Challenges in medical applications of whole exome/genome sequencing discoveries

Despite the well-documented influence of genetics on susceptibility to cardiovascular diseases, delineation of the full spectrum of the risk alleles had to await the development of modern next-generation sequencing technologies. The techniques provide unbiased approaches for identification of the DNA sequence variants (DSVs) in the entire genome (whole genome sequencing [WGS]) or the protein-coding exons (whole exome sequencing [WES]). Each genome contains approximately 4 million DSVs and each exome approximately 13,000 single nucleotide variants. The challenge facing researchers and clinicians alike is to decipher the biological and clinical significance of these variants and harness the information for the practice of medicine. The common DSVs typically exert modest effect sizes, as evidenced by the results of genome-wide association studies, and hence have modest or negligible clinical implications. The focus is on the rare variants with large effect sizes, which are expected to have stronger clinical implications, as in single gene disorders with Mendelian patterns of inheritance. However, the clinical implications of the rare variants for common complex cardiovascular diseases remain to be established. The most important contribution of WES or WGS is in delineation of the novel molecular pathways involved in the pathogenesis of the phenotype, which would be expected to provide for preventive and therapeutic opportunities.