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 1.0.2
• GENE/GENE PANEL: LMNA, TNNT2
• Condition: Dilated cardiomyopathy
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• LMNA ⇔ 150330: Assertion Pending
• TNNT2 ⇔ 191045: 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 / Surveillance and ICD	3	3C	2B	2	10CB
Sudden cardiac death / Surveillance and pharmacotherapy	3	3C	2C	3	11CC
Delay heart failure / Surveillance and ACE inhibitors	2	3C	2B	3	10CB

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

Prevalence of the Genetic Condition

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, 2, 3, 4]

Clinical Features

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 (fatigue, 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]

Natural History

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, 2, 3]

2. How effective are interventions for preventing harm?

Patient Management

ACE inhibitors and beta-blockers are recommended in patients with a reduced ejection fraction to prevent heart failure. (Tier 2) [5]

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=0.84-0.95, 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=0.59-0.75; RR in women=0.63, 95% CI=0.44-0.91). However, the heart failure mortality benefit of ACE inhibitors was detected in men (RR=0.82, 95% CI=0.74-0.90) but not women (RR=0.92, 95% CI=0.81-1.04). (Tier 5) [6, 7]

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=0.56-0.86; 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) [8, 9]

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

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) [1, 3]

Surveillance

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 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) [9]

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) [3]

Circumstances to Avoid

No circumstances-to-avoid recommendations have been provided for the Adult context.

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

Mode of Inheritance

Autosomal Dominant
TNNT2- and LMNA-associated FDC are inherited in an autosomal dominant manner. [3]

Prevalence of Genetic Variants

TNNT2 and LMNA are associated with 2.9% and 7.3% of FDC and 1.6% and 3.0% of sporadic DCM, respectively. (Tier 3) [9]

Information on the prevalence of genetic mutations associated with FDC in the general population was not available.

Penetrance

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]

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) [11]

Relative Risk

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

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.

Reference List

1. Familial isolated dilated cardiomyopathy. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=154

2. Posafalvi A, Herkert JC, Sinke RJ, van den Berg MP, Mogensen J, Jongbloed JD, van Tintelen JP. Clinical utility gene card for: dilated cardiomyopathy (CMD). Eur J Hum Genet. (2013) 21(10).

3. RE Hershberger, A Morales. Dilated Cardiomyopathy Overview. 2007 Jul 27 [Updated 2015 Sep 24]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1309

4. Hershberger RE, Morales A, Siegfried JD. Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals. Genet Med. (2010) 12(11):655-67.

5. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL. 2013 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):e147-239.

6. 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):1843-8.

7. Shekelle PG, Rich MW, Morton SC, Atkinson CS, Tu W, Maglione M, Rhodes S, Barrett M, Fonarow GC, Greenberg B, Heidenreich PA, Knabel T, Konstam MA, Steimle A, Warner Stevenson L. 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):1529-38.

8. 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, Tracy CM, Epstein AE, Darbar D, DiMarco JP, Dunbar SB, Estes NA 3rd, Ferguson TB Jr, Hammill SC, Karasik PE, Link MS, Marine JE, Schoenfeld MH, Shanker AJ, Silka MJ, Stevenson LW, Stevenson WG, Varosy PD. 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. J Am Coll Cardiol. (2013) 61(3):e6-75.

9. Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, Katz SD, Klapholz M, Moser DK, Rogers JG, Starling RC, Stevenson WG, Tang WH, Teerlink JR, Walsh MN. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. (2010) 16(6):e1-194.

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. RE Hershberger, A Morales. LMNA-Related Dilated Cardiomyopathy. 2008 Jun 12 [Updated 2016 Jul 07]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1674