Deciphering Developmental Disorders in Africa (DDD-Africa) - Evaluating Clinical Exome Sequencing in an African Setting

发育障碍是一种严重的慢性残疾， 低收入和中等收入国家的流行率。由于传染病的高负担 在许多非洲国家，对DD等罕见疾病的积极研究已经 忽视DD的遗传病因是复杂的，因此传统的诊断测试 成功率低。下一代测序改变了我们对 基因组变异及其与健康和疾病的相关性， DD诊断的准确性。总体而言，全外显子组测序（WES）作为一种 调查工具可以直接影响护理，而成本低于遗传级联 测试通常需要阐明DD的遗传原因。此外，其适用范围 在资源贫乏的环境中，许多非洲国家的情况就是如此，但尚未对这一问题进行评估。 我们建议的项目将仿照解密发育迟缓（DDD）-英国 这项研究成功地促进了基因组测序技术的翻译， 诊断DD在英国。这种合作关系将使我们能够利用现有的临床， 研究和生物信息学专业知识和资源，同时塑造它的成功 在非洲实施。我们的长期目标是评估 与WES相关的系统表型分析提高了识别前景的 非洲DD患者的致病性突变。为此，我们将招募至少500名 尚未确诊遗传诊断的DD受试者及其父母 加入本研究。我们将收集DD患者的详细临床信息和DNA样本 和他们的父母，并在三人组中表演WES。多部分生物信息学分析将是 进行解释和描绘参与者的DD的遗传病因。在整个 我们打算让参与者和相关利益攸关方参与评估的过程 基因组扫盲、与基因组研究有关的伦理问题以及提高 辅导拟议的项目将使非洲DDD框架得以启动， 创造一个独特的机会，以提高研究能力，提供培训机会， 并在未来在非洲大陆建立更广泛的合作网络。

Developmental disorders are severe, chronic disabilities that are systematically increasing in prevalence in low-and middle-income countries. Due to the high burden of infectious disease in many African countries, active research into rare disorders such as DD has been neglected. The genetic aetiology of DD is complex and therefore traditional diagnostic tests have a low success yield. Next-generation sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and has significantly impacted the precision of diagnosis for DD. Overall, whole-exome sequencing (WES) as a investigative tool can directly impact care, whilst costing less than the cascade of genetic testing typically required to elucidate the genetic cause of DD. Moreover, its applicable use in a resource-poor setting, as is the case in many African countries, has not been assessed. Our proposed project will be modeled on the Deciphering Developmental Delay (DDD)-UK study, which successfully facilitated the translation of genomic sequencing technologies for diagnosing DD in the UK. This partnership will enable us to leverage existing clinical-, research- and bioinformatics expertise and resources whilst shaping it for successful implementation in an African setting. Our long-term objective is to assess whether systematic phenotyping linked with WES improve the prospect of identifying likely pathogenic mutations in African patients with DD. To achieve this we will recruit at least 500 participants with DD in whom a genetic diagnosis has not been confirmed, and their parents to this study. We will collect detailed clinical information and DNA samples from DD patients and their parents and to perform WES on the trio. Multipart bioinformatics analyses will be performed to interpret and delineate the genetic etiology of DD in participants. Throughout the process we intend to engage with participants and relevant stakeholders to assess genomic literacy, ethical issues related to genomic research and opportunities for improved counseling. The proposed project will allow the initiation of the DDD-Africa framework, creating a unique opportunity to improve research capacity, to provide training opportunities and to build a wider collaborative network on the African continent in future.