Next-Generation Sequencing in Cardiovascular Disease
Present Clinical Applications and the Horizon of Precision Medicine
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The initial sequencing of the human genome took nearly a decade to complete. Today, the same can be accomplished in hours using next-generation sequencing (NGS). Before the invention of NGS, genetic testing was accomplished by traditional Sanger sequencing. In cardiovascular medicine, this approach typically involved the sequencing of a region of interest in a single affected patient’s DNA and then comparison of that sequence to the human genome reference sequence. Variants found were then compared to a panel of sequences from unaffected people, often anonymous blood donors. This strategy has been the mainstay of genetic testing to assess small numbers of disease-related genes across cardiovascular and noncardiovascular diseases. However, this approach is limited in its scalability.
NGS builds on these basic principles, extending them to allow billions of DNA molecules to be sequenced simultaneously. This multiplex technology yields billions of small polynucleotide reads, called “short reads.” Mapping and assembly of these short reads to a reference genome then allows discovery of genetic variants at scale (Figure 1), increasing the speed and reducing the cost of sequencing by orders of magnitude.1 Thus, NGS can easily be applied to panels of genes, every gene, or the whole genome in clinical settings. This scientific leap in sequencing technology has occurred over just 15 years and has brought the genetic code to the forefront of diagnosis and therapy, making it increasingly important for clinicians to be aware of its utility and limitations in practice.