Current perspective new insights into the molecular basis of familial dilated cardiomyopathy

Abstract

Genetic disease transmission has been identified in a significant proportion of patients with dilated cardiomyopathy (DCM). Variable clinical characteristics and patterns of inheritance, as well as recent molecular genetic data, indicate the existence of several genes causing the disease. Several distinct subtypes of familial DCM have been identified. Autosomal dominant DCM is the most frequent form (56% of our cases), and several candidate disease loci have been identified by linkage analysis. Three disease genes are presently known: the cardiac actin gene, the desmin gene, and the lamin A/C gene. This latter gene has recently been found to be responsible for both the autosomal dominant form of DCM with subclinical skeletal muscle disease (7.7% of cases) and the familial form with conduction defects (2.6% of cases) or the autosomal dominant variant of Emery-Dreifuss muscular dystrophy. The autosomal recessive form of DCM accounts for 16% of cases and is characterized by a worse prognosis. An X-linked form of DCM (10% of cases) manifests in the adult population and is due to mutations in the dystrophin gene. In the rare infantile form of DCM, mutations in the G4.5 gene have been identified. Finally, some of the rare unclassifiable forms (7.7% of cases) may be due to mitochondrial DNA mutations. Clinical and experimental evidence based on animal models suggest that, in a large number of cases, DCMs are diseases of the cytoskeleton. However, other causes, such as alterations in regulatory elements and in signaling molecules, are possible. Moreover, other genes called modifier genes can influence the severity, penetrance, and expression of the disease, and they will be a main objective of future investigations. Familial DCM is frequent, cannot be predicted on a clinical or morphological basis and requires family screening for identification. The advances in the genetics of familial DCM can allow improved diagnosis, prevention and genetic counseling, and represent the basis for the development of new therapies.