The Rise and Rise of Exome Sequencing

Abstract

Beginning in 2009, the advent of exome sequencing has contributed significantly towards new discoveries of heritable germline mutations and de novo mutations for rare Mendelian disorders with hitherto unknown genetic aetiologies. Exome sequencing is an efficient tool to identify disease mutations without the need of a multi-generational pedigree. Sequencing a single proband or multiple affected individuals has been shown to be successful in identifying disease mutations, but parents would be required in the case of de novo mutations. In addition to heritable germline and de novo mutations, exome sequencing has also succeeded in unravelling somatic driver mutations for a wide range of cancers through individual studies or international collaborative effort such as the Cancer Genome International Consortium. By contrast, the application of exome sequencing in complex diseases is relatively limited; probably it would be too expensive were it applied to thousands of samples to achieve the statistical power for rare or low frequency variants (<1%). On top of research discoveries, the application of exome sequencing as a diagnostic tool is also increasingly evident. In this article, we summarize and discuss the progress that has been made in these areas during almost a decade.

Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship

“…Indeed, an increasing number of genes have been related to pathological germline and somatic mutations since the use of NGS (Vogelstein et al 2013;Amberger et al 2015). Yet, only about 35% of exome sequencing tests result in the identification of a likely pathological mutation (Ku et al 2016). This is partly due to the current recommendations from the American College of Medical Genetics and Genomics (ACMG), which considers likely pathological mutations from a uni-coding dogma point of view (Richards et al 2015).…”

Effect of DNA insert length on whole-exome sequencing enrichment efficiency: an observational study

“…Exome sequencing has revolutionized clinical research and diagnostics. 1,2 In a typical exome sequencing workflow, libraries are constructed from purified DNA, enriched for the exon regions and then sequenced. Targeted enrichment can be useful in a number of situations where particular portions of a whole genome need to be analyzed.…”

The mouse curly whiskers (cw) mutations are recessive alleles of hephaestin-like 1 (Hephl1)

“…In recent years, modern methods (like whole-genome DNA sequencing) have supplanted positional cloning (sometimes called “reverse genetics”) as an approach for making causative-gene assignments for spontaneous mutations, in both mice and man [10,18,35]. And even if this powerful new method works best when the natural variant under study has had some prior positional characterization, genetic mapping as a means to gain initial access to gene structure and function appears (perhaps with this report) to have become outdated.…”