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The aim of the Translational Genomics research team at the University of Exeter (led by Professor Caroline Wright) is to use large-scale genomic sequencing datasets, coupled with other -omic datasets, to identify and understand genetic causes of disease and translate these findings into healthcare. Our work is highly collaborative, and has two primary aims: improving diagnosis and informing screening for rare genetic diseases.

Improving diagnosis

We aim to improve discovery and interpretation of novel causes of rare genetic (monogenic) disease, with a particular focus on paediatric neurodevelopmental disorders. Rare diseases are estimated to affect around 1 in 17 individuals, and around 80% of rare diseases have a single genetic cause; making a rapid and robust genetic diagnosis can be transformative for patients by enabling precision treatment. Current projects in the group include:

• re-analysing genome-wide sequencing data from rare disease cases to find new diagnoses
• investigating tissue-specific isoforms using long-read RNA sequencing data
• predicting the effect of protein-truncating variants
• analysing the genome-wide burden of de novo variants

Informing Screening

We aim to understand incomplete penetrance of pathogenic variants in population cohorts, including investigating modifiers of penetrance. As we move towards integrating genomics into public health for prediction and prevention, evidence is needed to inform implementation and understand the risks associated with monogenic conditions when found outside of symptomatic or familial genetic testing. Current projects in the group include:

• quantifying the penetrance of pathogenic variants in genes under consideration for newborn genome screening
• exploring ethical and policy issues raised by genomic screening
• investigating modifiers of penetrance
• performing biologically-informed aggregate variant burden testing across a range of phenotypes

Research Studies and Collaborations

Our researchers run and are involved with a number of large-scale studies, including:

• PARADIGM: Primary Annotated Resources to Advance Discovery In Genomic Medicine (Wellcome)
• DDD: Deciphering Developmental Disorders Study (Wellcome)
• Evaluating scientific and ethical approaches to newborn screening with whole genome sequencing using large-scale population cohorts (MRC)
• Using whole genome sequencing to identify non-coding elements associated with diabetes and related traits across ancestries (MRC)

We collaborate widely, and work with numerous large datasets including UK Biobank, Genomics England and DECIPHER. We are part of the NIHR Exeter Biomedical Research Centre (BRC), which has a specific Genetic & Genomics theme that aims to unlock the power of genetics to improve diagnosis of rare illnesses in children and rare cancers, and to create tailored treatments for common diseases. We also work closely with the Exeter NHS Genomics Laboratory (part of the South West Genomics Laboratory Hub) through the NHS Genomic Network of Excellence in Rare and Inherited Diseases.