Sequencing 10,000 whole genomes

The specific objective of the second phase of the Genome Tunisia Project is to sequence about 5 to 10% of the Tunisian adult population, reaching the optimal scale for precise population-based studies. The initial plan is to start by sequencing 10,000 healthy individuals without any familial history of diseases. Then we will progressively increase the sample size to achieve the international guidelines. However, by adhering to the inclusion and exclusion criteria of this project, we would probably need to collect much less samples than initially anticipated given that complex diseases are highly prevalent in the adult population in Tunisia, notably diabetes, hypertension, and cancer (affecting approximately 30% of the adult population). Researchers and medical personnel in specific recruitment offices continue to recruit participants throughout the country in order to ensure a better representativeness of the different ethnic groups. As detailed previously, participants will provide informed consent, blood samples, and data will be collected using the established GTCA protocols.

National sequencing and analysis platform

The implementation of a national sequencing and analysis platform will enable access to genomic medicine on a routine basis. This national platform will be linked to the regional hospitals, research centers, and universities to ensure consistency in offering sequencing testing types and clinical interpretations of the generated data. Indeed, this platform will be dedicated to (1) sequencing, (2) data analysis, and (3) data interpretation. Generated data will be centralized, trimmed, and analyzed using a standardized bioinformatic pipeline. VCFs files will then be shared with qualified medical geneticists to make appropriate annotations and interpretations using standardized tools to ensure appropriate genetic testing. Newly identified mutations will be integrated into the national portal facilitating further explorations by other investigators and to ensure knowledge transfer and sharing within the scientific community.

The implementation of this national platform will enable to address three main challenges:

Public health: by providing equal access to sequencing facilities for genetic diagnostic, prognostic, and theranostic purposes.

Scientific, technological, and biomedical research: by offering sequencing service to researchers allowing a better understanding of pathologies in the field of rare and common diseases, as well as by developing bioinformatics skills, data science expertise, computational capacities, and infrastructure.

Health economy: by offering outsourcing services to neighboring countries which will promote the development of a new genomic-based industry sector and reinforce medical tourism.

National biobank

As part of this national initiative, we are aiming to create a national biorepository that will gather biological material with associated genomics and clinical and phenotypic data from Tunisian patients and citizens. The national biobank will also constitute a valuable resource for biomedical research to establish new therapeutic and preventive measures at the population level. Genome Tunisia’s ambition is to create a healthcare system that can exploit the power of a centralized large cohort collection and massive data generation. Our long-term vision is to put in place a federated standards-led informatics infrastructure, spanning research, and healthcare domains to record and store biological material as well as the collected clinical and genomic data. To do so, clearly agreed standards for genotypic–phenotypic data and biospecimen collection protocols should be set up.

Authorities in Tunisia will use the biobank as part of the infrastructure they are building to accelerate the advancement of precision medicine based on national and international biobanking guidelines.

Special interest groups (SIGs)

Sequencing disease-based cohorts are under discussion to investigate the genetic risk factors associated with the most frequent diseases in the country. Six special interest groups (SIGs) on cancer, rare diseases, neurological, autoimmune, cardiovascular, and infectious diseases have been agreed on and are under construction (Fig. 5).

Fig. 5

The special interest groups that emerged from the Genome Tunisia Project. Tunisian Society of Human Genomics (TSHG)

WGS will be performed in unsolved cases previously investigated by gene panel or WES. The number of patients to be investigated as part of the disease cohorts has been fixed to 6000, as a first stage, and this was calculated after careful examinations based on the specific research objectives and resource considerations. This investigation will facilitate the detection of new disease-causing genes and/or novel alterations, especially within regulatory regions. Additionally, WGS will enable the identification of structural variants such as copy number variations (CNVs), inversions, and translocations, with greater accuracy and sensitivity. Using SNP genotyping arrays, we intend also to perform large-scale association studies such as GWAS to identify specific genetic variants associated with these diseases within the Tunisian population. The generated data will serve for the development of polygenic risk scores (PRS) that are specific to the Tunisian population, allowing for better risk stratification. We will employ a multidisciplinary approach engaging clinicians, geneticists, and researchers to determine the most suitable investigation strategy. This assessment will consider factors such as disease complexity, genetic variability, specific research objectives, and available resources.

Tumor board meetings will be implemented for the cancer SIG as a pilot phase. These multidisciplinary meetings will then be put in place for other diseases, mainly for the neurological and rare diseases.

To strengthen the capacities of the multidisciplinary scientific community constituting the GTCA consortium, the Tunisian Society of Human Genomics (TSHG) has been recently formed (March 2023). This initiative, which emerged from the GTCA consortium, is an independent society that will work in close collaboration with the African Society of Human Genetics as well as other African societies to build strong connections between Tunisian, African, and international scientists. The executive board of TSHG is composed of 17 scientists from different Tunisian regions and institutions, with a positive gender balance (13 women) and a significant youth representation (three early-career researchers).

Upon its official creation, the TSHG will organize its first general meeting in September 2024 and plans to invite the five existing African societies, to exchange experiences, and discuss the future directions of the Human Genomics field for the benefit of the African scientific community.

Socio-economic impact

In Tunisia, the government has long prioritized a healthcare system that is accessible to all citizens, offering equitable and affordable care. Over the past decade, particularly in the post-genomics era, significant efforts have been made to raise awareness about genetic testing facilities. However, more efforts are needed to ensure that individuals from all socio-economic backgrounds are aware of and have access to these services. The Genome Tunisia Consortium is aiming to address this issue by establishing two task forces on education and training (TF4) and communication and dissemination (TF12). So far, individuals from different socio-economic backgrounds have participated in the study representing therefore the socio-economic diversity.

In addition, genetic testing reimbursement is another important issue that we are working on by involving policy makers and insurance companies on board to ensure that cost does not serve as a barrier to access genetic testing. Furthermore, as outlined in Fig. 2, we have established a task force specifically focused on cost-effectiveness and health economics (TF9) to ensure equitable access to genomic testing in Tunisia.

GTCA includes competencies and stakeholders from the private and public sectors to lay the foundation for collaborations and to maximize the potential of health economics in Tunisia. The Ministry of Health of Tunisia has recently organized an open and informative day to discuss different aspects of precision medicine in Tunisia demonstrating the interest of the government to integrate genomics in its economic reform [32].

The Genome Tunisia Project could therefore present an opportunity for Tunisia to consolidate healthcare, setting digital infrastructure, improving the connection and the interoperability of its systems, and standardizing patient medical records. Also, it is an opportunity to elaborate patient registries and undertake collaborative work to tackle public health issues by exploring cost-effective plans.

Cost-effectiveness

Micro-costing and cost-effectiveness analysis of different genomic interventions, whole exome, whole genome, and large gene panels in different indications start to be evaluated, in different countries implementing genomics [33,34,35,36,37].

In the Genome Tunisia Project, the health economics task force is commissioned to analyze the cost-effectiveness of genomics applications for different indications considering what has been reported from genomic initiatives in other countries and also considering the local context (epidemiology, prevalence of the disease, public health issues, and the consanguinity rate).

The three main goals of the health economics task force of Genome Tunisia are to support decision-makers for an optimal allocation of resources, to lead collaborative work toward implementing cost-effective interventions, and to follow up the continuously evolving costs of sequencing and the evolving methodology for data modeling in order to capture and value genomic testing outcomes.

Synergy with ongoing projects: AGenDA, SEED, PerMediNA, GenCoE, and other international initiatives

Genome Tunisia is typically defined as a set of interrelated activities, task forces, and milestones aiming to strengthen the public health system and scientific research in the field of Human Genomics. Although conducting original research and launching national human genome initiatives are key factors to increase competitiveness at the international level, they are not sufficient to generate major advances in the field of Genomics. For these reasons, the GTCA consortium is participating in different regional and international initiatives, such as the Assessing Genomic Diversity in Africa (AGenDA) project, where GTCA represents the North African site.

Moreover, as an innovative initiative, the Genome Tunisia Project will enable the investigation of patients who have been previously investigated in previous research projects but have remained undiagnosed. One such project is the SEED (Strengthening the Sfax university expertise for diagnosis and management of epileptic encephalopathies) project (seedtwinning.com), which focuses on exploring monogenic forms of developmental and epileptic encephalopathies (DEE). The SEED project has already collected more than 300 patients with electrophysiological, neurologic, and radiological data. One hundred of these patients have already been explored with a customized panel of 116 genes associated with DEE, achieving a diagnosis rate of 30%. The Genome Tunisia Project represents a unique opportunity to support this initiative to draw the genetic landscape of this neurodevelopmental disorder in Tunisia by exploring undiagnosed cases and to position Tunisia as a reference center for the genetic diagnosis of DEE in the MENA region.

In addition, and to start preparing the ground for precision medicine implementation, Tunisia, represented by Institut Pasteur of Tunis (IPT), is coordinating a regional project called Personalized Medicine in North Africa (PerMediNA), funded by the European Ministry of Foreign Affairs. PerMediNA is a key project on the implementation of precision medicine in Tunisia and North Africa involving several stakeholders from different institutions and countries. The main goals of PerMediNA are strengthening collaboration within the ecosystem, generating omics data on cancer patients, and reinforcing patient care by facilitating access to genetic testing and targeted therapies.

Finally, the governmental support to the Genome Tunisia Project as well as the industry commitment and the scientific community engagement make Genome Tunisia an excellent candidate for the GenCoE initiative that was announced in the International Congress of Human Genetics (ICHG) in Cape Town 2023 (https://www.ichg2023.com/).

Precision medicine implementation

The Genome Tunisia Project endeavors to implement precision medicine in Tunisia using an evidence-based model informed by local stakeholders and based on real settings, population specificities, and national context.

The key to a successful implementation of precision medicine in Tunisia will be a bottom-up approach in which members of the project join forces with academia, healthcare authorities, policy makers, and stakeholders to build a nationally distributed infrastructure and to raise awareness on the importance and the impact of the implementation of precision medicine. During the first phase of Genome Tunisia Project, we are evaluating the readiness level at the different centers involved in the project focusing on the infrastructure and bioinformatics human resources, identifying stakeholders and funders, and working on regulation and ethical aspects to support translational and clinical research projects and adapt precision medicine national plan. The readiness level for precision medicine implementation was assessed through a multidimensional approach, which included the organization of two workshops and interviews with key opinion leaders (KOLs). These workshops served as dynamic platforms for brainstorming and idea generation. Additionally, interviews with KOLs allowed for in-depth exploration of challenges and opportunities relevant to precision medicine implementation. Moreover, further efforts are ongoing to ensure that our study is thorough and exhaustive. This includes further interviews and data collection activities, such as focus groups, surveys, and questionnaires. Regarding the findings, while some initial insights have been collected, the analysis of the gathered data is still ongoing to ensure a well-documented illustration of the current readiness level.

As illustrated in Fig. 6, a key step was to gather information on all available NGS platforms, existing biobanks, and healthcare facilities and identify gaps that need to be filled to be able to implement precision medicine in Tunisia and the North African region. Several NGS platforms are available in the different centers; however, to be able to set up an optimal environment and ecosystem, it is essential to implement a national genomics platform which will optimize the use of sequencing technologies.

Fig. 6

Key steps for precision medicine (PM) implementation in Tunisia and the North African region (adapted from Chanfreau-Coffinier et al. 2019)

Illustrating its cutting-edge activities, Tunisia takes a step forward to move toward the goal of delivering the right treatment for the right patient at the right time and at the right site of care. For a continuous development of new methods and treatment strategies, Genomic Medicine Centers will be established at all university hospitals and data generated in healthcare will be fed back to research through the Tunisian National Genomics Platform.

These Genomic Medicine Centers will be consolidated and reinforced with highly skilled bioinformaticians incorporating high throughput omics data analysis to medical routine. In this way, an innovative care pathway ensuring total or partial healthcare reimbursement and involving all national public and private stakeholders will be established to facilitate equal access to precision medicine at the national level.