Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Cardiomyopathy, familial dilated form (DCM) [I42.0]

OMIM numbers: 115200, 150330 (LMNA), 160760 (MYH7), 600958 (MYBPC3), 191045 (TNNT2)

Dr. rer. nat. Christoph Marschall

Scientific Background

Dilated cardiomyopathy (DCM) is characterized by dilation and limited contraction of the left or of both ventricles. The prevalence is approximately 1 in 2,500. The disease is usually accompanied by progressive cardiac insufficiency. DCM is generally detectable with echocardiography. There is a significant risk of arrhythmia, thromboembolism and sudden cardiac death. Although treatment has improved, the 5 year survival rate is 36-80%. Terminal cardiac insufficiency frequently indicates heart transplantation. It has been shown that only half of all DCM cases with seemingly unknown cause are in fact idiopathic (IDCM) and not secondary due to other primary diseases. It is therefore important to rule out secondary DCM before genetic diagnostic procedures are being arranged. IDCM is genetic (FDCM) in up to 35% of all cases and usually follows an autosomal dominant pattern of inheritance. To ensure a more favorable course of the disease, it is essential to identify carriers as early as possible.

The genetic causes of IDCM/FDCM are heterogenous; by now, more than 30 causative genes have been identified. More than ten years ago, mutations in the LMNA gene, which encodes structural proteins of the inner membrane of the cell nucleus, have been identified in association with DCM. An extensive study showed that approx. 6-8% of all IDCM/FDCM patients are carrying mutations in LMNA. Changes in various sarcomer proteins were in many cases also identified as cause of IDCM/FDCM. Approximately one quarter of all cases are carrying mutations in the genes of the ß myosin heavy chain (MYH7), the myosin binding protein C (MYBPC3), troponin T (TNNT2) and troponin I (TNNI3). Mutations in these genes have been mentioned a lot more often in connection with HCM; however, by now more than 100 different mutations specific for DCM are known. By analyzing the four mostly affected genes, causative mutations can be detected in approx. one third of all IDCM/FDCM cases.

More recent studies involving over 300 IDCM patients showed that mutations in the largest human gene titin (TTN) are causing the disease in approx. 25% of all cases. These mutations are severe and lead to functional loss. The penetrance of these mutations, however, is reduced. Therefore, the cause should be confirmed in every family by analyzing several family members. Due to its size, the gene can only be analyzed with innovative sequencing procedures. Another advantage of this procedure is that at least 20 genes that exhibit several mutations associated with DCM can be analyzed at the same time.