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Professors Siobhan Burns and Helen Lachmann have received a major project grant from Rosetrees supported by an MBPhD fellowship supported by the Royal Free Charity to work on enriching genetic testing in diagnosis of rare systemic autoinflammatory disorders by performing functional testing looking for changes in how immune cells function.
This work will rely on collaboration between the Royal Free Hospital, UCL Divisions of Immunology and Medicine and the North London Genomic Hub (NTGLH) generously supported by Rosetrees and The Royal Free Charity.
Background
Wider availability of next generation genetic sequencing (NGS) for patients with suspected rare conditions has improved diagnosis and a particularly striking example of this has been the Systemic Autoinflammatory Disorders (SAID). This group of disorders of the innate immune system causes recurrent attacks of severe inflammation and fever. They usually onset in childhood and undiagnosed, can have devastating consequences. Fortunately many of them respond exceptionally well to specific treatments targeting the innate immune system.
Accurate genetic diagnosis has improved our understanding of SAID, identifying an expanded range of disease presentations and more complex patterns of genetic inheritance, and most importantly has allowed us to identify patients who will benefit from treatments, many of which are high cost and specifically commissioned by NHS England.
Paradoxically, NGS has also made diagnosis more complicated by identifying many variants of unknown significance (VUS) that are not clinically actionable. Current experience is that more than 60% of tested individuals will have at least one rare variant on a panel on genes of interest. As a result, patients can be left in a frustrating position without a clear diagnosis nor management plan.
Functional testing on fresh blood could help in working out the significance of VUS on immune function and support better understanding the consequences of the genetic changes and therefore inform decisions around diagnosis and appropriate therapeutic intervention. At present these tests are not routinely available and have not been validated in clinical practice.
The Jack O’Neil Amyloid Laboratory (JONAL) in the Royal Free is part of North London Genomic Hub and provides national genetic diagnosis of SAID and is co-located with an NHS England Highly Specialised Service commissioned clinical unit caring for the largest and broadest cohort of adults and adolescents in the world with these group of diseases. The Pears building, part of UCL Division of immunology is on the same site and this collaboration will allow for:
1. Development of a panel of laboratory-based tests of immune cell function focused on SAID genes for which robust functional validation is not currently available in clinical diagnostic laboratories.
2. Validation of these tests in patients with a variety clinical SAIDS confirmed by pathogenic mutations compared with healthy controls.
3. Testing of blood samples from clinically worked up patients with variants of unknown significance to assess for functional consequences
4. Development of in vitro cell line models of disease using known pathogenic SAID mutations and compare there with cell lines bearing variants of unknown significance