The sum of all coding regions in a genome is called the exome. In humans, this includes 23,000 genes with approximately 50 million bases. With Whole Exome Sequencing (WES), all exons (protein-coding regions) are analyzed. The genetic testing is therefore focused on the analysis of the 1-2% of the human genome where 85% of known pathogenic mutations are found.
Exome diagnostics includes the sequencing of a patient’s exome (and possibly the patient’s relatives), the analysis of sequencing data, and the summary of the results in a comprehensive medical report. Exome analysis is based on next-generation sequencing (NGS), and is used to identify variants in single genes that cause rare genetic diseases. This testing is the method of choice to detect the cause of disease in patients with complex, unspecific symptoms and indefinite diagnoses.
Sequencing of a whole exome is also useful if a specific panel used to analyse the patient’s symptoms is not available.
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The number of variants detected using Exome Diagnostics is very high. To accelerate and focus the interpretation of the results, the symptoms of the patients are recorded with as much precision and detail as possible. A team of experts and human geneticists create an individual list of candidate genes that are known to be associated with the symptoms of the patient with the help of the Human Phenotype Ontology (HPO). In the context of single Exome Diagnostics, detected variants within candidate genes are evaluated and the results and interpretation are summarized in a medical report that is returned to the treating physician.
Trio Exome Diagnostics is a powerful way to identify causative variants. The parents of the patient are also tested and an exome-wide segregation analysis is performed. This allows variants to be filtered and non-pathogenic variants to be eliminated. Reports in the literature demonstrate a significant increase in diagnostic detection rates, from 21% for single Exome Diagnostics to 37% for Trio Exome Diagnostics (Farwell, 2015). The higher detection rates are achieved because Trio Exome Diagnostics:
-Enables the better identification and interpretation of genes and variants that are not known to be clinically associated with the disease, and
-Crucially, improves the detection of causative mutations which are frequently new (de novo) in the patient.)
A delineated approach, WES presents an attractive alternative to WGS. With a specific focus on just the exome, which essentially refers to the coding region within a genome, WES achieves ten times the coverage for a fraction of the cost compared to WGS. The iterative detailing of the data amassed from WES can be very resourceful for teasing out, with high precision and reliability, single-nucleotide variants and de novo mutations associated with both Mendelian and common diseases.
