The ability to sequence a patient’s genome can be an invaluable tool in healthcare, especially as we move towards more personalised treatments. It can aid clinicians in diagnosis, assess patient risk and provide suitable treatment options.
Despite the falling cost of genomic sequencing, whole genome sequencing (WGS) remains an expensive technique, and requires a lot of analysis. Whole exome sequencing, however, is a genomic technique that gathers information in the protein-coding region of the DNA only. This allows tests to be completed and interpreted in a much timelier and cost-effective manner.
Here, we summarise a blog post by Health Education England, where they caught up with Dr Julia Baptista, who works within Exeter’s exome sequencing service to follow what the testing process looks like as part of the Genomic Medicine Service in the UK.
Inside the lab
Despite making up less than 2% of our DNA, sequencing the exome requires a large gene panel analysis to target the roughly 20,000 known protein-coding genes. Exeter’s exome sequencing service uses a commercially available kit, to identify variants in the exomes. Typically, they test samples from the affected individual and both parents through wet lab preparations (called a trio). Sometimes, samples from a trio may not be available, and so they also run singleton and duo (one parent and affected patient) tests. Using DNA from blood, the exome libraries are loaded onto one of the sequencers.
Around 26 hours after the samples are loaded, the bioinformaticians receive alerts that the data is ready for analysis, so they run the data through one of the designated in-house pipelines: one for trios, duos and singletons.
The trio pipeline is maintained and continually improved by a team of NHS bioinformaticians, which forms the process needed to filter the data from 30,000-40,000 variants seen in the exome. This allows the team to create a manageable list of high-quality variants for analysis and interpretation by a scientist, within a reasonable time frame for the patient.
Sample adaption – a virtual gene panel
Without the power of three related exomes to do genetics-based filtering, analysing the samples from singletons or duos is done differently and so they use an alternative pipeline. Using a phenotype-driven approach, the team sequences the usual 20,000 genes but with analysis restricted to the genes that can cause specific aspects of the phenotype.
Once the list of rare variants is reduced, the clinical scientists look at the data. With a wealth of resources at their disposal, the job of the clinical scientist is to look for a disease-causing variant in a gene that fits in the clinical presentation of that patient to in order reach a diagnosis.
Exeter’s exome sequencing service provides the most complex genomic testing that is available on the NHS. Rare disorders are one of the key remits of the Genomic medicine service, and in practice, this means that they are working to accommodate limited knowledge whilst dealing with anxious families in tight timeframes.
Julia says the biggest strength in the exome sequencing service is the multidisciplinary approach, the different skills and backgrounds of those involved are crucial in providing successful outcomes.
