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，在 在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 被忽视了。DD的遗传病因很复杂，因此传统的诊断试验 成功率很低。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，并显著影响了 诊断的精确度。总体而言，完整外显子组测序(WES)作为一种 研究工具可以直接影响医疗保健，同时成本低于遗传基因的级联 通常需要进行检测来阐明DD的遗传原因。此外，它的适用用途 在资源贫乏的情况下，就像许多非洲国家的情况一样，没有对其进行评估。 我们建议的项目将以解密发展延迟(DDD)为模型-英国 这项研究成功地促进了基因组测序技术的翻译 在英国诊断痴呆症。这一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 在非洲的背景下执行。我们的长期目标是评估 与WES连锁的系统表型分析提高了识别可能性的前景 非洲DD患者的致病基因突变。为了实现这一目标，我们将招聘至少500人 基因诊断未得到确认的DD患者及其父母 这项研究。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，并在三人组中表演韦斯。多部分生物信息学分析将 用来解释和描述受试者中DD的遗传病因。贯穿始终 我们打算让参与者和相关利益攸关方参与评估的过程 基因组素养、与基因组研究有关的伦理问题和改进的机会 心理咨询。拟议的项目将启动非洲发展筹资框架， 创造独特的机会，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.