RNA sequencing - generating evidence to facilitate embedding RNA-based sequencing approaches in the NHS.

Introduction to project

Central and South GMSA are working with the North West and South West GMSAs on this exciting RNA sequencing project. Commissioned by NHSE as part of the programme of national transformation projects supported in 2022-2023, it aims to pave the way for RNA sequencing to be made available on the National Genomic Test Directory, as part of standard NHS care. It is hoped that RNA sequencing can provide a new diagnosis to patients who have undergone genetic testing such as whole genome sequencing but have yet to have a diagnosis confirmed. This in turn will make targeted gene therapies available.

The South West GMSA are also running a project in parallel which looks specifically at Long Read DNA sequencing, more information about this project can be found on their website. 

What is the condition?  

This project is focussing on three groups of patients:

  1. A candidate variant of uncertain significance (VUS) identified via whole-genome sequencing (WGS), exome, panel or single-gene sequencing that warrants further assessment.
  2. No genetic diagnosis following WGS or suitable exome/panel test where clinically there is still high suspicion of a genetic cause.
  3. Autosomal recessive disorders where there is only one mutation identified and a second has not been found or may be a VUS.

What are we doing? 

The CAS project team, lead by Professor Diana Baralle, has a depth of experience in the field of RNA research, developed over the last decade, and has become world renowned; Professor Baralle represents the UK in the newly formed RNA sequencing Global Taskforce, alongside eminent colleagues in Netherlands, Australia and America. 

This project is important because by sequencing RNA it becomes possible to establish which genes are actively producing proteins and which are not. This can be useful in identifying aberrant gene activity, mutations and potential drug targets to inhibit or enhance gene activity to alter gene expression. Current genetic testing options such as Whole Genome Sequencing (WGS) has a diagnostic mutation identification rate of 19%, meaning diagnosis is not achieved in most patients. Finding of variants of uncertain significance is common and the ability to interpret non-coding variants are major limitations of the current approach.  

Research shows that by using RNA-based assays diagnostic yield can be increased, meaning more patients can potentially commence targeted therapies. This not only improves patient experience and outcomes but reduces clinical risk by the patient being treated more precisely. Until now RNA sequencing has predominantly been undertaken in the research environment, and where it is being undertaken in the NHS a variety of approaches and techniques are being utilised.

To deliver this project in the NHS setting we have:

  • Implemented an oversight group meeting monthly – membership from all 7 GMSAs/GLHs
  • Implemented 3 x Task and Finish groups meeting fortnightly – sequencing, bioinformatics, data sharing
  • Identified the types of patients we think will benefit the most from this technology
  • Commenced collection of 300 patient samples across the 3 GMSAs – both in blood PAXgene tubes and other tissue types
  • Commenced RNA extraction and preparation for short read and long read sequencing
  • Worked with research, academic and commercial partners to identify the best protocols and pipelines to utilise for the best chance of success
  • Identified a data storage and sharing requirement for large data generating projects such as this and are actively engaging with academic, NHS and biomedical research centres to seek both long and short term solutions.

Who can I contact?


Sarah.Willis@uhs.nhs.uk – CAS Programme Manager