Familial dilated cardiomyopathy: Evidence for genetic and phenotypic heterogeneity

OBJECTIVES This study was performed to evaluate the characteristics, mode o f inheritance and etiology of familial dilated cardiomyopathy (FDC). BACKGROUND A genetic form of disease transmission has been identified in a relevant proportion of patients with dilated cardiomyopathy (DCM). Variable clinical characteristics and patterns of inheritance, and an increased fre quency of cardiac antibodies have been reported. An analysis of FDC may imp rove the understanding of the disease and the management of patients. METHODS Of 350 consecutive patients with idiopathic DCM, 281 relatives from 60 families were examined. Family studies included clinical examination, e lectrocardiography, echocardiography and blood sampling. Of the 60 DCM inde x patients examined, 39 were attributable to FDC and 21 were due to sporadi c DCM. Clinical features, histology, mode of inheritance and autoimmune ser ology were examined, molecular genetic studies were undertaken and the diff erence between familial and sporadic forms was analyzed. RESULTS Only a younger age (p = 0.0005) and a higher ejection fraction (p = 0.03) could clinically distinguish FDC patients from those with sporadic D CM. However, a number of distinct subtypes of FDC were identified: 1) autos omal dominant, the most frequent form (56%); 2) autosomal recessive (16%), characterized by worse prognosis; 3) X-linked FDC (10%), with different mut ations of the dystrophin gene; 4) a novel form of autosomal dominant DCM wi th subclinical skeletal muscle disease (7.7%); 5) FDC with conduction defec ts (2.6%), and 6) rare unclassifiable forms (7.7%). The forms with skeletal muscle involvement were characterized by a restrictive filling pattern; th e forms with isolated cardiomyopathy had an increased frequency of organ-sp ecific cardiac autoantibodies. Histologic signs of myocarditis were frequen t and nonspecific. CONCLUSIONS Familial dilated cardiomyopathy is frequent, cannot be predicte d on a clinical or morphologic basis and requires family screening for iden tification. The phenotypic heterogeneity, different patterns of transmissio n, different frequencies of cardiac autoantibodies and the initial molecula r genetic data indicate that multiple genes and pathogenetic mechanisms can lead to FDC. (C) 1999 by the American College of Cardiology.