Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 1.0.0
• GENE/GENE PANEL: MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL3, ACTC1, PRKAG2, MYL2
• Condition: Familial Hypertrophic Cardiomyopathy
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• MYBPC3 ⇔ 115197: Assertion Pending
• MYH7 ⇔ 192600: Assertion Pending
• TNNT2 ⇔ 115195: Assertion Pending
• TNNI3 ⇔ 613690: Assertion Pending
• TPM1 ⇔ 115196: Assertion Pending
• MYL3 ⇔ 608751: Assertion Pending
• ACTC1 ⇔ 612098: Assertion Pending
• PRKAG2 ⇔ 600858: Assertion Pending
• MYL2 ⇔ 608758: Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Sudden Cardiac Death / ICD	3	2E	2B	2	9EB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

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. [1, 2, 3, 4, 5]

Clinical Features

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, 2, 3, 4, 5, 6]

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.
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. [1, 2, 3, 5]

2. How effective are interventions for preventing harm?

Patient Management

No treatments currently exist to prevent or decrease disease development or to reverse established manifestations [1]

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) [2]

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) [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 left-ventricular 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) [2, 3, 5, 7, 8]

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) [9]

Pregnant women with HCM seeking a first trimester induced abortion should be referred to a hospital-based provider (with patient permission). (Tier 2) [10]

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) [2, 3]

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) [2]

Surveillance

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 one-quarter 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) [2]

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) [2]

In pregnant women with HCM, increased surveillance for fetal bradycardia is warranted. (Tier 2) [2]

Circumstances to Avoid

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) [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]

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) [2]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

No genetic variant prevalence information has been provided for the Adult context.

Penetrance

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). Information on the penetrance of SCD was not identified. (Tier 5) [11, 12, 13, 14, 15, 16]

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) [17]

Relative Risk

Information on relative risk was not available for the Adult context.

Expressivity

HCM has variable expressivity; clinical manifestations vary from individual to individual even within the same family. [1, 4]

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. [2]

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]

Date of Search: 06.07.2015

Reference List

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2. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW. 2011 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):2761-96.

3. Guidelines for the diagnosis and management of hypertrophic cardiomyopathy. Other. (2013) Website: http://www.csanz.edu.au/documents/guidelines/clinical_practice/Hyertrophic_Cardiomyopathy.pdf

4. Familial isolated hypertrophic cardiomyopathy. Orphanet encyclopedia

5. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO. 2012 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):e283-352.

6. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1; CMH1. MIM: 192600: 2016 Aug 04. World Wide Web URL: http://omim.org.

7. Implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure. NICE. (2014) Website: https://www.nice.org.uk/guidance/ta314

8. Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, O'Callagan P, Stuart G, Watkins H. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with familial sudden cardiac death syndromes. Europace. (2010) 12(8):1156-75.

9. Prophylaxis against infective endocarditis Antimicrobial prophylaxis against infective endocarditis in adults and children undergoing interventional procedures.. NICE. (2008) Website: https://www.nice.org.uk/guidance/cg64

10. Guiahi M, Davis A. First-trimester abortion in women with medical conditions: release date October 2012 SFP guideline #20122. Contraception. (2012) 86(6):622-30.

11. Calore C, De Bortoli M, Romualdi C, Lorenzon A, Angelini A, Basso C, Thiene G, Iliceto S, Rampazzo A, Melacini P. A founder MYBPC3 mutation results in HCM with a high risk of sudden death after the fourth decade of life. J Med Genet. (2015) 52(5):338-47.

12. Terauchi Y, Kubo T, Baba Y, Hirota T, Tanioka K, Yamasaki N, Furuno T, Kitaoka H. Gender differences in the clinical features of hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations. J Cardiol. (2015) 65(5):423-8.

13. Page SP, Kounas S, Syrris P, Christiansen M, Frank-Hansen R, Andersen PS, Elliott PM, McKenna WJ. 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) 5(2):156-66.

14. Oliva-Sandoval MJ, Ruiz-Espejo F, Monserrat L, Hermida-Prieto M, Sabater M, Garcia-Molina E, Ortiz M, Rodriguez-Garcia MI, Nunez L, Gimeno JR, Castro-Beiras A, Valdes M. Insights into genotype-phenotype correlation in hypertrophic cardiomyopathy. Findings from 18 Spanish families with a single mutation in MYBPC3. Heart. (2010) 96(24):1980-4.

15. Christiaans I, Birnie E, van Langen IM, van Spaendonck-Zwarts KY, van Tintelen JP, van den Berg MP, Atsma DE, Helderman-van den Enden AT, Pinto YM, Hermans-van Ast JF, Bonsel GJ, Wilde AA. 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) 31(7):842-8.

16. Michels M, Soliman OI, Phefferkorn J, Hoedemaekers YM, Kofflard MJ, Dooijes D, Majoor-Krakauer D, Ten Cate FJ. Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers. Eur Heart J. (2009) 30(21):2593-8.

17. Spirito P, Autore C, Formisano F, Assenza GE, Biagini E, Haas TS, Bongioanni S, Semsarian C, Devoto E, Musumeci B, Lai F, Yeates L, Conte MR, Rapezzi C, Boni L, Maron BJ. Risk of sudden death and outcome in patients with hypertrophic cardiomyopathy with benign presentation and without risk factors. Am J Cardiol. (2014) 113(9):1550-5.