathy (HCM) 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 Information on the prevalence of HCM mutations was not identified. Penetrance OR Relative Risk (include high risk racial or ethnic subgroups) 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. (Tier 5) N/A (12-17) (18) Expressivity 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;4) (1) 4

5 Final Consensus Scores Gene(s) Outcome/intervention pair Severity Likelihood Effectiveness Nature of the Intervention Total Score MYBPC3 MYH7 TNNT2 TNNI3 TPM1 MYL3 ACTC1 PRKAG2 MYL2 Suddent cardiac death/icd implantation 3 2E 2B 2 9EB To see the scoring key, please go to: Date of Search: 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 Dec 13;124(24): (3) The Cardiac Society of Australia and New Zealand, Semsarian C. Guidelines for the diagnosis and management of hypertrophic cardiomyopathy (4) Charron P. Orphanet: Familial isolated hypertrophic cardiomyopathy (5) 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 Jan 22;127(3):e283-e352. (6) McKusick V, Hamosh A. OMIM: Cardiomyopathy, Familial Hypertrophic, 1; CMH (7) National Institute for Health and Care Excellence. Implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure (8) 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 2010 Aug;12(8):

6 (9) National Institute for Health and Care Excellence. Prophylaxis against infective endocarditis: Antimicrobial prophylaxis against infective endocarditis in adults and children undergoing interventional procedures (10) Guiahi M, Davis A, Society of Family Planning. First-trimester abortion in women with medical conditions. Contraception 2012 Dec;86(6): (11) 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 (12) 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 2015 Mar 4. (13) 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 2014 Aug 7. (14) 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. Circ Cardiovasc Genet 2012 Apr 1;5: (15) 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 2010 Dec;96(24): (16) 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. Eur Heart J 2010 Apr;31(7): (17) 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. Eur Heart J 2009 Nov;30(21): (18) 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 May 1;113(9):