The Utility of Clinical Exome Sequencing as a First-Tier Diagnostic Tool in Critically Ill Infants in South Africa

Abstract

Genetic disorders are significant contributors to infant mortality, morbidity, hospitalisation, and the need for intensive care globally. The identification and diagnosis of genetic disorders in ill infants is challenging due to their indistinct, and often atypical disease presentations. Diagnosis is traditionally driven by a differential clinical diagnosis; however, broad genotype-first approaches are now the recommended strategy in ill infants. The use of NGS-based testing, including gene panels, whole exome sequencing and whole genome sequencing, has successfully been utilised to diagnose genetic disorders in ill infants and has begun to be implemented in global settings; however, representation of low- and middle-income countries is lacking. Local infrastructure, capacity and expertise significantly affect successful implementation in these contexts. We therefore aimed to investigate the utility and implementation of singleton virtual exome sequencing panels in a cohort of 32 ill infants in the South African State healthcare system, providing the first investigations into the use of NGS in a neonatal intensive care unit setting in Africa. Three virtual panels were used to analyse exome sequencing data: a curated panel of genes implicated in neonatal-onset conditions and enriched for variants in South African populations; a ClinVar panel; and the Developmental Disorders Genotype-to- Phenotype (DDG2P) panel. A diagnostic yield of 22% was achieved across the three virtual panels, providing a definitive molecular diagnosis in seven ill infants. These infants experienced changes in their clinical management as a result of this diagnosis, including the initiation of palliative care, familial screening and prenatal testing for future pregnancies. The adaptation of recommended implementation strategies was necessary in the South African context to address shortages in resources, infrastructure and bioinformatics capacity through the use of gene panels instead of whole exome sequencing and the use of locally available technologies; shortages in the trained genetics workforce through the reliance on primary care clinicians for referrals; and through the singleton sequencing approach to address the unavailability of parents for trio-sequencing and the additional cost factors. This pilot study demonstrated the utility of NGS for the diagnosis and management of ill infants in the South African State healthcare system and explored the challenges in implementing NGS technologies in resource-limited settings. The implementation strategy explored through this research provides a baseline from which advanced NGS diagnostic v strategies can be developed and from which scaled up investigations of utility in the South African State setting can commence.