Clinical applications of sequencing
The aims of this sub-theme are the application of whole genome and exome sequencing and targeted re-sequencing to disease gene discovery, and the assessment of the clinical utility of genome-wide scale sequencing.
Whole genome and exome sequencing
The WGS500 programme provided proof of concept to leverage additional funding for whole genome sequencing, including a successful application to the Health Innovation Challenge Fund who have provided £6m to translate this technology into clinical practice (due to commence late 2013). Demand for genome-wide sequencing remains high, so to address this, a programme of exome sequencing is underway as an interim measure, with the ultimate aim of establishing a clinical service. These projects are being run in close collaboration with the clinical scientists at the Molecular Diagnostics Centre and OUH Regional Genetics Laboratory, with samples routed through their service as a step toward building a clinical pipeline for this process.
Members of the Taylor lab will play key roles in bioinformatics, and genetic validation and targeted follow-up studies for these projects.
Investigating the genetic basis of structural brain abnormalities
Development of the human cerebral cortex is a complex process involving cellular proliferation, migration and organisation. Spontaneous and inherited mutations that disrupt this process result in cortical malformations which can be responsible for various forms of intellectual disability, in some cases in conjunction with epilepsy.
Limited diagnostic testing is currently available for individuals with brain malformations in the UK. Individually the diseases are rare and genetic tests are often only available in overseas laboratories so comprehensive testing takes significant time. In this project, a collaboration with Dr Usha Kini and Dr David Keays, we are exploring how next-generation sequencing can be used to rationalise genetic testing for brain malformations. As well as helping the families involved in our studies we hope our results will both increase the understanding of the genetic basis of these heterogeneous conditions and provide the basis for novel tests in the NHS.
As part of a Technology Strategy Board programme on tumour profiling, we have evaluated and optimised a commercial 46 gene cancer hotspot panel produced by Life Technology which runs on their PGM/ Ion Torrent system. This test is now in routine use at the OUH Molecular Diagnostics Centre.
Work is now concentrated on the development and testing of a larger cancer panel designed by scientists from the Taylor group. This panel comprises 148 genes for which there is an approved therapeutic or drug in early or late stage clinical trials, a relevance to multiple solid tumour types, and a significant mutation rate in the COSMIC database. Patients whose tumours are analysed using this method could then theoretically be offered a targeted treatment or the opportunity to enter an appropriate clinical trial for their tumour type. We are also testing whether this process could be used for non-invasive monitoring of tumours in plasma by assessing its suitability for analysing circulating tumour DNA.
Genetic profiling for inherited erythrocytosis
The Life Technology Ion Torrent system is being used to validate mutations identified though the WGS500 programme and screen for known variants in a cohort of erythrocytosis patients. A panel of 21 genes has been designed and is being used to test 130 patient samples.