Wrestling the Giant

In the recent past, the clinical availability of genetic information has increased exponentially and with it the opportunity to use this information to aid in diagnosis and treatment of cardiovascular disease. One of the greatest challenges we face with this wealth of potentially useful diagnostic information is determining the pathogenicity of the myriad genetic variants identified. Dilated cardiomyopathy (DCM) is a particularly salient example of this challenge. Compared with other inherited cardiovascular diseases, such as long QT syndrome, with a diagnostic yield of genetic testing of ≈80%, only 15% to 40% of DCM genetic tests yield a pathogenic variant. This reduced diagnostic capability is due in part to our lack of precision in defining phenotypes, as well as the sheer size and number of genes thought to be involved, rendering the examination of a large number of variants in an individual cumbersome.