Evaluating clinical exome sequencing for the benefit of the management of patients with rare diseases

Around 20,000 genetic tests are requested from the All Wales Medical Genetics Service (AWMGS) every year. Providing patients with fast, accurate diagnoses benefits them and their families.

Currently most NHS gene tests are performed by a technique called 'Sanger' sequencing (first developed in the1970s). Sanger sequencing is reliable but only tests one gene at a time. This makes testing slow and expensive (roughly two-three months and £500-£1000 per gene).

Many common disorders (e.g. intellectual disability or familial cancer) can be caused by a change in any one of 10-100's of genes. These gene tests are often not available. It is now possible to test many or all genes at once with a new sequencing technique called exome (or genome) sequencing.

Our aim is to determine the impact of exome sequencing on patients, and the NHS genetics service.

We have selected 'clinical' exome sequencing (CES) for this project. CES targets those genes that are associated with disease (about a quarter of all genes). We will first perform CES on 16 samples from patients with known genetic changes to validate this new technique. In the main experiment we will perform CES on 100 patients with rare diseases.

For some we will also analyse the patients' parents (this will help us determine if genetic changes are new or have been inherited). The patient CES data will undergo computer analysis. The analysis will only look at those genes that are relevant to the patient's health problems. The rest of the patient's CES data will not be analysed.

Participants will still receive standard NHS genetic testing. This will allow us to compare the performance of CES with standard methods. We expect that CES will increase the number of genetic diagnoses made, provide answers more quickly and save costs for the NHS in the future.

We will also be asking for patients and families to tell us how they feel about genomic analysis. We want to understand if they are concerned about genomic sequencing. This research has been discussed with several patients seen by the doctors on the research team. In addition we have invited patient representatives to contribute to the design of the project. The patient representatives have helped prepare this summary and will participate in the ongoing management of the project.

The results of this project will be fed back to participants who will receive information about the health implications of their own CES results. In addition, we plan to present the results at conferences and through publications in scientific journals.

We will provide a summary of findings for commissioners (the Clinical Evidence and Evaluation Group for Rare Diseases) to support service development.