ABSTRACT
Prior to 1992, the importance of hereditary factors in the pathogenesis of idiopathic dilated cardiomyopathy (DCM) was not fully recognized. Even a focused family history identified a hereditary form of DCM in only 6-8% of cases.1 Moreover, when familial and non-familial cases of idiopathic DCM were compared, no differences in baseline clinical, serological, or histopathological characteristics or in long-term outcome were observed to help distinguish familial cases.1,2 The concept of DCM as a monogenic disorder received major impetus from a 1992 study in which first-degree relatives of index patients were screened by echocardiography.1 DCM, defined as left ventricular ejection fraction <50%, and left ventricular dimensions >95th percentile for body surface area and age, was identified in presymptomatic members of several families, accounting for a 20% frequency of familial disease in this patient cohort. These findings were reproduced in a similar study, which identified familial disease in 25% of cases.3 In both studies, the average age at diagnosis in probands and their relatives was in the fourth to fifth decade, yet children in their first decade of life were also diagnosed with either symptomatic or clinically silent DCM. In studies that have performed screening echocardiograms on relatives of the index cases, 9-18% of asymptomatic individuals had left ventricular (LV) enlargement with normal ejection fraction, suggesting that cardiac dilation is a precursor of DCM.1,3 Indeed, progression to DCM was confirmed in subsequent longitudinal follow-up studies.4,5 If less stringent criteria, such as isolated LV enlargement or sudden unexplained death, are used to diagnosis DCM in relatives, the frequency of familial disease may be as high as 35-48%.4,6 The importance of genetics in the pathogenesis of DCM, in fact, may be even greater than suggested by these studies. For example, sporadic cases can be caused by de novo mutations, inheritance of two copies of a recessive mutation due to parental consanguinity, or the combined effects of two or more distinct mutations which are clinically silent in isolation.
