Genetics of dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a primary heart muscle disorder characterized by cardiac dilatation and impaired systolic function. In approximately half of all DCM patients a specific etiology can be identified and in the remaining cases DCM is termed idiopathic. There is wide variation of the clinical presentation in DCM. The majority of patients manifest classical disease, i.e., heart failure due to left (and right) ventricular systolic dysfunction. However, some cases may first come to clinical attention because of supraventricular arrhythmias such as sinus node dysfunction, AV-block or atrial fibrillation. Although a multitude of etiologies may be responsible for DCM (e.g., viral, immunological, toxic), the disease is inherited in at least 30–40% of cases. Most genetic forms of DCM are caused by autosomal dominant gene defects. Six dominant disease loci on chromosomes 1p1-q1, 1q32, 3p22-p25, 6q23, 9q13, and 10q21-q23 have been mapped by linkage analyses. Cardiac actin chromosome 15q 14–22 was recently suspected as a DCM disease gene, and two point mutations were identified. Presumably these mutations cause perturbations in anchoring the thin filament to the Z-band of the sarcomere. The effect may be destabilization of the force generating apparatus. The prevalence of actin mutations in DCM is, however, unknown and it remains unclear whether mutations in other cytoskeletal proteins account for the remaining cases of autosomal dominant DCM. Mutations in another gene, dystrophin, can cause X-linked forms of DCM. In contrast to Duschenne or Becker muscular dystrophy, skeletal muscles are clinically unaffected in X-linked DCM. However, X-linked DCM as well as autosomal recessive mutations and mutations in mitochondrial DNA are rare causes for genetic forms of DCM.