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

神经肌肉疾病（NMD）影响全球至少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疾病，并造成经济影响。它们包括许多影响肌肉和神经功能的不同疾病，占所有非感染性神经系统疾病的约20%。实例包括肌营养不良症、先天性肌病、神经病、运动神经元疾病、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，这改善了患者护理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，遗传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医学培训的神经学家。NMD通常是遗传的，并且是遗传的。识别遗传途径和应用基因检测已经导致了疾病理解方面的一些最重要的进展，以及患者管理计划和新疗法的开发。许多关键的干预措施涉及广泛提供的医疗技术的廉价实际应用（例如低成本的非许可证药物、有针对性的疫苗接种、心脏监测和呼吸护理），但其应用取决于作出准确的诊断。例如，精确的基因诊断可以根据既定的护理指南制定个性化且通常简单的管理计划，其中包括对已知并发症（例如心脏，呼吸，胃肠和代谢）的基本筛查以及通常可以改善健康结果的简单干预措施-可以在LMIC中轻松实施的干预措施，提供准确的基因诊断。在英国，肌肉活检一直是许多患者研究算法的支柱，但这需要一个配备冷冻切片分析的专业实验室，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具有种族多样性的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比较遗传结构的了解。这是一个全新的跨大陆项目，由伦敦大学学院，纽卡斯尔和剑桥大学的英国教授领导。该研究方案将培养新一代的学术医生，产生世界上最大的15 000名不同种族的NMD患者队列，并将调查致病基因。我们将与印度、土耳其、南非、赞比亚和巴西的五个LMIC临床和学术中心合作。经过培训的医生将成为未来的临床学术领导者，在这些国家开展研究和改善NMD患者的护理。研究员将在神经病学方面接受全面培训，并将在英国接受一年的NMD基因组医学专业培训，并在他们的国家花费三年时间建立NMD患者队列，这些患者队列将进行详细的临床评估，并将进行全面的遗传分析，以实现精确的诊断和优化患者管理。所有产生的数据将匿名化，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Genomics England 100，000基因组项目、NIHR BioResource和国际合作资源提供的资源。我们将培养新一代的国家医学博士，他们将在自己的国家从事研究事业，发现新的基因，改善病人护理。

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.