Designing and evaluating the utility of a panel of de novo mutation enriched genes for diagnosing South African patients with developmental delay

Abstract

Developmental disorders (DDs), are diverse and life-altering conditions, with a higher prevalence in sub-Saharan Africa. Approximately 50% of DDs have a genetic basis, but many patients remain undiagnosed due to limitations in current testing methods. Whole exome sequencing (WES) and whole genome sequencing (WGS) are recommended due to their high diagnostic rates, but their routine use is impractical in many low- and middle-income countries (LMICs), including South Africa. Thus, cost-effective alternatives are needed. Targeted gene panels, despite declining global use, might still be relevant in LMICs. This study explored a targeted de novo mutation (DNM)-enriched gene panel in two cohorts: a well-phenotyped group and a group with developmental delay but less phenotypic detail. The analysis included WES on samples from 96 patients in each cohort, followed by a virtual DNM-enriched gene panel analysis. Results showed that 15% of the well-phenotyped cohort and 5% of the unphenotyped cohort had causal variants, which aligns with global diagnostic yields for targeted gene panels in DDs. Among these variants, 47% were de novo mutations, 5% were maternally inherited, and 47% had indeterminate inheritance due to the absence of parental samples. Significant clinical interventions were identified for the majority of patients. Approximately 50% of the causative variants were novel, thus expanding the mutation profile of DDs. Additionally, we identified key factors influencing diagnostic yield, such as the availability of phenotypic data and the use of trio analysis. These findings provide valuable insights into the implementation of routine genetic testing in LMICs, highlighting the importance of comprehensive clinical data submission, trio sequencing and/or analysis, and the evaluation of copy number variants in the diagnostic workup of individuals with DDs. We developed a DNM-enriched gene panel as a starting point for creating practical, resource- efficient diagnostic strategies for DDs. We conclude that this approach would be beneficial for the diagnostic evaluation of DDs and developmental delays in resource-constrained settings.