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Current, Basic and Advanced Telegenetics Information about genetics DNA structure
The George Washington University Medical Center

Case Study # 29

Dilated Cardiomyopathy and Genetics
-Payal Amin GWUMC SOM 2007

Goals and Objectives:

- Briefly define dilated cardiomyopathy (DCM) and explain the major presenting symptoms
- Describe the genetics and various modes of transmission with DCM
- Describe the idiopathic and nonidiopathic causes of DCM
-Be able to clinically manage patients with DCM

Case Study:
You are a third year medical student asked to do a history and physical on a 30 year-old patient presenting with 3-month history of palpitations and shortness of breath. Family history is significant for sudden death in a maternal uncle at a young age. Physical examination reveals a heart murmur. An electrocardiogram and an echocardiogram are ordered; these tests reveal that the patient likely has dilated cardiomyopathy.

Pretest Questions:

  1. What are the features of DCM?
  2. What type of murmur would you expect to hear?
  3. What are nonidiopathic causes of DCM?
  4. What are idiopathic causes of DCM?
  5. What are the different modes of transmission of familial DCM?
  6. What stages have been described in the Autosomal dominant form of this disease?
  7. What are the diagnostic criteria for familial DCM?
  8. Is genetic testing needed for a patient found to have DCM? What more needs to be done?
  9. Dilated cardiomyopathyWhat is the clinical management of these patients?



  1. What are the features of DCM?

Dilated cardiomyopathy, which is characterized by cardiac dilation and reduced systolic function, represents an outcome of a heterogeneous group of inherited and acquired disorders. The earliest sign of the disease most often seen is arrhythmia and/or conduction defects. Symptoms of pump failure usually are seen in adulthood, in the twenties or thirties. Patients often present with fatigue, dyspnea on exertion, shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, and edema—symptoms of right heart failure. On physical exam one would expect to see signs of heart failure and volume overload—tachypnea, tachycardia, hypertension, jugular venous distension (JVD), pulmonary edema (crackles and/or wheezes), S3 gallop, enlarged liver or hepatojugular reflex, and peripheral edema.

  1. What type of murmur would you expect to hear?

One would expect to hear I/VI-VI/VI holosystolic murmur as a result of mitral valve insufficiency secondary to the dilated ventricles.

  1. What are nonidiopathic causes of DCM?

Causes range from a wide variety of acute diseases, chronic diseases, and toxins. Some include: alcohol, drugs (heavy metals, emetine, doxorubicin, cocaine, methamphetamine, cobalt), infections (HIV, viral endocarditis, parasites, protozoa, Chagas disease), high output states (anemia, thyrotoxicosis, pregnancy), collagen vascular disease, glycogen storage disease, thiamine deficiency, zinc deficiency, hypophosphatemia, amyloidosis, and neuromuscular disorders

  1. What are idiopathic causes of DCM?

Idiopathic DCM causes approximately one-half of all DCMs. Prevalence occurs up to 36.5 per 100,000 and accounts for more than 10,000 deaths in the U.S. annually. It is also the primary indication for cardiac transplantation. Among cases of idiopathic DCM, familial occurrence accounts for 30%, according to surveys. Gene studies have shown isolated DCM to have resulted from mutations in the dystrophin gene. This familial DCM is characterized by an Autosomal dominant pattern of inheritance with age-related penetrance. These patients present with development of ventricular dilatation and systolic dysfunction usually in the second or third decade of life.

  1. What are the different modes of transmission of familial DCM?
  1. Autosomal Dominant (AD)

            Genes associated with AD transmission include: those encoding actin, lamin A/C (CMD1A), and desmin (all cytoskeletal proteins). Mutations are also observed in genes that produce sarcomere protein, alpha-tropomyosin, cardiac troponin T, and cardiac troponin C. These patients tend to develop early-onset ventricular dilation and dysfunction. Additionally, multiple other loci, designated CMD1B-J, have also been identified as causing DCM transmitted as an AD trait.
            AD DCM can present with or without an associated conduction system disease. DCM without conduction system disease has been associated with mutations at loci on chromosomes 1q32, 9q13-22, 10q21-23, and 2q31 (CMD1G). These abnormalities are associated with early-onset and rapidly progressive HF, but may fail to penetrate in some individuals who are carriers. Multiple candidate genes have been identified at some of these loci, but neither disease genes nor mutations have been defined in all cases. However, several genes have been identified: mutation in the gene encoding for the giant-muscle filament titin (2q31 (CMD1G)), the delta-sarcoglycan gene (a member of the dystrophin-associated protein complex), and the gene for phospholamban.
            DCM with conduction system disease is associated with mutations in the gene on chromosome 1p1-q21 that encodes for the nuclear-envelope proteins lamin A and lamin C . Symptoms can range from HF and sudden death to cardiomyopathy with mild skeletal abnormalities. Mutations in the lamin A/C gene can also cause Emery-Dreifuss muscular dystrophy, a childhood-onset disease characterized by joint contractures and abnormalities of conduction in adults. Other mutations associated with conduction disease include genes at chromosome 3p22-25 loci (cardiac sodium channel gene (SCN5A)), chromosome 1p1-1q1 (gap junction protein connexin 40), an unidentified gene on chromosome 19q13.2-13.3 (encodes myotonin protein kinase), and a gene on chromosome 6q23 (CMD1F).

  1. Autosomal Recessive (AR)

            Genes associated with AR transmission include mutations in the ALMS1 gene on chromosome 2p13. This mutation is also associated with Alstrom syndrome, which causes a dilated cardiomyopathy and hearing impairment in association with cone-rod ocular dystrophy, obesity, and type 2 diabetes. A family with Autosomal recessive dilated cardiomyopathy has been reported to have a mutation in the gene for cardiac troponin I.

  1. X-linked

            Dystrophin gene mutationsFamilial dilated cardiomyopathy that is transmitted as an X-linked trait most often results from mutations in the dystrophin gene (Xp21), especially in the 5’ muscle promoter, which can cause a predominant cardiac phenotype. Most dystrophin mutations produce either Duchenne or Becker muscular dystrophy, both of which are associated with cardiac involvement. Skeletal muscle biopsies of individuals with X-linked dilated cardiomyopathy due to dystrophin deletions demonstrate the classic pathologic changes of Duchenne or Becker dystrophies, but the muscle manifestations may be subclinical. Absence of, versus reduction in, dystrophin has been hypothesized to account for the variable dysfunction observed in cardiac compared with skeletal muscle. One study of a family with X-linked cardiomyopathy, without skeletal muscle abnormalities, found that all affected family members had a translation-termination mutation (C4148T) in exon 29 of the dystrophin gene. This mutation was associated with a reduction of beta-sarcoglycan and delta-sarcoglycan in the sarcolemma of cardiac, but not skeletal, muscle.

  1. What stages have been described in the Autosomal dominant form of this disease?

Stage I occurs in the second and third decades and is characterized by absence of symptoms, normal heart size, sinus bradycardia, and premature atrial contractions. Stage II is marked by first-degree AV block in the third and fourth decades. Stage III occurs in the fourth and fifth decades and is accompanied by chest pain, fatigue, lightheadedness, and advanced AV block, followed by the development of atrial fibrillation or flutter. Stage IV occurs in the fifth and sixth decades of life, and is characterized by congestive heart failure and recurrent ventricular arrhythmias.

  1. What is the diagnostic criteria for familial DCM?

One individual diagnosed with idiopathic DCM in a family, with at least:
=>One relative also diagnosed with idiopathic DCM
=>One first-degree relative with an unexplained sudden death under the age of 35 years.

8.    Is genetic testing needed for a patient found to have DCM? What more needs to be done?
Family history should be reviewed in all patients with DCM, especially in those patients who present before the age of 60. Further investigation of relatives should be performed if there are cases of unexplained heart disease, sudden unexpected death, or syncopal episodes. Investigation can be as simple and noninvasive as echocardiography. Early diagnosis is indicated for 2 reasons: treatment of significant arrhythmias may prevent sudden unexpected death, and genetic counseling can be provided. Studies have shown that the familial form of dilated cardiomyopathy is more malignant, occurring at an earlier age, and progressing more rapidly. Thus it is imperative that all patients with this disease have their family members be tested and followed--The 2005 American College of Cardiology/American Heart Association heart failure guidelines concluded that the weight of evidence supported the efficacy (class IIa) of screening asymptomatic first-degree relatives with an electrocardiogram and echocardiography and that families with a highly positive family history should be referred to a cardiovascular genetics center [19].

9.    What is the clinical management of these patients?
Management for these patients is based on symptoms and what is found during testing.  For those with progressive conduction block and sinus block, pacemaker implantation is indicated. However, studies have shown that patients with dilated cardiomyopathy associated with the lamin A/C mutation are better treated with implantable cardioverter-defibrillators (ICD) compared to the standard pacemaker to prevent lethal tachyarrhythmias.

Resources for patients:

American Heart Association
National Center
7272 Greenville Avenue
Dallas, TX 75231
Phone: 1-800-AHA-USA-1

Texas Heart Institute
St. Luke's Episcopal Hospital
6720 Bertner Ave.
Houston, TX  77030 
Phone: 832-355-4011

Cardiomyopathy Association
40 The Metro Centre
Tolpits Lane
Watford Herts WD18 9SB
United Kingdom
Phone: (+44) 1923 249 977
Fax: (+ 44) 1923 249 987


Hunt, SA, Abraham, WT, Chin, MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005; 112:e154.

McKenna W. Genetics of dilated cardiomyopathy. Retrieved August 21, 2006 at

Mestroni L, Maisch B, McKenna WJ, et al. Guidelines for the study of familial dilated cardiomyopathies. Eur Heart J. 1999; 20: 93–102.

Ku L, Feiger J, Taylor M, Mestroni L. Familial dilated cardiomyopathy. American Heart Association. Retrieved August 21, 2006 at 

Last Modified: September 8, 2006
page maintained by Dr. Macri
© 2004 GWUMC