A Feasible Molecular Diagnostic Strategy for Rare Genetic Disorders Within Resource- Constrained Environments

Abstract Background The timeous and accurate diagnosis of rare genetic disorders is critical, as it enables a better understanding of patient management, prognosis and more personalized treatment. A confirmed genetic diagnosis also enables accurate genetic counselling for affected individuals and their relatives by offering options for prenatal and cascade testing. In a resource-constrained environment such as the South African State healthcare system, the challenge is to design appropriate and cost-effective assays that will enable accurate genetic diagnostic services in patients of African ancestry across a broad disease spectrum. Next-generation sequencing (NGS) has transformed testing approaches for many Mendelian disorders, but this technology is still relatively expensive to implement. The paucity of baseline genetic data on African populations adds to the complexity of implementing an appropriate NGS-based service and interpretation of results. Result In the current study, the approach taken aimed at balancing NGS cost, efficiency, data quality as well as diagnostic utility of results. As a proof of concept, we describe a feasible diagnostic strategy for genetic disorders frequently seen in our genetics clinics (RASopathies, Cornelia de Lange syndrome, Treacher Collins syndrome, CHARGE syndrome and other phenotypically overlapping syndromes. The custom-designed targeted NGS gene panel enabled mutation screening for these disorders that range in incidence from 1 in 1000 to 1 in 100 000 newborns. Samples were batched during sequencing and analyzed selectively based on the clinical phenotype. This study had an overall diagnostic yield of 54.5%. Conclusion The strategy employed is cost-effective as it allows batching of samples from patients with different diseases in a single run, an approach that can be utilized with rare and less frequently ordered molecular diagnostic tests. The subsequent selective analysis pipeline allowed for timeous reporting back of patients results. This is feasible and can be employed for the molecular diagnosis of a wide range of rare monogenic disorders in resource-constrained environment.