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

神经肌肉疾病(NMD)在全球至少影响1700万儿童和成人。它们要么导致过早死亡，要么是造成终身残疾的慢性病，具有经济影响。它们包括许多影响肌肉和神经功能的不同疾病，约占所有非传染性神经疾病的20%。例子包括肌营养不良症、先天性肌病、神经病、运动神经元病、肌肉通道病和线粒体疾病。遗传学的进步提高了我们在英国诊断患者的能力，这导致了患者护理的改善，并使临床试验成为可能。然而，在官方发展援助(ODA)定义的中低收入国家(LMIC)中，基因进步的好处尚未实现，部分原因是缺乏专门接受过基因组NMD药物培训的神经学家。NMD通常是遗传的，是遗传的。识别遗传途径和应用基因测试导致了疾病理解方面的一些最重要的进步，以及患者管理计划和新疗法的开发。许多关键干预措施涉及广泛可用的医疗技术的廉价实际应用(例如低成本的无证用药、有针对性的疫苗接种、心脏监测和呼吸护理)，但这些技术的应用取决于作出准确的诊断。例如，精确的基因诊断可以导致遵循既定护理指南的个性化且往往简单的管理计划，其中包括对已知并发症(例如心脏、呼吸系统、胃肠病和代谢)的基本筛查，以及通常是改善健康结果的简单干预--在提供准确基因诊断的情况下，可以容易地在LMICs中实施的干预措施。在英国，肌肉活检一直是许多患者研究算法的主要手段，但这需要配备专门的实验室进行冰冻切片分析，并配备越来越多的诊断抗体。然而，基因组学的最新进展提供了基于DNA样本和远程收集的临床数据进行高精度诊断的机会。我们的中心目标是建立种族多样化的NMD儿童和成人队列，并进行基因组分析，以发现已知的和识别新的疾病基因。我们将增加接受精确基因诊断的患者数量，以改善患者护理，并增加对四大洲NMD的比较遗传结构的了解。这是一个全新的跨洲计划，由伦敦大学学院、纽卡斯尔大学和剑桥大学的英国教授领导。该研究计划将培养新一代学术医生，产生世界上最大的1.5万名不同种族的NMD患者队列，并将调查致病基因。我们将与位于印度、土耳其、南非、赞比亚和巴西的五个LMIC临床和学术中心合作。受过培训的医生将是未来临床学术领袖，在这些国家承担研究和改善NMD患者护理。这些研究员将在神经学方面接受全面培训，并将在英国花费一年时间接受NMD基因组医学方面的专家培训，并在他们的国家花费三年时间建立NMD患者队列，这些患者将在临床上进行详细评估，并将接受全面的基因分析，以实现准确的诊断和优化患者管理。所有产生的数据都将匿名，并由所有研究人员共享。重要的是，我们已经获得了数千个种族匹配的对照DNA，并将进一步建立这种对照资源，以补充通过基因组学英国100,000基因组计划、NIHR生物资源和国际合作资源提供的资源。我们将培养新一代NMD医生，他们将在自己的国家从事研究事业，发现新的基因，改善患者护理。

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.