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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

基本信息

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
项目类别：
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

项目摘要

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.

发育障碍是一种严重的慢性残疾，其在儿童中系统性地增加低收入和中等收入国家的患病率。由于传染病负担沉重在许多非洲国家，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，因此传统的诊断测试成功率较低。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，并产生了重大影响 DD诊断的精确度。总体而言，全外显子组测序（WES）作为研究工具可以直接影响护理，同时成本低于基因级联通常需要进行检测来阐明 DD 的遗传原因。此外，其适用用途在资源匮乏的环境中，如许多非洲国家的情况，这一点尚未得到评估。我们提议的项目将以英国解密发育迟缓 (DDD) 为模型研究，成功促进了基因组测序技术的转化在英国诊断 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，同时塑造其成功在非洲环境中的实施。我们的长期目标是评估是否与 WES 相关的系统表型分析提高了识别可能的非洲 DD 患者的致病突变。为了实现这一目标，我们将招募至少 500 名尚未确认基因诊断的 DD 参与者及其父母到这项研究。我们将收集 DD 患者的详细临床信息和 DNA 样本以及他们的父母，并对三人组进行 WES。多部分生物信息学分析将旨在解释和描述参与者 DD 的遗传病因。自始至终我们打算让参与者和相关利益相关者参与评估的过程基因组素养、与基因组研究相关的伦理问题以及改进的机会咨询。拟议的项目将启动 DDD-非洲框架，创造独特的机会来提高研究能力，提供培训机会未来将在非洲大陆建立更广泛的合作网络。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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
影响因子：
0
作者：
Mubungu,Gerrye;Roelants,Mathieu;Lumaka,Aimé;Makay,Prince;Tshika,Dahlie;Lubala,Toni;TshiloboLukusa,Prosper;Devriendt,Koenraad
通讯作者：
Devriendt,Koenraad

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

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

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