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.

Public Health Relevance

Developmental disorders (DD) are serious disabilities that inflict life-long suffering for affected children and their families, and are major healthcare and economic burden especially in low income countries. The genetic contribution to DD in Africa is poorly understood and DDD-Africa therefore aims to address this through the creation of a framework for research and evidence-based healthcare reform. Our long-term goal for the project is to develop a pragmatic and effective approach for the sustainable integration of whole-exome sequencing in DD diagnostics in a way that will enable precision public health approach for Africa.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZHG1)
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Senthil, Geetha
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Wits Health Consortium (Pty), Ltd
South Africa
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