Dilated Cardiomyopathy Genetic Testing


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Dilated Cardiomyopathy and its Genetics

Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy accounting for one third of cases. Dilated cardiomyopathy is often the end result of damage to the myocardium produced by a variety of insults (e.g. ischemia, virus, toxins such as alcohol and chemotherapeutic agents). In a significant portion of cases of DCM, a definitive etiology cannot be established by standard testing and among these patients; a substantial percentage may have an underlying genetic cause. In general, approximately 20-50% of DCM patients have familial forms of the disease, with mutations of genes encoding cytoskeleton, contractile, or other proteins present in myocardial cells. The incidence of dilated cardiomyopathy has been estimated to be five to eight cases per 100,000 with a prevalence of 1 / 2,700 individuals. However, these figures may underestimate the frequency of the disorder because so many patients with dilated cardiomyopathy are asymptomatic.

Clinical Presentation and Diagnosis

DCM is characterized by dilation and impaired contraction of one or both ventricles (Figure 1). Patients have impaired systolic function (e.g. a reduced ejection fraction) and may or may not develop overt heart failure (HF). The presenting manifestations can include signs and symptoms of heart failure (dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and edema), atrial and/or ventricular arrhythmias. Sudden death can occur at any stage of the disease. Other presentations include the incidental detection of asymptomatic cardiomegaly and symptoms related to coexisting arrhythmia, conduction disturbance or thromboembolic complications.

Figure 1. (Right) Illustration of dilated cardiomyopathy (right), showing a dilated left atrium and left ventricle, bulging interventricular septum from left to right, and thin ventricular walls. For comparison, a normal heart is shown on the left.


Genes involved in DC

Symbol Gene
ACTC1 Alpha cardiac actin
ACTN2 Actinin, alpha2
ANKRD1 Ankyrin repeat domain-containing protein 1
CSRP3 Cysteine- and glycine-rich protein 3
DES Desmin
EDM Emerin
LAMP2 Lysosome-associated membrane protein 2
LMNA Lamin A/C
MTND1 NADH dehydrogenase subunit 1
MTND5 NADH dehydrogenase subunit 5
MTND6 NADH dehydrogenase subunit 5
MTTD Mitochondrial transfer RNA aspartic acid
MTTH Mitochondrial transfer RNA histidine
MTTI Mitochondrial transfer RNA isoleucine
MTTK Mitochondrial transfer RNA lysine
MTTL1 Mitochondrial transfer RNA leucine
MTTL2 Mitochondrial transfer RNA leucine
MTTM Mitochondrial transfer RNA methionine
MTTQ Mitochondrial transfer RNA glutamine
MTTS1 Mitochondrial transfer RNA serine 1
MTTS2 Mitochondrial transfer RNA serine 2
MYBPC3 Cardiac myosin binding protein C
MYH7 Beta myosin heavy chain
NEXN Nexilin-like protein
PLN Phospholamban
RBM20 RNA-binding motif protein 20
SCN5A Sodium channel, voltage-gated, type V, alpha subunit
SGCD Delta-sarcoglycan 
TAZ Tafazzin
TCAP Titan-Cap
TNNC1 Troponin C, slow
TNNI3 Cardiac troponin I
TNNT2 Cardiac troponin T
TPM1 Alpha tropomyosin
TTN Titin
TTR Transthyretin (Amyloidosis)
VCL Vinculin
ZASP Z-band alternatively spliced PDZ motif-containing protein

Genetics of DCM

One-fifth to one-half of patients with DCM have a familial or genetic basis to their disease. Transmission can occur in an autosomal dominant, autosomal recessive or X-linked pattern, depending on the causative genetic abnormality, but autosomal dominant is most common. DCM is genetically heterogeneous and mutations in more than 20 genes have been described (Table: DCM Gene Panel). Many of these mutations have proved to be unique to individual families. It is believed that the abnormal proteins cause contractile dysfunction by impairing the production and/or transmission of force. Mutations in genes encoding sarcomeric proteins, such as a cardiac actin; ß -myosin; heavy chain a -tropomyosin; and troponins T and I account for the majority of identified mutations and are inherited in an autosomal dominant manner. Patients with genetic DCM may also exhibit skeletal myopathies, particularly Duchenne and Emery-Dreyfuss muscular dystrophy. Mutations in the gene encoding the nuclear envelope protein lamin A/C are inherited as an autosomal dominant trait; they are responsible for the development of DCM associated with atrioventricular (AV) conduction disorder and other electrophysiologic disturbances that may cause sudden cardiac death. Mutations in mitochondrial genes have also been reported in DCM and may be maternally inherited.

Genetic testing for Dilated Cardiomyopathy and its utility:

There are several reasons an individual or family may be referred for genetic testing in DCM. Genetic testing in a clinically affected patient can clarify the diagnosis, assist in treatment decisions and stratify risk management. Diagnostic genetic testing may be considered for patients who clinically manifest with symptoms of DCM and for asymptomatic family members of patients with a known mutation. Testing should be performed first on the family member who is symptomatic, i.e. has clinical manifestations of DCM. Preferably, the youngest of most severely affected family members should be tested first. The three possible outcomes of genetic testing are: positive, negative, and variant of unknown clinical significance (VOUS). Identification of a mutation in the family can lead to genetic identification of at risk family members who are clinically asymptomatic and who may have normal echocardiograms. Family members who test positive for the familial mutation should receive regular echocardiographic surveillance. Alternatively, a negative genetic test result for the familial mutation would obviate the need for repeated follow-up examinations. Genetic testing can also be used for prenatal diagnosis, if desired. All patients who undergo genetic testing should receive pre-test and post-test genetic counseling to understand the implications of testing.

Resources for Patients


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