Title: Translational genomics- maximising potential for NHS patient care.
Funder: Department of Health and Social Care

Abstract: Genomics is the foundation of modern personalised medicine with the acknowledged potential to improve diagnostic accuracy, stratify disease and personalise treatment for immediate patient benefit. Projects to develop genomics in clinical practice are the epitome of the NIHR vision to improve the health and wealth of the nation through research and translation to patient care. Genomics England have kick-started a genomics industry with the 100,000 genomes project which targets patients with rare disease and cancer. One in seventeen people are born with or develop a rare disease during their lifetime and at least 80% of rare diseases have an identified genetic component; 50% of new cases are identified in children. Accurate diagnosis is fundamental in medicine enabling discussion of prognosis, screening, prenatal testing, family cascade testing and possible treatments. 1 in 3 people will get cancer and genomics transforms pathology to enhance the right treatment to the right patient. As implementation of high throughput sequencing into medicine escalates, the challenge remains to effectively translate these findings into diagnostic tests and future treatments. It is estimated that genomes will generate >10 million sequence variants between one individual and another. Each sequence variant must undergo functional verification, herein lies the bottleneck. l aim to use RNA to find missing mutations and provide a legacy for the interpretation of genetic variation in human disease, transforming clinical care. Many mutations in coding regions or introns may appear not to affect protein function but are still potentially causing disease through affecting pre-mRNA splicing. Between 15-50% of unclassified sequence variants (UVs) found at genomic analysis could influence RNA splicing.? Other forms of RNA have also been shown to be important in disease, e.g. non-codingRNA. Aim Development of a diagnostic RNA pipeline, maximising the impact of genome tests for patient benefit and provide a national resource for the NHS. Deliverables Short term- i)Construct RNA pipeline for testing. Medium term- i)Diagnostic uplift through variant verification in a known disease gene for clinical care (not possible without RNA pathway output). ii) Diagnostic uplift through discovery of new genomic causes of disease. iii)RNA based disease signatures. Long Term- Understand disease processes, for personalised medicine and therapies. The Southampton comprehensive RNA analysis diagnostic pipeline Pipeline overview- Figure 6 will have 3 components Design and Methods? Strategic Patient cohorts i)50 Primary ciliary dyskinesia patients; exome sequencing of key PCD genes completed ii) 50 Clinical immunology patients. RNA samples stored iii)200 patients selected from the 100,000 genomes project where RNA is available and genome testing has identified variants of unknown significance [Genomics England supported] Optimisation of RNA tests to establish the pathway In silico/bioinformatic prediction of effect of sequence variants on both genome and transcriptome. In collaboration, research and development of bioinformatics computer software tools for genetic diagnostic testing with regards to splicing and RNA, including, machine learning and RNA Seq.? RNA analyses through patient RNA samples and minigene assays -measurement of RNA levels by RT-PCR or minigene analyses. Develop standard operating procedures for progress through bioinformatics to wet' lab. Transcriptome analysis (blood, tissue, single cell (immunology cohort); messenger RNA and non-coding RNA). Each sample will be sequenced at sufficient depth to be able to perform an accurate and exhaustive analysis of RNA splicing patterns as well as identification of long non-coding RNAs and fusion transcripts. Gene function hub. Ultimately this technology will be an integral arm to a functional genomics hub- in collaboration, to prove gene pathogenicity. Including cell assays, biochemical assay, in vivo studies, RNA or methylation assays. Figure 5 for network of facilities and support.

Lay abstract: Background One in seventeen people are born with or develop a rare disease during their lifetime. 1 in 3 will get cancer. At least 80% of rare diseases have an identified genetic component, with 50% of new cases of rare diseases being identified in children. However, it can take considerable time and expense between a patient first presenting at a doctors and receiving an accurate diagnosis. Accurate diagnosis is fundamental in medicine providing answers for individuals, and facilitating informed decision-making for families and their doctors. This allows discussion about how the disease is likely to progress, screening, prenatal testing, testing of family members and possible treatments. In recent years, technological advances have opened up significant new opportunities within the fields of Genomics and Transcriptomics. Genomics is the study of the whole genome (a set of all your genes within each cell of your body plus all the DNA between your genes). Transcriptomics describes how the genes send their message (via RNA) to the body to make protein. Through Genomics and Transcriptomics we are able to diagnose and identify the cause of genetic diseases quicker and more accurately than ever before. In addition, Genomics and Transcriptomics can be used to predict how well a person will respond to a treatment or find one that will work best for them so-called personalised medicine. In order to bring the expected benefits of genomics to NHS patients, the Department of Health is spearheading a new genomic medicine service, Genomics England, which is reading (sequencing) 100,000 genomes (https://www.genomicsengland.co.uk/the-100000-genomes-project/). This work will kick-start change in clinical genetic methods and our understanding of disease pathways. The research undertaken as part of this Professorship, will complement the activities of Genomics England. Aims When genes are sequenced, many differences (>10 million) are seen between one individual and another. The challenge with this large amount of data, is interpreting which differences are clinically important and which are normal variation. During this award, I will improve the utility of genomic data by looking at how a gene is processed, and how this process goes wrong to cause disease or susceptibility to disease. I will incorporate new gene technologies into diagnostic testing, making new diagnoses where not possible before and facilitating personalised medicine. I will rapidly transfer gene discovery to clinic. This will be achieved through development of a new diagnostic decision pathway that will look at how genes are activated, significantly improving our diagnostic capabilities, fully in line with the NIHR vision of improving the health and wealth of the nation. Design and Methods Each aspect listed below will be researched and optimised for the delivery of personalised medicine. i)Researching and development of computer software tools for genetic diagnostic testing ii) Looking at how and when genome sequence results should be analysed further iii)Developing diagnostic transcriptomicsiv) Development of a hub to move new findings rapidly into medical practice, proving causality and documenting clinical findings.I am ideally placed both as a clinician in genetics and a researcher in genomics to translate new fundamental discoveries into improved testing and future treatments for patients; driving this into routine clinical practice. I already lead the RNA/transcriptomics genomic clinical interpretation partnership (GeCIP) for Genomics England. In addition, the University of Southampton alongside University Hospital Southampton NHS Trust have world-class infrastructure and experience to support this research, including the Wessex Genomic Medicine Centre. PPI (Patient and Public Involvement)The Wessex Genomic Medicine Centre has an established patient group that is consulted regularly with regards to future research directions. The group has already indicated that better, efficient interpretation of genomic data is important. As part of this project I will have regular meetings, one-to one with end-users. I will consult the active PPI groups at UHS and UoS throughout. Their perspective through real-time experience of what genomics means in clinical practice is critical.Dissemination The results of my work will be of interest to academics, those in the genomics industry and the wider public. The findings will be made available via publication in high impact open access academic and clinical journals.We will participate in national and international scientific meetings, feed back through the national Genomics England structure and give public talks, to help publicise our work.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: DISPUTED AETIOLOGY AND OTHER