BACKGROUND:
Children with developmental disorders in low- and middle-income countries often face prolonged and inequitable diagnostic pathways due to limited access to genomic services. The DDD Africa study evaluates the feasibility, acceptability, and health system value of introducing genomic diagnostics within selected public-sector genetics clinics in South Africa.

METHODS:
We recruited 371 families from specialised state-sector genetics clinics. Participants were phenotyped using standardised Human Phenotype Ontology (HPO) terms, and exome sequencing was introduced within defined clinical care pathways. Variant interpretation was undertaken by multidisciplinary teams, and all candidate diagnoses were reviewed in virtual multidisciplinary team meetings involving diagnostic scientists, clinicians, and genetic counsellors from both local sites and the international DDD-Africa network, with results returned through established genetic counselling pathways. In unresolved cases, exome results were used to guide additional molecular investigations, enabling selective use of costly follow-up testing. Implementation outcomes included feasibility, clinician engagement, workforce development, and perceived clinical and personal utility.

RESULTS:
Exome sequencing achieved a diagnostic yield of 35.6% thus far. In a subset of unresolved cases, ongoing exome-guided additional molecular testing has begun to identify additional diagnoses, suggesting potential to improve overall diagnostic resolution. Genomic diagnostics were feasible to deliver within specialised public-sector clinics and were well accepted by clinicians and families. Results informed clinical management, surveillance, and reproductive counselling. Structured assessment tools supported clinical processes, while training activities strengthened local clinical and laboratory capacity.

CONCLUSIONS:
DDD Africa demonstrates that integrating genomic diagnostics into public-sector health services is feasible and delivers value beyond diagnostic yield alone. The use of virtual multidisciplinary review enabled local services to be strengthened through access to international rare disease expertise, supporting high-quality decision-making in resource-constrained settings. These findings support phased adoption of genomic diagnostics, including exome-guided testing strategies, as a promising pathway to strengthen paediatric health services in resource-constrained settings.