Exome sequencing

Exome sequencing, also known as whole exome sequencing (WES or WXS), is a technique for sequencing all of the expressed genes in a genome (known as the exome). It consists of two steps: the first step is to select only the subset of DNA that encodes proteins. These regions are known as exons - humans have about 180,000 exons, constituting about 1% of the human genome, or approximately 30 million base pairs. The second step is to sequence the exonic DNA using any high-throughput DNA sequencing technology.

The goal of this approach is to identify genetic variants that alter protein sequences, and to do this at a much lower cost than whole-genome sequencing. Since these variants can be responsible for both Mendelian and common polygenic diseases, such as Alzheimer's disease, whole exome sequencing has been applied both in academic research and as a clinical diagnostic.

Exome sequencing is especially effective in the study of rare Mendelian diseases, because it is an efficient way to identify the genetic variants in all of an individual's genes. These diseases are most often caused by very rare genetic variants that are only present in a tiny number of individuals; by contrast, techniques such as SNP arrays can only detect shared genetic variants that are common to many individuals in the wider population. Furthermore, because severe disease-causing variants are much more likely (but by no means exclusively) to be in the protein coding sequence, focusing on this 1% costs far less than whole genome sequencing but still detects a high yield of relevant variants.

In the past, clinical genetic tests were chosen based on the clinical presentation of the patient (i.e. focused on one gene or a small number known to be associated with a particular syndrome), or surveyed only certain types of variation (e.g. comparative genomic hybridization) but provided definitive genetic diagnoses in fewer than half of all patients. Exome sequencing is now increasingly used to complement these other tests: both to find mutations in genes already known to cause disease as well as to identify novel genes by comparing exomes from patients with similar features.

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