Cardiomyopathies, a group of disorders characterized by disease of the heart muscle, are some of the most common genetic disorders and are a major cause of heart disease in all age groups. Cardiomyopathy can be caused by inherited genetic factors or by nongenetic (acquired) factors 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 may be considered. A considerable percentage of patients with cardiomyopathies have a genetic contribution to their condition and over the past 2 decades there has been a dramatic increase in our understanding of the genetic causes of these 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). The inherited cardiomyopathies display both allelic and locus heterogeneity, whereby a single gene may cause different forms of cardiomyopathy (allelic heterogeneity) and mutations in different genes can cause the same form of cardiomyopathy (locus heterogeneity). The hereditary forms of cardiomyopathy are most frequently associated with an autosomal dominant form of inheritance; however, X-linked and autosomal recessive forms can also occur. In some cases, compound heterozygous (biallelic mutations in the same gene) or homozygous mutations may be present in genes typically associated with autosomal dominant inheritance, often leading to a more severe phenotype. Digenic mutations (2 different heterozygous mutations in separate genes) in autosomal dominant genes have also been reported to occur in patients with severe disease (particularly HCM and ARVC).
Next-generation sequencing (NGS) is a form of genetic analysis that allows the laboratory to analyze a large number of genes in a more efficient manner compared to other technologies. NGS technology has been increasingly used for a number of genetic conditions that display allelic and locus heterogeneity, such as cancer and inherited cardiac disorders. The following multi-gene NGS panels related to inherited forms of cardiomyopathy are now available through Mayo Medical Laboratories.
- DCMGP / Dilated Cardiomyopathy Multi-Gene Panel, Blood
- HCMGP / Hypertrophic Cardiomyopathy Multi-Gene Panel, Blood
- ARVGP / Arrhythmogenic Cardiomyopathy Multi-Gene Panel, Blood
- CCMGP / Comprehensive Cardiomyopathy Multi-Gene Panel, Blood
Dilated cardiomyopathy (DCM) is diagnosed by the presence of left ventricular enlargement and systolic dysfunction. DCM may present with heart failure with symptoms of congestion, arrhythmias and conduction system disease, or thromboembolic disease (stroke). The most recent estimates of the incidence of DCM suggest that the condition affects approximately 1 in every 250 people. These estimates are higher than originally reported due to subclinical phenotypes and underdiagnosis. After exclusion of nongenetic causes such as ischemic injury, DCM is traditionally referred to as “idiopathic” dilated cardiomyopathy. Approximately 20% to 50% of individuals with idiopathic DCM may have an identifiable genetic cause for their disease. Families with 2 or more affected individuals are classified as having familial dilated cardiomyopathy.
Compared with a normal heart, dilated cardiomyopathy causes the chambers of the heart to enlarge, which can lead to heart failure if left untreated.
The majority of familial dilated cardiomyopathy is inherited in an autosomal dominant manner; however, autosomal recessive and X-linked forms can also occur. At least 28 genes have been reported in association with DCM, including genes encoding the cardiac sarcomere and other proteins responsible for cardiac muscle contraction. Some genes associated with DCM also cause other forms of hereditary cardiomyopathy, cardiac channelopathies, skeletal myopathies, or metabolic defects. See Table 1 for details regarding the genes tested by DCMGP / Dilated Cardiomyopathy Multi-Gene Panel, Blood and the conditions associated with them.
The hereditary form of hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy in the absence of other cardiac or systemic causes of hypertrophy of the heart muscle, such as longstanding, uncontrolled hypertension, or aortic stenosis. The pathological hallmark of HCM is “myocyte disarray” where there is a loss of parallel alignment of myocytes in the heart wall. HCM is most often caused by genes encoding the cardiac sarcomere, the functional contractile unit of the heart muscle.
Illustrations of a normal heart (left) and a heart with hypertrophic cardiomyopathy (HCM). Note that the heart walls (muscle) are much thicker (hypertrophied) in the HCM heart.
The clinical presentation of HCM can be variable, even within the same family. HCM can be asymptomatic in some individuals, but can cause life-threatening arrhythmias, which increase the risk of sudden cardiac death. In fact, HCM and ARVC are major contributors to heart-related sudden death in people under age 35 as well as sudden death in athletes. The incidence of HCM in the general population is approximately 1 in 500. Inheritance is autosomal dominant, but compound heterozygosity and digenic inheritance do occur.
Left ventricular hypertrophy can also be caused by metabolic or storage disorders such as Fabry disease (GLA gene), Danon disease (LAMP2 gene), and Wolf-Parkinson-White syndrome (PRKAG2 gene). The TTR gene causes familial transthyretin amyloidosis, which is characterized by buildup of amyloid protein that affects the peripheral and autonomic nervous system. Other nonneuropathic changes may also be involved, including cardiomyopathy.
See Table 2 for details regarding the genes tested by HCMGP / Hypertrophic Cardiomyopathy Multi-Gene Panel, Blood and the conditions associated with them.
Arrhythmogenic cardiomyopathy (ARVC) is 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. Mutations 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. The incidence of ARVC is approximately 1 in 1,000 to 1 in 2,500. 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.
Inheritance of ARVC typically follows an autosomal dominant pattern and mutations in DSC2, DSP, and PKP2 account for approximately one-half of the mutations identified in ARVC. However, simultaneous testing of all known ARVC genes is recommended due to the potential for compound heterozygosity or digenic heterozygosity. See Table 3 for details regarding the genes tested by ARVGP / Arrhythmogenic Cardiomyopathy Multi-Gene Panel, Blood and the conditions associated with them.
In some cases, the diagnosis of a hereditary form of cardiomyopathy may be complicated by borderline or ambiguous clinical findings. Additionally, some families may display more than one form of cardiomyopathy. In these cases, choosing the most appropriate diagnosis-specific panel may be challenging. The comprehensive cardiomyopathy multi-gene panel includes sequence analysis of 55 genes and may be considered for individuals with HCM, DCM, ARVC, or LVNC, who have had uninformative test results from a more targeted, disease-specific test. This test may also be helpful when the clinical diagnosis is not clear, or when there is more than one form of cardiomyopathy in the family history. It is important to note that the number of variants of uncertain significance detected by this panel may be higher than for the disease-specific panels, making clinical correlation more difficult. See Table 4 for details regarding the genes tested by CCMGP / Comprehensive Cardiomyopathy Multi-Gene Panel, Blood and the conditions associated with them.
Inherited cardiomyopathies are some of the most common genetic disorders and are a major cause of heart disease in all age groups, often with an onset in adolescence or early adult life. All of the inherited cardiomyopathies are genetically heterogeneous with multiple associated genes and several different mutations within each category. Genetic testing can play an important role in the confirmation of the diagnosis of cardiomyopathy, appropriate medical management decisions, and more informed genetic counseling for patients and families. Advances in the discovery of the genetic basis of the various forms of cardiomyopathy may serve to guide clinical practice and raise expectations for new forms of novel treatment.
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Authored by Linnea Baudhuin, PhD
Michelle Kluge, CGC
Kate Kotzer, CGC