Investigation of cystic fibrosis transmembrane conductance regulator variants in South African patients with cystic fibrosis

Abstract

Cystic Fibrosis is a genetic disease caused by variants in the CFTR gene. It is one of the most thoroughly studied genetic diseases, with remarkable advances being seen in the ability to diagnose and specifically treat CF patients based on the nature of their variants. Diagnostic protocols have gained in specificity and sensitivity, with high variant detection rates being achieved using new-born screening in populations with higher frequencies of known, common mutations. However, there are several obstacles impeding the improvement of care in LMICs with diverse populations carrying CFTR variants, including challenges in establishing accurate and reliable diagnostics and overcoming misdiagnosis. African populations are known to have high genomic diversity but remain largely understudied. In South Africa, greater knowledge of the CFTR variant spectrum and clinical presentation is needed to enable earlier diagnosis with more specific gene panels, since the variants common to European populations are less frequent in this population. To bridge this gap, next generation sequencing data from a cohort of 60 South African patients and 5 parents of CF patients was used for variant discovery across the exon regions of the CFTR gene. Thereafter, variant effect prediction was performed, and potentially pathogenic variants were identified. Lastly, these potential variants were validated experimentally using Sanger sequencing. Next-generation sequencing of this cohort enabled 27 individuals that were lacking a complete molecular diagnosis to be fully genotyped. 23 confirmed variants have been functionally studied and proven to cause CF; however, 11 variants are yet to have their functional significance characterised. This study demonstrates the extent of diversity that is likely present in the southern African CF population. As the emerging field of precision medicine and the development of specific CFTR therapies gains momentum with the help of high-throughput screening, individuals with CF in LMICs such as South Africa stand to benefit greatly through earlier molecular diagnosis as well as more specific treatment protocols.