Dilated Cardiomyopathy Panel, Sequencing

Dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement with impaired contractility and systolic dysfunction (typically defined as a left ventricular ejection fraction of <50%). DCM is a leading cause of symptoms requiring heart transplantation in children and adults. Although it is often an acquired condition, it may also be familial or a feature of a heritable syndrome. Familial DCM is most commonly inherited in an autosomal dominant manner. It typically manifests in adults during the fourth to sixth decade of life; however, it can present at any age and risk for developing DCM after 50 years of age is reduced.

Affected individuals are at risk for heart failure, arrhythmias or conduction disease, pregnancy-related cardiomyopathy, stroke, and sudden cardiac death. Symptoms may include dyspnea, chest pain, palpitations, fatigue, fainting, or edema. Some individuals remain asymptomatic. Syndromic forms of DCM include extracardiac manifestations, and identification of such disorders is important to enable appropriate management.

Molecular testing for individuals with DCM is recommended to determine if a genetic etiology can be identified, which can facilitate patient management and screening of at-risk relatives.

Disease Overview

Associated Disorders

Nonsyndromic Familial DCM

Should be considered if two or more individuals within a single family experience DCM or if a relative of an individual with DCM has experienced unexplained sudden death <35 years of age

Genetics

Genes

See table of Genes Tested.

Etiology

Pathogenic germline variants in genes associated with familial DCM:

• Genetically heterogeneous disease with unique or "private" variants being common 
• Genes implicated include those encoding components of the cytoskeleton, sarcomere, Z-disk, nuclear envelope, and those involved with calcium regulation/ion channels.

Other heritable forms of cardiomyopathy may have phenotypic overlap with DCM :

• Cases of arrhythmogenic right ventricular cardiomyopathy (ARVC) with predominant left ventricular involvement
• Hypertrophic cardiomyopathy (HCM) progressing to end-stage disease with impaired systolic function and/or left ventricular dilation

Penetrance

Variable; influenced by gene, age, and nongenetic factors

Prevalence of DCM

• Estimated at 1:250 to 1:2,500
• 20-50% of cases are familial

Inheritance

• Familial DCM is typically autosomal dominant.
• Compound heterozygous or digenic heterozygous variants may result in severe and early onset disease.
• Genes with X-linked, autosomal recessive, or mitochondrial inheritance are also associated with DCM.
• De novo variation may be found in children or adults.

Clinical Sensitivity

• 25-40% for familial DCM and 10-25% for isolated DCM 
• Core genes for HCM and ARVC are included on this DCM panel due to gene/phenotype overlap.

Analytic Sensitivity

For massively parallel sequencing:

Limitations

• A negative result does not exclude a diagnosis of familial dilated cardiomyopathy.
• Diagnostic errors can occur due to rare sequence variations.
• Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
• The following will not be evaluated:
  • Variants outside the coding regions and intron-exon boundaries of targeted genes
  • Regulatory region and deep intronic variants
  • Large deletions/duplications/inversions in any of the tested genes (Large deletions/duplications account for <1% of causative variants for familial DCM. )
  • Noncoding transcripts
  • The following exons are not sequenced due to technical limitations of the assay:
    • FLNC (NM_001458) exons 47, 48
    • PRKAG2 (NM_016203) exons 10, 13
    • TTN (NM_001267550) exons 172, 173, 175, 176, 177, 178, 179, 180, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 215
    • TTN (NM_133378) exons 153, 154, 155
• The following may not be detected:
  • Deletions/duplications/insertions of any size by massively parallel sequencing
  • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
  • Low-level somatic variants