The Genomic Medicine Theme has for many years pioneered the development of novel genomics technologies and tests to help diagnose and treat patients with genetic diseases. These genetic changes may be inherited or acquired during a person’s lifetime – and the conditions encompass a broad spectrum of rare diseases as well as cancers.
Until recently, molecular genetic testing of rare diseases relied on panels of genes known to cause a particular disorder. Since many genes have not yet been discovered, the diagnostic yield of these tests is low and patients with rare disease can undergo a diagnostic odyssey in which sequential genetic tests are conducted over many years.
To overcome this, the Genomic Medicine Theme has pioneered the clinical application of whole genome sequencing, i.e. interrogating the entire complement of genes in a patient in order to find the faulty one. This allows us to identify likely disease-causing variants even in hitherto unknown genes.
Genome sequencing for rare disease and cancer patients has now been offered at national level through the Genomics England (GeL) 100,000 Genomes Project. The Oxford BRC works closely with GeL to help provide molecular diagnoses for the patients recruited to the programme. Importantly, genome sequencing has now been commissioned as an NHS service for selected rare diseases, with more likely to follow.
Now that the provision of genetic diagnoses for patients is on a more robust footing, we are turning our attention to how this genetic information can inform new treatments. Genome editing techniques are being developed which may help us correct the defects in particular diseases, for example in inherited anaemias or neurodevelopmental disorders. An important development in our programme will be the partnership with the Harrington Discovery Institute, which will be instrumental in developing therapies for rare disease patients.
Although our ability to reliably diagnose people with or at risk of developing genetic disease has limited us to rare monogenic conditions to date, new developments in statistical and population genetics are helping us to predict those at risk of common diseases such as heart disease, diabetes and cancers. These conditions all arise from a combination of genetic and environmental factors but identifying those individuals with a higher genetic risk (a polygenic risk score) will help to intervene with effective treatments.
The key themes of our programme are:
- Analysis and interpretation of genome sequence data: development of novel and comprehensive bioinformatics pipelines for analysis of genome sequencing encompassing all mutation types, including non-coding, structural and copy number variants (Assoc Prof Jenny Taylor).
- Clinical application of polygenic risk scores: piloting the use of polygenic risk scores for cancer and cardio-metabolic conditions in primary care, enabling GPs to triage patients for secondary care follow up.
- Functional studies to understand the effect of disease-causing genetic variants leading to improved understanding of mechanisms of disease. Genetic conditions of particular interest include inherited cardiomyopathies (Prof Hugh Watkins, in collaboration with Cardiovascular Theme), developmental disorders arising from premature fusion of cranial sutures (Prof Andrew Wilkie), endocrine disorders (Prof Raj Thakker) and neurodevelopmental conditions (Prof Georg Hollander and colleagues, Depts Paediatrics and Neuroscience).
- Genome editing for therapy: development of methods to edit genes underlying inherited anaemias (Prof Paresh Vyas and Prof James Davies) and neurodevelopmental disorders such as ataxias (Prof Laurent Servais), with a view to commencing clinical trials and introducing these into the clinic.
- Health economics: understanding the cost effectiveness of providing genetic diagnoses for patients with rare diseases and the potential impact of introducing genome sequencing earlier in the diagnostic pathway (Prof Sarah Wordsworth).