Clinical Genome Sequencing

INTRODUCTION The completion of the first draft of the Human Genome Project in 2001, and subsequent refinements since then, have stimulated an explosion of research about the human genome, the inherent variability of DNA sequences among humans, and the relationship of sequence variation to human health. The scientific impact of this research in understanding the pathophysiology of disease and in spurring new lines of pharmaceutical development has been profound in numerous disease areas, but the impact on the day-to-day practice of medicine has been modest so far, because genomic technologies are still expensive, because the management and interpretation of genome-scale data is challenging, and because the value of genomic data in the practice of medicine has not yet been demonstrated to practicing physicians. This situation is rapidly changing. The cost of sequencing individual exomes and genomes continues to drop and will soon be comparable to other common medical tests and procedures. The accuracy of next-generation sequencing (NGS) is improving and innovative methods for efficiently analyzing and interpreting vast amounts of genomic data are being developed. Examples of how whole-exome or whole-genome information may be used in clinical diagnosis and decisionmaking are no longer rare, and both commercial and academic molecular laboratories all over the world are beginning to offer whole-exome (WES) or whole-genome sequencing (WGS) as a clinical service. Due to lower costs, laboratories have initially focused on WES, but there is general agreement that WGS will eventually predominate since, in addition to knowledge of variation within protein-coding genes, it provides additional information about genome structure and regulation. In anticipation of these developments, this chapter will focus primarily upon WGS. The arrival of genomic medicine, so long anticipated (Feero et al., 2010; Guttmacher and Collins, 2003; Guttmacher et al., 2010), is truly underway, and patients will be looking to the medical establishment for guidance in the use of this technology to improve their health. Yet serious near-term, longerterm and ongoing challenges remain as genome sequencing begins to be integrated into the daily practice of medicine.