Different approaches to gene sequencing
A table showing the differences between gene sequencing approaches, including the number of genes sequenced, costs, advantages and disadvantages.
Overview
There are several different possible approaches to sequencing: targeted gene panel sequencing of a curated set of genes (from 2 to over 1000) known to cause a particular disease, syndrome or phenotype; whole exome sequencing of all around 20,000 known genes; and whole genome sequencing of almost the entire genome, including coding and non-coding regions. Each approach has its advantages and disadvantages, summarised in the table below.
Comparison of the different approaches to gene sequencing
| Targeted gene panel | Whole exome sequencing (WES) | Whole genome sequencing (WGS) | |
|---|---|---|---|
| Number of genes | 2–1000+ genes. | Around 20,000 genes (1%–2% of genome). | Almost the entire genome: all coding and non-coding regions are included, though some parts – such as highly repetitive regions – are more difficult to sequence so are not routinely included. |
| Cost | £200–£700 | £750 | £1,000 (and falling) |
| Advantages | Customisable.
Lowest cost. Deep coverage (detects mosaicism). |
May identify novel genetic causes of disease.
No need to update as new genes discovered (compared with targeted gene panel). Fewer variants of uncertain significance (VUS) for analysis than WGS. |
May identify novel genetic causes of disease.
May identify disease-causing variants in regulatory intronic/ enhancer regions. Best for detecting copy number variants (CNVs) and structural rearrangements due to uniform coverage. |
| Disadvantages | Does not identify variants in genes not already known to cause a particular condition or phenotype.
Difficult to update as new genes included. Does not detect CNVs/structural rearrangements. |
More VUS identified (compared with targeted gene panel).
Poor sequencing depth – may not detect mosaicism (compared with targeted gene panel). Misses intronic and regulatory/enhancer mutations. Increased risk of incidental findings (compared with targeted gene panel). Limited ability to detect CNVs/structural rearrangements. |
Highest cost.
Huge data volume with requirement for secure storage. Highest chance of identifying VUS. Significant burden of clinical interpretation of variants identified. Increased risk of incidental findings (compared with other sequencing tests). |
Key messages
- Targeted gene panel sequencing offers the lowest cost and deepest coverage, but cannot identify novel genomic causes of disease or detect CNVs/structural rearrangements.
- Whole exome sequencing may identify novel genomic causes of disease but has a higher chance of identifying VUS and incidental findings than targeted gene panel sequencing, and has less sequencing depth (so less likely to detect mosaicism). It has a limited ability to detect CNVs/structural rearrangements as compared to WGS.
- Whole genome sequencing may additionally identify disease-causing variants in regulatory regions, and is best for detecting CNVs and structural variants, but has the highest cost, data storage requirements and risk of identifying VUS and incidental findings.