Clinical Guidance

No specific genotype-phenotype correlations have been established for LMNA-related DCM. A few studies focusing on pathogenic variant type suggest a correlation between splice site variants and increased risk for sudden cardiac death , and between non-missense variants (indel, truncating, splice site) and risk for malignant ventricular arrhythmias.

Source: GeneReviews — "LMNA-Related Dilated Cardiomyopathy"

Penetrance

LMNA-related DCM demonstrates age-related penetrance with onset in the third and fourth decades, so that by the seventh decade penetrance is considered greater than 90%-95%.

Source: GeneReviews — "LMNA-Related Dilated Cardiomyopathy"

Diagnostic Criteria

Suggestive Findings

LMNA-related dilated cardiomyopathy (DCM) should be considered in individuals with the following clinical findings and family history.

Clinical findings

Source: GeneReviews — "LMNA-Related Dilated Cardiomyopathy"

Differential Diagnosis

The genetic differential diagnosis of idiopathic dilated cardiomyopathy (DCM) should include all genes known to be associated with nonsyndromic DCM. Particular attention can be focused on nonsyndromic DCM-related genes that have been associated with arrhythmia and conduction system disease phenotypes (see Dilated Cardiomyopathy Overview, Table 2. Nonsyndromic Dilated Cardiomyopathy Genes: Distinguishing Features).

Source: GeneReviews — "LMNA-Related Dilated Cardiomyopathy"

Management Guidelines

Guidelines for the clinical evaluation and surveillance of individuals with LMNA-related DCM and other genetic cardiomyopathies have been published . Additional guidance regarding the management of arrhythmic disease in LMNA-related DCM is also available . Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with LMNA-related DCM, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with LMNA-Related DCM

Source: GeneReviews — "LMNA-Related Dilated Cardiomyopathy"

Clinical Guidance

Drugs (beta blockers, calcium channel blockers, others) that exacerbate heart block, if present, should be avoided in LMNA-related DCM unless an electronic pacemaker or implantable cardioverter defibrillator is in place.

Source: GeneReviews — "LMNA-Related Dilated Cardiomyopathy"

Therapies Under Investigation

Drugs aimed at reducing mitogen-activated protein (MAP) kinase signaling, a mechanism which has been shown to be increased in LMNA-associated DCM, are actively under investigation (ClinicalTrials.gov identifier NCT02351856) . Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "LMNA-Related Dilated Cardiomyopathy"

Surveillance Guidelines

Table 5.

Recommended Surveillance for Individuals with LMNA-related DCM

System/Concern | Evaluation | Frequency

LMNA variant w/any EKG abnormality

| Cardiovascular eval for disease progression w/EKG, 24-48 hr rhythm monitoring, LV function measurement | Annually (at a minimum)

LMNA variant in an asymptomatic person

| Cardiovascular eval (medical history, physical exam, echocardiogram, EKG) | Every 1-2 yrs /or whenever new symptoms arise

Source: GeneReviews — "LMNA-Related Dilated Cardiomyopathy"