Retrospective file review shows limited genetic services fail most patients – an argument for the implementation of exome sequencing as a first-tier test in resource-constrained settings

BACKGROUND: Exome sequencing is recommended as a first-line investigation for patients with a developmental delay or intellectual disability. This approach has not been implemented in most resource-constraint settings, including Africa, due to the high cost of implementation. Instead, patients have limited access to services and testing options. Here, we evaluate the effectiveness of a limited genetic testing strategy and contrast the findings to a conceivable outcome if exome sequencing were available instead. RESULTS: A retrospective audit of 934 patient files presenting to a medical genetics clinic in South Africa showed that 83% of patients presented with developmental delay as a clinical feature. Patients could be divided into three groups, representing distinct diagnostic pathways. Patient Group A (18%; mean test cost $131) were confirmed with aneuploidies, following a simple, inexpensive test. Patient Group B (25%; mean test cost $140) presented with clinically recognizable conditions but only 39% received a genetic diagnostic confirmation due to limited testing options. Patient Group C – the largest group (57%; mean test cost $337) – presented with heterogenous conditions and DD, and 92% remained undiagnosed after limited available testing was performed. CONCLUSIONS: Patients with DD are the largest group of patients seen in medical genetics clinics in South Africa. When clinical features are not distinct, limited testing options drastically restricts diagnostic yield. A cost- and time analysis shows most patients would benefit from first-line exome sequencing, reducing their individual diagnostic odysseys. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13023-023-02642-4.