Clinical Information

Sudden cardiac death (SCD) is estimated to occur at an incidence of between 50 to 100 per 100,000 individuals in North America and Europe each year, claiming between 250,000 and 450,000 lives in the United States annually. In younger individuals (15-35 years of age), the incidence of SCD is between 1 to 2 per 100,000 young individuals. Sudden cardiac death, particularly in young individuals, may suggest an inherited form of heart disease. In some cases of sudden cardiac death, autopsy may identify a structural abnormality, such as a form of cardiomyopathy. Postmortem diagnosis of a hereditary cardiomyopathy may assist in confirmation of the cause and manner of death, as well as risk assessment in living family members.

Cardiomyopathies are a group of disorders characterized by disease of the heart muscle. Cardiomyopathy can be caused by either inherited, genetic factors or 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, 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 (LVNC).(1)

The hereditary form of HCM is characterized by left ventricular hypertrophy in the absence of other cardiac or systemic causes that may cause hypertrophy of the heart muscle, such as longstanding, uncontrolled hypertension or aortic stenosis. The incidence of HCM in the general population is approximately 1:200 to 1:500, and it is estimated that 30% to 60% of cases can be attributed to a genetic etiology.(2) Hereditary forms of HCM are most often caused by genes encoding proteins of the cardiac sarcomere, the functional contractile unit of the heart muscle.

Hereditary forms of DCM are characterized by ventricular dilation with reduced cardiac performance in the absence of other cardiac or systemic causes that may cause dilation of the heart muscle, such as hypertension and ischemic heart disease. The incidence of DCM in the general population is approximately 1 in 2500, and it is estimated that approximately 50% of cases can be attributed to a genetic etiology.(3) Hereditary forms of DCM are most often caused by genes encoding proteins of the cardiac cytoskeleton and sarcomere.

LVNC is characterized by prominent trabeculations of the left ventricle with trabecular recesses extending into the ventricular cavity. The incidence of LVNC in the general population is estimated to be 1 in 5000.(3) It is currently unclear if LVNC represents a genetically distinct form of cardiomyopathy, as many familial cases of LVNC have been linked to the same genes associated with other forms of hereditary cardiomyopathies and many affected individuals also meet diagnostic criteria for DCM or HCM.(3,4)

Arrhythmogenic cardiomyopathy (ACM) is characterized by the presence of arrhythmogenic cardiac muscle in the absence of ischemic, hypertensive, or valvular cardiac disease. ARVC, the most well-defined form of ACM, is characterized by the breakdown of the myocardium and replacement of right ventricular muscle tissue with fibrofatty tissue, resulting in an increased risk of arrhythmia and sudden death. In some cases, there may also be left ventricular involvement. The prevalence of ARVC (genetic and acquired) is estimated to be 1 in 2000 to 1 in 5000 in the general population.(5)

Hereditary forms of cardiomyopathy may be an isolated finding or may be a feature of an underlying systemic condition. Hereditary forms of cardiomyopathy can follow autosomal dominant, autosomal recessive, X-linked, and digenic patterns of inheritance. Mitochondrial inheritance is also possible, however, genes associated with mitochondrial inheritance of cardiomyopathy are not assessed on this panel.