Clinical Interpretation and Management of Genetic Variants

Abstract

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.

Keywords: CNV, copy number variants; HCM, hypertrophic cardiomyopathy; LoF, loss of function; SNV, single nucleotide variant; SV, structural variant; WES, whole exome sequencing; WGS, whole genome sequencing; genetic testing; genetic variants; indel, insertion/deletion; nsSNV, nonsynonymous single nucleotide variant; sequencing.

Graphical abstract

Central Illustration

Genetic Disorders as a Continuum Genetic variants impart a gradient of functional and clinical effect sizes that vary from negligible to very large. Population frequency of the genetic variants inversely correlates with their effect sizes. Those with large effect sizes are rare and those with small effect sizes are common. The classic single-gene disorders result from the very large effects of rare variants, whereas the polygenic disorders result from the cumulative effects of multiple variants with small effect sizes. Most genetic disorders are in between the 2 ends of the spectrum.