Dilated cardiomyopathy

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Genes: DMD (HGNC:2928) LMNA (HGNC:6636) TNNT2 (HGNC:11949)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 07/29/2015
• Curation Status: Released - Under Revision (2.1.3)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
DMD	dilated cardiomyopathy 3B (0010542)	302045	Assertion Pending
LMNA	dilated cardiomyopathy 1A (0007269)	115200	Assertion Pending
TNNT2	dilated cardiomyopathy 1D (0011095)	601494	Assertion Pending

Actionability Assertion 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.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Sudden cardiac death / Surveillance and implantable cardiac device (ICD)	3	2B	2B	2	9BB
Sudden cardiac death / Surveillance and pharmacotherapy	3	2B	2N	3	10BN
Earlier heart failure / Surveillance and ACE inhibitors	2	3B	2N	3	10BN

Severity of Outcome

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. The prevalence of DCM has likely been underestimated due to the fact that individuals may remain asymptomatic until marked ventricular dysfunction has occurred. However, further studies have not been published. It is not clear how many DCM cases are due to genetic pathogenic variants in LMNA, TNNT2, and DMD.

Clinical Features (Signs / symptoms)

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, paroxysmal nocturnal 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.

Natural History (Important subgroups & survival / recovery)

DCM may be asymptomatic with only mild ventricular dilation and dysfunction for years. Presentation of clinical symptoms usually occurs late in the disease course. Usually, by the time of the diagnosis individuals have severe impairment of the left ventricular ejection function (LVEF) and are in New York Heart Association (NYHA) functional class III-IV. 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. DCM 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.DCM due to pathogenic variants in LMNA presents with mild dilation and severe dysfunction of the left ventricle, conduction defects, supraventricular arrhythmias, variable skeletal muscle involvement and variable serum creatine kinase (CK) levels. The prognosis for many of these patients is not favorable. DCM due to pathogenic variants in DMD has a less severe prognosis and presents with increased CK, muscular abnormalities, and the typical signs of dystrophinopathy at the skeletal muscle biopsy. A meta-analysis of DCM cases, estimated that patients with LMNA pathogenic variants had a mean age of onset of 40 years (95% CI: 35-45), while patients with TNNT2 pathogenic variants had an earlier mean age of onset at 35 years (95% CI: 23-47). Among patients included in the meta-analysis, the rate of heart transplantation was 27% for LMNA and 17% for TNNT2.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

TNNT2- and LMNA- associated DCM is inherited in an autosomal dominant manner. DMD-associated DCM is inherited in an X-linked manner.

Prevalence of Genetic Variants

>1-2 in 100

A meta-analysis reported that pathogenic variants in LMNA had a pooled frequency of 5% (95% CI: 3-7%) among familial and sporadic DCM cases, and TNNT2 had a pooled frequency of 2% (95% CI: 1-3%).

Tier 1

It is unknown how many cases of DCM are associated with DMD.

Tier 4

Information on the prevalence of pathogenic variants associated with DCM in the general population was not available.

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

Overall, DCM has age-related penetrance: 10% by age <20 years, 34% by age 30, 60% by age 40, and 90% for more advanced ages (>40).

Tier 3

>= 40 %

A meta-analysis reported rates of heart transplantation of 27% for LMNA and 17% for TNNT2. Additional penetrance estimates specific to LMNA-related DCM were also reported:DCM or left ventricle dysfunction = 45%

Conduction system disorders (included sinus dysfunction, atrioventricular conduction blocks, bundle branch blocks, or hemiblocks) =52% (74% in those with DCM, 40% in those without DCM)

Supraventricular tachycardia (included atrial fibrillation, atrial flutter, or ectopy) = 43% (62% in those with DCM, 13% in those without DCM)

Ventricular arrhythmia = 29% (50% in those with DCM, 5% in those without DCM)

SCD = 6% (19% in those with DCM, 3% in those without DCM)

Skeletal muscle affection: 26% (46% in those with DCM, 26% in those without DCM.

Tier 1

Unknown

Specific penetrance estimates of DCM were not available for TNNT2- or DMD- related DCM.

Tier Not provided

Expressivity

DCM has highly variable age of onset.

Tier 3

Intervention Effectiveness

Patient Management

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=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

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

Pregnant women with DCM seeking a first trimester induced abortion should be referred to a 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

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

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

Nature of Intervention

Nature of Intervention

Identified interventions include non-invasive surveillance, pharmacotherapy, and possible ICD implantation, which could be associated with moderate risk.

Context: Adult

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.

Context: Adult

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			DMD			302045	0010542
LMNA			115200	0007269
TNNT2			601494	0011095

References List

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Kayvanpour E, Sedaghat-Hamedani F, Amr A, Lai A, Haas J, Holzer DB, Frese KS, Keller A, Jensen K, Katus HA, Meder B. (2017) Genotype-phenotype associations in dilated cardiomyopathy: meta-analysis on more than 8000 individuals. Clinical research in cardiology : official journal of the German Cardiac Society. 106(2):127-139.

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Posafalvi A, Herkert JC, Sinke RJ, van den Berg MP, Mogensen J, Jongbloed JD, van Tintelen JP. (2013) Clinical utility gene card for: dilated cardiomyopathy (CMD). European journal of human genetics : EJHG. 21(10).

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