DNA sequence variants and the practice of medicine

To discuss potential clinical utility of the DNA sequence variants (DSVs) present in the human genome.

Advances in the sequencing technology have led to discovery of a very large number of DSVs in the human genome. Accordingly each genome has approximately 4 million DSVs, of which single-nucleotide polymorphisms (SNPs) dominate in number (about 3 million) but the structural variations, including the copy number variants (CNVs), encompass a much larger number of the nucleotides. The biological and clinical impacts of DSVs are innate to their effect sizes and follow a gradient from negligible to drastic. DSVs responsible for single gene disorders impart the largest effect sizes, whereas those with small or moderate effect sizes modify phenotypic expression of the single gene disorders. In contrast, the common complex disorders result from intricate interactions of a very large number of DSVs, each imparting a modest and often clinically indiscernible effect size, with each other and with the environmental factors. DSVs with large effect sizes, under certain circumstances, might have clinical utility in individualization of therapy, early diagnosis and the risk stratification. In contrast, DSVs with small effect sizes are unlikely to provide useful clinical information.

DSVs, under certain circumstances, could provide valuable information for genetic-based diagnosis, risk stratification and treatment. However, the primary utility of DSVs is in providing insight into the molecular mechanisms that govern the pathogenesis of the human diseases and applying the mechanistic insight to the cure of such disorders.