Whole-exome sequencing (WES) is a genetic analysis that examines the protein-coding regions of the genome (around 20,000 genes) in a single test using next-generation sequencing. The exome makes up only 1–2% of the genome, yet the great majority of known disease-causing variants lie in this region. It is preferred in rare and inherited disorders, when targeted panels have not provided an answer.
What is the exome, and why is it enough?
The parts of genes that direct protein production are called exons, and the sum of all exons is the exome. The exome is only a small fraction of the 3-billion-base-pair genome, yet the majority of known variants causing single-gene disorders are found here. Exome sequencing therefore delivers most of the diagnostic yield without reading the whole genome.
At Lue GEN, exome tests are run on blood samples. After sequencing, the data are filtered according to the patient's clinical findings (phenotype); candidate variants are classified according to ACMG rules and the report is prepared with the interpretation of a clinical genetics specialist.
Who is it suitable for?
Whole-exome sequencing is recommended as a first-line test particularly in patients whose condition affects more than one body system or whose diagnostic journey has been prolonged:
- Unexplained developmental delay, intellectual disability or features of autism spectrum disorder
- Epilepsy, neuromuscular disease, inherited cardiomyopathy and arrhythmias
- Congenital anomalies, suspected metabolic disease, a history of rare disease
- Cases in which targeted panels or microarray analysis have given no answer
- Recurrent pregnancy loss, infertility, and carrier screening for recessive disorders
- An unidentified disorder that recurs in the family across generations
What is the diagnostic yield?
In the first large series of clinical exome sequencing (250 patients), a molecular diagnosis was made in 25% of patients1. A later meta-analysis pooling 37 studies estimated the diagnostic yield in children at 36% for exome sequencing, 41% for genome sequencing and 10% for chromosomal microarray2.
The yield depends on the patient's findings and on whether the analysis is performed together with the parents. Trio analysis (patient + mother + father) raises the diagnostic yield and speeds up interpretation because it directly distinguishes newly arisen (de novo) variants; at Lue GEN, ExoSeq® Trio is offered for this purpose.
Panel, exome or genome: which, and when?
| Targeted panel | Whole exome | Whole genome | |
|---|---|---|---|
| Coverage | Genes linked to a specific disease group (e.g. ExoSeq® Cardio, 784 genes) | Coding regions of ~20,000 genes | All coding and non-coding regions |
| When? | When the clinical picture points to a specific system | When findings involve several systems or are unclear | When the exome gave no answer; suspected structural or deep intronic variants |
| Secondary findings | Limited | Possible; reported on request according to the ACMG list | Possible |
| Turnaround | 4–6 weeks | 6 weeks | 4–6 weeks |
| Lue GEN test | ExoSeq® organ-system panels | ExoSeq® Comp / Duo / Trio | WholeSeq® Comp |
What does the report contain, and what is a secondary finding?
The report explains the pathogenic and likely pathogenic variants related to the clinical findings, VUS where relevant, and the mode of inheritance. In broad tests such as the exome, findings unrelated to the condition being investigated but medically important may also emerge; these are called secondary findings. The ACMG recommends optional reporting of a list of genes linked to actionable conditions such as hereditary cancer and heart disease. You decide before testing whether you wish to learn about these findings.
Process and turnaround
Exome tests are planned together with a clinical genetics specialist or the relevant specialist physician; when you submit an appointment request, our team helps you identify the right test. Blood samples are collected at Akasya Partner Clinics; for trio analyses, samples are also taken from the mother and father. Reports are usually ready in 6 weeks. Raw data are stored, and re-analysis can be requested in the future, because gene–disease associations expand every year.
Questions about exome sequencing
Wouldn't it be better to have whole-genome sequencing straight away instead of the exome?
The genome captures structural and intronic variants that the exome cannot see; however, for most clinical questions the exome is sufficient, easier to interpret and more cost-effective. If the exome gives no answer or there is a specific suspicion, the genome (WholeSeq® Comp) is planned as the second step.
If the result is negative, does that mean my condition is not genetic?
A negative exome shows that no explanatory variant was found in known genes; it does not prove that the condition is not genetic. As new gene–disease associations are identified, re-analysis of the data or genome sequencing may be recommended.
Does testing my child also require samples from the parents?
It is not mandatory; however, trio analysis raises the diagnostic yield and speeds up interpretation. Depending on the clinical picture, your physician will recommend singleton, duo or trio analysis.
Which test is suitable for carrier screening?
ExoSeq® CS uses the exome platform to screen carrier status for recessively inherited disorders. For couples before marriage or planning a pregnancy, assessing both partners together is recommended.