Why Africa needs to address deafness
Ambroise Wonkam is a medical geneticist and Principal Investigator for the Hearing Impairment Genetics Studies in Africa (HI-GENES Africa) project under the Human Heredity and Health in Africa (H3 Africa) programme. The H3 Africa programme supports population-based studies that use genetic, clinical and epidemiological tools to better understand how the interplay between human genes and the environment influence disease susceptibility, pathogenesis and prevention with the goal of improving the health of African populations. H3 Africa is supported by the Alliance for Accelerating Excellence in Science in Africa (AESA), a platform of the African Academy of Sciences and African Union Development Agency (AUDA-NEPAD), in partnership with the National Institute of Health (NIH), Wellcome, and African Society of Human Genetics (AfSHG).
Hearing impairment (HI) remains one of the most disabling congenital — present from birth — diseases. HI burden is higher in Sub-Saharan Africa than elsewhere in the world: congenital HI occurs in 1-2 per 1,000 newborns globally, based on early hearing detection and intervention (EHDI) programs, but up 6 per 1,000 in Africa. Early diagnosis and intervention for children with HI is recommended to maximize their cognitive, social-emotional, speech and language development. Availability of EHDI services is rare in Africa and in the absence of newborn screening, the age at diagnosis is usually quite late in Africa, e.g. 3.3 years in Cameroon. Non-syndromic hearing impairment (NSHI) can be caused by a change or mistakes in one or more of our genes (a piece of DNA), which are the instructions for the normal functioning of a person.
HI can also be caused by environmental factors such as infections of a child before or after birth, head or ear injuries and noise pollution, this is referred to as syndromic HI. People with NSHI caused by a change in their genes represent about half (~50%) of all people born with HI. Whenever there is a mistake that causes a change in the genes, people are usually affected with HI in the same family regardless of gender. However, the person diagnosed with HI might be the first and only person that is affected in their family. In most cases, both parents do not have hearing problem themselves, but each of them carries a gene with a mistake that may be passed onto their children. This is called autosomal recessive (AR) inheritance and accounts for 77% of NSHI. Each child who inherits these two genes with mistakes from both parents (one from each parent) will have HI at birth or within their first few years of life. In some cases, however, one or both parents carrying mistakes in their genes have hearing impairment themselves and can pass it on to children. More than 1,000 NSHI genes may remain to be identified. These undiscovered genes are not necessarily rare causes of NSHI, because populations that have been understudied such as sub-Saharan Africans (SSA), may yield genes that play a crucial role in NSHI.
Despite hundreds of identified genes that can cause HI, only two genes (GJB2 and GJB6) have been systematically studied among Africans, for which prevalence of known causal changes is close to zero. With limited knowledge on the major genetic causes of HI in Africa, there is an urgent need to identify the major causes of HI in developing countries to aid the design and development of screening tools that will be sensitive and specific to African populations. HI-GENES Africa has great public health significance, since it will improve genetic screening and has the potential to predict cochlear implant and treatment outcomes in Africans, and in people of African descent.
Description of study
HI-GENES Africa proposes to use Whole Exome Sequencing (WES), bio-informatic analysis and functional studies to study the largest sample of sub-Saharan Africans to-date with prelingual autosomal recessive Non-syndromic hearing impairment (ARNSHI), from Cameroon, Mali, Ghana and South Africa, to identify novel and relevant NSHI genes in African populations. In addition, we will employ qualitative methods to examine the psychosocial challenges experienced by parents and individuals affected by HI, and execute appropriate community engagement activities at the study sites.
Whole Exome Sequencing of families segregating NSHI in Africa will enable 1) discovery of novel genes, and 2) revealing the most relevant genes and mutations in African populations living with HI. Our research in Cameroon has already identified several genes and novel variants linked to HI. Therefore, the results of the present project will have a huge impact on understanding NSHI genes in Africans, and towards fine-tuning diagnostic protocols for NSHI globally. We will use the following strategy, which has been very successful in the identification of novel NSHI:
HIGENES-Africa is a multi-site (South Africa, Ghana, Cameroon, Mali) and multi-funded (NIH, Wellcome/AAS) research project which aims to understand the genetics and genomics of congenital NSHI in Africa. The aim is to collect DNA samples from 125 families with children with early-onset HI (diagnosed before 6 years of age) to understand the genetics and heritability of HI. We will also collect DNA samples from 500 individuals who are isolated cases or probands (first case in their family with HI). Genetic techniques and cutting-edge scientific tools will be used to identify novel NSHI genes. The novel NSHI genes will be validated as a cause of HI through cell-based techniques and in a mouse-model. These scientific methods are used to verify that the genes we identified cause HI. As part of social responsiveness, the project engages with stakeholders who include participants, communities, the public and the schools for the Deaf. The aim of this engagement is: increased knowledge about causes of HI, increased knowledge the importance of genetic research of HI, increased intentions towards improved quality of life and increased understanding, lived perceptions, experiences, challenges and needs due to HI.
When this study is completed, the largest collection of families and probands with NSHI will have been identified from SSA, consisting of 125 families and 500 probands with early-onset HI. Using data from the NHLBI-Exome Sequencing Project (ESP), we demonstrate that known causal NSHI gene/variants are under-represented in African-Americans and only explain 4.1% of ARNSHI compared to 64% in European-Americans. This can be due to different genes and variants underlying NSHI in sub-Saharan Africans who are the predominant ancestors of African-Americans. Our research team has considerable expertise in recruiting patients with monogenetic conditions in SSA, analyzing pedigrees and next generation sequence (NGS) data and developing methods to tackle the problems of data analysis, in particular for NGS data, and have been highly successful in identifying disease causality of NSHI.
Outcome of study
We have been successful in mapping out different locations in Cameroon, Ghana, Mali and South Africa, and have established contact persons for continuous recruitment of study participants. Pilot recruitment teams have been mobilised and trained to coordinate the recruitment activities. The training of researchers and establishment of recruitment sites are important to ensure that good quality studies are conducted, and that the effort is sustainable through capacity building. We have obtained results for samples that are relevant for the type of study (WES co-segregation studies) and have selected only the samples that tested negative for the common GJB2 gene HI mutations. In total, we have done rich whole-exome sequencing at the Perkin Elmer Laboratory (Whole Exome Sequencing (CREv2) 13GB Data) of 1000 samples.
Our students have been trained in WES data analyses, focusing on association analysis of sequence data using variant association tools for complex traits. Presently, we have developed pipelines for the analyses of the sequenced data. This is important for the project to be able to analyse data independently and to develop data analysis capacity on the African continent. The project has produced six scientific publications in high impact journals. Important highlights from these publications indicate that it is critical to intensify efforts to explore the roles of novel causative genes in African populations with HI. HI-GENES Africa has organised different outreach initiatives in deaf communities in Ghana, Mali, Cameroon and South Africa with the aim to educate people about the genetics of HI. Team members have been featured on radio and television programmes in Ghana and South Africa in focused interviews that later generated government response. The project also produced a short video which has been viewed several times at local and international conferences. The aim of these initiatives is to create awareness of genetics in HI and also to advocate for the importance of genetic research in HI.
The collaboration and commitment of co-PI’s, students and staff is imperative for the success of the project. Recruitment is very difficult and recruiting families is even more difficult. We have learned through our interactions with the deaf community that the most effective approach is to have all the necessary skilled people and documents in place before recruitment starts. The project is committed to educating and training students and staff. This continued investment in capacity building has resulted in great success. HI-GENES Africa held a scientific advisory board meeting in July 2019 at the University of Cape Town, South Africa. We have also conducted annual strategic planning meetings. The results and guidance from these events have been very useful in developing a more coordinated plan for the project.
One of the project’s recent publications, The Hearing Impairment Ontology (HIO): A Tool for Unifying Hearing Impairment Knowledge to Enhance Collaborative Research is being rapidly recommended on ResearchGate and Google Scholar. We have received enormous positive feedback on this publication, largely because HI-GENES Africa produced the first and currently the only active HI ontology tool in Africa. This was collaboratively developed by a group of experts in different aspects of HI and ontology to provide a well-structured system, which aims to exhaustively include unambiguously described HI terminology and concepts. The HIO will allow researchers and clinicians alike to readily access standardised HI-related knowledge in a single location and promote collaborations and HI information sharing, including epidemiological, socio-environmental, biomedical, genetic and phenotypic information. Baobab Laboratory Information System (LIMS) is a sample management system which has been implemented in the HI-GENES Africa project. On the LIMS, greater control is exerted on biospecimen storage and shipment. This system has been very helpful in managing samples and is proving to be an important addition to the data management of the project. HI-GENES Africa also provides training and support to attend scientific training/workshops, grant writing and project management. Training targets the next generation of scientific leaders who would be able to raise research funds to develop their own research groups and to generate new, cutting edge biomedical research. The project site in Ghana is currently engaging with policymakers to develop a recommendation to implement newborn screening based on the scientific results obtained from the study.
HI-GENES Africa will have great public health significance, especially for people of African descent. Identifying novel genes can help doctors to improve their capacity to detect HI early and offer appropriate treatment and counselling to affected people and families. HI-GENES Africa envisions being the next frontier of HI genetic research, of global importance by discovering novel genes, and local relevance by identifying mutations that matter most for people of African descent, though the use of cutting-edge sequencing, bioinformatic, and functional analysis technologies. Such knowledge could be used towards the design and fine-tuning diagnostic protocols for NSHI, projecting the need for hearing aids, e.g., cochlear implants, outcomes for HI, and possibly the development of new therapeutic strategies for NSHI. HI-GENES Africa will advocate for a greater commitment to HI biomedical research, by demonstrating successful research and impact on patients. To date, we have received funding from the National Institutes of Health (NIH) and the African Academy of Sciences (AAS) to be able to conduct this research.