Novel Insights into the Prevalence of TNNI3K -Mediated Dilated Cardiomyopathy and Putative Disease Mechanisms

摘要

The genetic background of familial dilated cardiomyopathy (DCM) is substantially more heterogeneous than that of other genetic cardiomyopathies such as arrhythmogenic or hypertrophic cardiomyopathy, which are predominantly due to genetically determined defects in desmosomal or sarcomeric proteins, respectively.1,2 Genetic variants affecting various proteins involved in maintaining the structural integrity or the function of the myocardium are proposed to contribute to a DCM phenotype. As a result, an average of 60 genes is typically included in genetic panel testing for DCM, although only 19 genes have been appraised as high-evidence genes by an international panel of experts on DCM gene curation.2 Despite the use of such comprehensive gene panels, a causative variant can only be identified in about 20 to 50 of the DCM cases,1,3 with variant interpretation additionally challenged by variable expressivity and incomplete penetrance.1 Nevertheless, genetic testing is highly recommended especially in patients with DCM and a conspicuous family history or other clinical features suggesting a heritable disease.3 A genetic diagnosis may enable a better risk stratification, especially since variants in some genes are associated with a higher arrhythmic risk.4 In addition, it allows screening of family members, offering the opportunity of timely diagnosis and (preventive) treatment of affected individuals even before they become symptomatic.4 Therefore, there is a crucial need for both, the identification of new genes involved in the pathogenesis of DCM and the confirmation and validation of candidate genes and variants through further genetic and functional analyses.