Challenges and perspectives in implementing whole-exome sequencing in Algeria lessons from a fully autonomous in-country cohort

Despite the multidimensional value of implementing genomic medicine, in terms of diagnostic yield, cost-effectiveness, and optimisation of care trajectories, its deployment in many African countries, including Algeria, remains constrained by major structural and interpretive challenges, compounded by the persistent underrepresentation of African populations in genomic databases with direct consequences for variant interpretation and clinical decision-making. We implemented a fully in-house whole-exome sequencing (WES) workflow structured through a clinically driven sequential framework in 14 unrelated patients with unexplained neurodevelopmental disorders, in a context of high consanguinity and enriched recessive inheritance. A definitive molecular diagnosis was established in 8 cases, with pathogenic or likely pathogenic variants identified in MECP2, PTPN11, FOXG1, ARV1, GNAO1, ATM, ROBO3, and CHD3. Five cases yielded variants of uncertain significance and one clinically relevant incidental finding was identified. Beyond its diagnostic contribution, this study reveals persistent interpretive limitations: a disproportionate VUS burden, complex incidental finding management, and reduced accessibility to classification criteria, reflecting database underrepresentation, the predominance of private variants, and the limits of current frameworks in consanguineous settings. These findings underscore the necessity of population-specific reference datasets, iterative phenotyping, adapted ethical frameworks, and strategies addressing territorial disparities in access. This work demonstrates that WES implementation requires a structured multidisciplinary ecosystem integrating clinical, bioinformatic, and ethical dimensions, and provides a transferable model for the sustainable integration of genomic medicine in under-resourced settings, while highlighting the global scientific value of incorporating underrepresented populations into genomic research.