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

解读非洲发育障碍 (DDD-Africa) - 评估非洲环境中的临床外显子组测序

• 批准号: 10220707
• 负责人: Zane Lombard
• 金额: $ 17.88万
• 依托单位: WITS HEALTH CONSORTIUM (PTY), LTD
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220707
• 关键词: Address; Adoption; Affect; Africa; African; Benchmarking; Bioinformatics; Caring; Child; Chronic; Clinical; Clinical Research; Clinical Services; Collaborations; Communicable Diseases; Complex; Counseling; Country; DNA; Data; Data Analyses; Democratic Republic of the Congo; Developmental Delay Disorders; Diagnosis; Diagnostic; Diagnostic tests; Disease; Economic Burden; Ensure; Environmental Risk Factor; Ethical Issues; Ethics; Etiology; Family; Funding; Future; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic Services; Genetic Variation; Genomics; Geography; Goals; Health; Health Care Reform; Healthcare; Inequality; Institutes; Investigation; Life; Link; Modeling; Mutation; National Health Services; Outcome; Parents; Participant; Pathogenicity; Patients; Phenotype; Prevalence; Process; Public Health; Rare Diseases; Research; Resolution; Resources; Sampling; Scientist; Shapes; Site; South Africa; Technology; Testing; Training; Translating; Translations; Trust; Work; clinical phenotype; clinical practice; clinically actionable; cost; developmental disease; disability; evidence base; exome; exome sequencing; genetic disorder diagnosis; genetic testing; genome sciences; genomic variation; health care economics; health economics; improved; literacy; low and middle-income countries; low income country; neglect; next generation sequencing; recruit; research clinical testing; socioeconomics; success; tool; training opportunity

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.

发育障碍是严重的慢性残疾，系统地增加了 中低收入国家的患病率。由于传染病的负担很大 在许多非洲国家，对DD等罕见疾病的积极研究一直是 被忽视。 DD的遗传病因很复杂，因此是传统的诊断测试 成功产量低。下一代测序改变了我们的理解 基因组变异及其与健康和疾病的相关性，并显着影响 DD的诊断精度。总体而言，全外观测序（WES）作为 调查工具可以直接影响护理，同时成本低于遗传的级联 通常需要进行测试以阐明DD的遗传原因。此外，它适用 与许多非洲国家一样，在资源贫乏的环境中，尚未得到评估。 我们提出的项目将以解密的发育延迟（DDD）-uk进行建模。 研究，成功促进了基因组测序技术的翻译 在英国诊断DD。这种伙伴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，同时为成功而塑造它 在非洲环境中实施。我们的长期目标是评估是否 与WES相关的系统性表型改善了识别可能的前景 非洲DD患者的致病突变。为了实现这一目标，我们将招募至少500 尚未确认遗传诊断的DD的参与者及其父母 进行这项研究。我们将从DD患者那里收集详细的临床信息和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 进行解释和描述参与者DD的遗传病因。自始至终 我们打算与参与者和相关利益相关者进行评估的过程 基因组素养，与基因组研究有关的道德问题以及改善的机会 咨询。拟议的项目将允许启动DDD-AFRICA框架， 创造一个独特的机会来提高研究能力，提供培训机会 并在未来在非洲大陆建立更广泛的协作网络。

项目成果

Retrospective file review shows limited genetic services fails most patients - an argument for the implementation of exome sequencing as a first-tier test in resource-constraint settings.

• DOI: 10.1186/s13023-023-02642-4
• 发表时间: 2023-04-12
• 期刊: ORPHANET JOURNAL OF RARE DISEASES
• 影响因子: 3.7
• 作者: Wiener, Emma K.;Buchanan, James;Krause, Amanda;Lombard, Zane
• 通讯作者: Lombard, Zane

Could Africa be the future for genomics research?

非洲会成为基因组学研究的未来吗？

• DOI: 10.1038/d41586-023-00222-x
• 发表时间: 2023
• 期刊: Nature
• 影响因子: 64.8
• 作者: Lombard,Zané;Landouré,Guida
• 通讯作者: Landouré,Guida

Objective evaluation of facial features in Congolese newborns by facial measurements. The need for population-specific measurements.

通过面部测量客观评估刚果新生儿的面部特征。

• DOI: 10.1002/ajmg.a.62958
• 发表时间: 2022
• 期刊: American journal of medical genetics. Part A
• 作者: Mubungu,Gerrye;Roelants,Mathieu;Lumaka,Aimé;Makay,Prince;Tshika,Dahlie;Lubala,Toni;TshiloboLukusa,Prosper;Devriendt,Koenraad
• 通讯作者: Devriendt,Koenraad

Incorporating CNV analysis improves the yield of exome sequencing for rare monogenic disorders-an important consideration for resource-constrained settings.

• DOI: 10.3389/fgene.2023.1277784
• 发表时间: 2023
• 期刊: FRONTIERS IN GENETICS
• 影响因子: 3.7
• 作者: Louw, Nadja;Carstens, Nadia;Lombard, Zane
• 通讯作者: Lombard, Zane

Ending a diagnostic odyssey-The first case of Takenouchi-Kosaki syndrome in an African patient.

• DOI: 10.1002/ccr3.3966
• 发表时间: 2021-04
• 期刊: Clinical case reports
• 影响因子: 0.7
• 作者: Flynn K;Feben C;Lamola L;Carstens N;Krause A;Lombard Z;for DDD‐Africa as members of the H3Africa Consortium
• 通讯作者: for DDD‐Africa as members of the H3Africa Consortium