MRC Strategic Award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases

Neuromuscular Diseases (NMD) affect at least 17 million children and adults globally. They cause either premature death or are chronic diseases causing lifelong disability with economic impact. They include many different disorders affecting muscle and nerve function and account for ~20% of all non-infectious neurological diseases. Examples include muscular dystrophies, congenital myopathies, neuropathies, motor neuron diseases, muscle channelopathies and mitochondrial diseases. Advances in genetics have improved our ability to diagnose patients in the UK, and this has resulted in improved patient care and enabled clinical trials. However the benefits of genetic advances have not been realised in Official Development Assistance (ODA) defined Lower and Middle Income Countries (LMICs), partly because of a lack of neurologists trained specifically in genomic NMD medicine.

NMDs are commonly genetic and are inherited. Identifying genetic pathways and applying genetic testing has led to some of the most important advances in disease understanding alongside patient management plans and the development of new therapies. Many of the key interventions involve the inexpensive practical applications of widely available medical technology (e.g. low-cost off-licence medication, targeted vaccination, cardiac monitoring and respiratory care), but their application is contingent on making a precise diagnosis. For example, a precise genetic diagnosis can lead to a personalised and often simple management plan following established care guidelines that includes basic screening for known complications (e.g. cardiac, respiratory, gastroenterological and metabolic) and often simple interventions that improve health outcomes - interventions that could be implemented easily in LMICs providing an accurate genetic diagnosis is made. In the UK, a muscle biopsy has been the mainstay in the investigation algorithm in many patients, but this requires a specialist laboratory equipped for frozen section analysis with a growing panel of diagnostic antibodies. However, recent advances in genomics provide the opportunity to diagnose with high precision based on a DNA sample and clinical data collected remotely.

Our central objective is to build ethnically diverse cohorts of children and adults with NMDs and undertake genomic analysis to find known and identify new disease genes. We will increase the number of patients with a precise genetic diagnosis to both improve patient care and to increase knowledge on the comparative genetic architecture of NMDs across four continents.

This is a brand new transcontinental programme led by UK professors at UCL, Newcastle and Cambridge Universities. The research programme will train a new generation of academic doctors, generate the world's largest cohort of 15,000 ethnically diverse NMD patients and will investigate the causative genes. We will work with five LMIC clinical and academic centres in: India, Turkey, South Africa, Zambia and Brazil. The trained doctors will be the future clinical academic leaders to undertake research and improve NMD patient care in these countries. The fellows will already be fully trained in neurology and will spend a year in the UK for specialist training in NMD genomic medicine and spend three years in their country building NMD patient cohorts that will be assessed in detail clinically and will undergo full genetic analysis to achieve a precise diagnosis and optimise patient management. All data produced will be anonymised and shared by all researchers. Importantly, we have access to several thousand ethnically matched control DNAs already and will build this control resource further, complementing those available through the Genomics England 100,000 genomes project, the NIHR BioResource and international collaborative resources. We will train a new generation of NMD doctors who will pursue their research career in their own country, discover new genes and improve patient care.

We will train a new group of clinical academic fellows to ultimately benefit patients in each partner LMIC. Fellows will be trained to build a cohort of 15,000 Neuromuscular disease (NMD) patients for deep phenotyping and comprehensive genotyping, we will:

(i) Establish an easy to use platform for deep clinical phenotyping and sharing of genome data/results between all project members. We will adopt the pseudo-anonymised, secure and cloud based RD-Connect platform (http://rd-connect.eu/), that uses PhenoTips (https://phenotips.org/) and Human Phenotype Ontology (HPO) (http://human-phenotypeontology.github.io/) terminology. This freely available software platform will be used for each patient/family, entered on secure iPAD locally. This platform allows future collaboration with European and International rare disease initiatives. We will also adopt Open-Clinica for natural history of disease, and later therapeutic trials. This approach ensures cross compatibility with national (GEL, NIHR BioResource) and international efforts (RD-connect).
(ii) Establish a common laboratory framework for high quality DNA extraction from blood, logged and stored in the cloud database following guidelines of UK accredited diagnostic laboratories.
(iii) Establish common genetic screening platform across laboratories, based on a tiering genetic analysis system hierarchy we developed and tested in the UK. This accounts for the molecular test complexity, number of genes and analysis requirements.
(iv) Train fellows in core bioinformatics skills and basic genetic laboratory techniques to ensure an equal skill set in each LMIC.
(v) Employ integrated genomic-phenotype cloud based platform for effective interpretation and gene discovery.

We will identify known and new disease genes, and assess comparative genetic architecture across 4 continents. This will improve understanding of phenotypic variability, disease progression and disease mechanisms, and build "trial ready" cohorts.

The mission is to create a transcontinental genomics research and capacity building partnership between the UK & India, Turkey, South Africa, Zambia and Brazil. The beneficiaries include:
1) Patients and patient organisations
2) Basic and clinical scientists in neurology, neuroscience and genetics
3) Policy and guidelines
4) Pharmaceutical industry
There are particular challenges faced in the field of NMD which apply across stakeholder groups, and impact in all challenge areas will be achieved through our outputs. Patients and the patient organisations face uncertain access to diagnosis and care, have limited access to clinical trials and the majority are without effective therapies. The clinical and academic groups who work with NMD require resources and know-how to underpin delivery of care and translational research. The policy-makers determine care delivery, and need information on which to base health recommendations. Industrial partners frequently lack knowledge in the disease areas and perceive that the field lacks "trial readiness". By targeting the needs of these distinct stakeholder groups, we will provide outputs which will promote health in this patient group, as well as promoting UK international research competitiveness. Strong relationships are already in place to ensure that impact can be maximised. These include:
1) Key roles for our PIs in national/international patient organisations
2) Strong involvement of our patients and patient organisations in research design and oversight
3) Leading roles of our PIs in host clinical/academic organisations
4) Existing relationships in key areas of liaison with policy makers involved in rare disease public health decision making in UK and LMICs
5) Many links to industry (as detailed in Pathway to Impact)

PATIENTS AND PATIENT ORGANISATIONS: They will benefit from precise genetic diagnosis and cohort stratification enabling trial ready cohorts for the experimental medicine studies and increased trial activity, aimed at defining better therapeutic strategies. Improved diagnostics and treatments will ultimately impact on health, quality of life and societal benefit via greater participation of this patient group in their communities.

CLINICIANS AND ACADEMICS: The clinical and academic groups working with NMD require resources and know-how to deliver care and genomic translational research effectively. Underpinning the experimental medicine potential will be the development of international stratified genetic cohorts, enabling personalised medicine and a much larger group of patients to contribute to experimental clinical studies and access standardised procedures for care and assessment internationally. Training LMIC fellows in genomic medicine will benefit the local academic community and increase research in NMD and benefit patients through more expert clinical care, accurate genetic diagnosis and through "trial ready" cohorts.

POLICY AND GUIDELINES: Policy makers in LMICs who determine care delivery in this area need information on which to base health recommendations. Detailed understanding of prevalence and population specific genetic variations in NMD cohorts, and the important insights these data will provide to NMD patients globally, will aid healthcare policy development. These data will also facilitate development of national and international diagnostic and management guidelines. Policy makers will have access to clearer and more harmonised guidance on the management of these patient groups which can be applied to healthcare planning.

INDUSTRY: Stratified cohorts, research know-how, and a strategic programme of preclinical research provide a conducive environment for increased industry engagement with the presence of trial expertise and ready access to rare patients. We will identify targets for new areas of industrial exploitation.