Author + information
- Wolfgang Poller, MD⁎ (, )
- Heinz-Peter Schultheiss, MD and
- Uwe Kühl, MD, PhD
- ↵⁎Charite-Universitätsmedizin Berlin, Cardiology and Pneumology, Hindenburgdamm 30, Berlin, 12200, Germany
In their interesting and recent state-of-the-art study, Burkett and Hershberger (1) stated that “familial dilated cardiomyopathy (DCM) demonstrates incomplete penetrance, variable expression, and significant locus and allelic heterogeneity, making clinical and genetic diagnosis complex.” The statement clearly describes a key problem encountered during the genetic dissection of human DCM. This problem reaches beyond the fact that multiple genes may cause the DCM phenotype in humans and that further loci shall be revealed in the future. Even within a single DCM family or within a group of unrelated DCM patients harboring defects in the same gene, there is often very large and currently unexplained phenotypic heterogeneity. There are at least two possible sources for this heterogeneity.
First, unless representative healthy control populations are screened for a given mutation one cannot be sure that this mutation is capable of causing the phenotype without additional cofactors (modifier genes or environmental agents) being present. In other genetic disorders the screening of large control populations has been the indispensable basis for the discovery of such cofactors. For example, smoking was identified as an essential environmental factor for the development of lung disease in genetic α1-antitrypsin deficiency, initially assumed to cause the disease per se on a pure genetic basis. For most mutations associated with DCM we do not yet have frequency data representative of the general healthy population that can be compared with the rather small DCM patient cohorts from which the disease association is usually derived. The relative pathogenic contribution of the gene defect per se as compared to hitherto unknown cofactors is therefore uncertain.
Second, data on possible environmental agents are sparse in molecular genetic studies of familial DCM. Regarding such cofactors, we have recently detected cardiac viral infections in 165 (67.4%) of 245 cases in a molecular virological survey based on myocardial biopsies from a series of DCM patients (2), with a broad spectrum of virus species being involved. Cardiotropic viruses thus emerged as prevalent environmental factors that may possibly cause or influence the course of DCM. The high frequency of cardiotropic viruses detected in that DCM series makes it highly likely that cardiac viruses are also encountered in familial DCM. They may explain part of the large phenotypic heterogeneity mentioned by Burkett and Hershberger (1), but will go unnoticed unless cardiac biopsies are specifically investigated using molecular virological methods. A synopsis of the current data suggests that a comprehensive picture of the pathogenesis of familial DCM can only be obtained if both genetic and environmental factors are analyzed. Studies of this type may lead to the identification of important new genome-environment interactions in DCM pathogenesis (3) and also have implications for the clinical management of DCM patients.
- American College of Cardiology Foundation
- Burkett E.L.,
- Hershberger R.E.
- Kühl U.,
- Pauschinger M.,
- Noutsias M.,
- et al.