Clinical Interpretation and Management of Genetic Variants.

Genetic variants are major determinants of susceptibility to disease, response to therapy, and clinical outcomes. Advances in the short-read sequencing technologies, despite some shortcomings, have enabled identification of the vast majority of the genetic variants in each genome. The major challenge is in identifying the pathogenic variants in cardiovascular diseases. The yield of the genetic testing has been limited because of technological shortcomings and our incomplete understanding of the genetic basis of cardiovascular disorders. To advance the field, a shift to long-read sequencing platforms is necessary. In addition, to discern the pathogenic variants, genetic diseases should be considered as a continuum and the genetic variants as probabilistic factors with a gradient of effect sizes. Moreover, disease-specific physician-scientists with expertise in the clinical medicine and molecular genetics are best equipped to discern functional and clinical significance of the genetic variants. The changes would be expected to enhance clinical utilities of the genetic discoveries.