Clinical Information

The cardiomyopathies are a group of disorders characterized by disease of the heart muscle. Cardiomyopathy can be caused by inherited, genetic factors, or by nongenetic (acquired) causes such as infection or trauma. When the presence or severity of the cardiomyopathy observed in a patient cannot be explained by acquired causes, genetic testing for the inherited forms of cardiomyopathy may be considered. Overall, the cardiomyopathies are some of the most common genetic disorders. The inherited forms of cardiomyopathy include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC or AC), and left ventricular noncompaction.

ARVD is characterized by breakdown of the myocardium and replacement of the muscle tissue with fibrofatty tissue, resulting in an increased risk of arrhythmia and sudden death. The incidence of ARVC is approximately 1 in 1000 to 1 in 2500. Age of onset and severity are variable, but symptoms typically develop in adulthood. ARVC is present in 4% to 22% of athletes with sudden cardiac death, and there is some debate whether high-intensity endurance exercise may cause development of ARVC.

ARVC is typically considered a disease of the desmosome, the structure that attaches heart muscle cells to one another. The desmosome provides strength to the muscle tissue and plays a role in signaling between neighboring cells. Variants in the genes associated with ARVC disrupt this function, causing detachment and death of myocardial cells when the heart muscle is under stress. Damaged myocardium is replaced with fat and scar tissue, eventually leading to structural and electrical abnormalities that can lead to arrhythmia.

Inheritance of ARVC typically follows an autosomal dominant pattern of inheritance, and variants in DSC2, DSP, and PKP2 account for approximately half of the variants identified in ARVC. However, simultaneous testing of all known ARVC genes is recommended due to the potential for compound heterozygosity (biallelic variants on the same gene) or digenic heterozygosity (variants in 2 different genes). See table for details regarding the genes tested by this panel and associated diseases.

Table: Genes included in this panel

Abbreviations not previously defined: Restrictive cardiomyopathy (RCM), limb-girdle muscular dystrophy (LGMD), Emory muscular dystrophy (EMD), catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome (LQTS), autosomal dominant (AD), autosomal recessive (AR)