What is exome sequencing?Rater than be limited to analysing single genes, or predefined panels of genes, exome sequencing is aimed to cover the human exome, the coding region of all (20000) human genes. All types of mutations are potentially detectable by this assay. Due to this, exome sequencing has proven to be a diagnostic test with a very high diagnostic yield.
Advantages of exome sequencing:
- The diagnostic yield of exome sequencing is higher than achieved by Sanger sequencing
- Exome sequencing can solve complex clinical cases
- Exome sequencing can lead to a quicker genetic diagnosis
Our exome sequencing approach:
Exome Sequencing Diagnostics has been developed and implemented in our Genome Diagnostics laboratory in 2011, in close collaboration with clinicians, clinical laboratory geneticists and scientists. In an initial phase, the test was focused on the 5 specializations of our laboratory, but rapidly expanded to other disorders. Since 2011 we have processed over 10000 clinical exome requests. Our current sample load exceeds 500 samples per month.
Our Exome sequencing Diagnostics consists of 3 major steps:
- Exome Sequencing
- Exome Data Analysis
- Clinical Interpretation & Reporting
Clinical interpretation & reportingThe variants identified will be interpreted in the clinical context provided by the referring clinicians.
There are several possible outcomes:
- One or more pathogenic variants are identified that may explain the disorder of the patient
- One or more variants are identified of wich the significance is not immediately clear; additional testing in family members, or other (biochemical) testing, may be required
- No variants are identified that might explain the disorder; after a gene panel analysis, an exome-wide analysis can be considered
However, if no causative mutation is found within the gene panel, we can proceed with the analysis of the rest of the exome data. The interpretation in the exome-wide analysis is focused on likely-disruptive variants in all genes. Besides the identification of causative mutations in disease genes not (yet) suggested in a particular patient (broadening the phenotype) or the identifcation of novel (candidate) disease genes, exome-wide analysis does bear the risk of the identification of medically relevant variants for other (late onset) disorders; for example a variant associated with an increased cancer risk. These so called unsolicited findings could have important consequences for the patient and/or other family members. The risk of such unsolicited findings is reduced by variant filtering using gene panels or trio analysis.
Unsolicited findings will be discussed by a dedicated committee, which determines the clinical relevance. In general, the committee decides only to report (likely) pathogenic variants indicative of a treatable or preventable health problem, when it is regarded to be in the counselee's best interest to be informed. Unsolicited findings are described in a separate report issued to the referring medical doctor. In all situations, the patient will be informed of the results of exome sequencing by their physician.