Implementation of an Inherited Diseases Gene Panel to Accelerate Precision Medicine in the South African Public Healthcare System

BACKGROUND: While whole genome and exome sequencing is already being implemented in clinics across the globe, there is still very little uptake of these technologies in African healthcare facilities. Significant hurdles remain that impede the translation of these highly effective mutation screening strategies into appropriate and effective clinical services in low- and middle-income countries. METHODS: We developed, validated, and implemented a phenotype-driven genetic testing platform using a 500-gene Ion AmpliSeq Inherited Diseases Panel (IDP) within the South African State healthcare system. This panel enables testing for over 1000 Mendelian disorders using a single laboratory workflow, followed by selective, phenotype-guided analysis to minimize the risk of incidental or secondary findings. A pooled sequencing strategy was used to optimize resource efficiency, achieving an average coverage of 200-400× per sample. RESULTS: Among 276 patients tested during the validation phase, a molecular diagnosis was identified in 46% (127/276) of cases. All pathogenic and likely pathogenic variants were submitted to ClinVar to support global data sharing and variant interpretation. The high coverage achieved reduced the need for additional validation testing, supporting the panel's efficiency and reliability in a clinical diagnostic setting. DISCUSSION: This IDP enables us to improve genetic counselling, identify patients with well-described genetic disorders for whom appropriate interventions are needed and/or available and identify patients that would benefit from whole exome or genome-based testing, and allow for risk clarification for close relatives. This system has laid the foundation for rare disease genetic testing in the South African public healthcare system and can be used as a point of departure for genetic service implementation in resource-constrained environments.