Genetic variant detection in a South African haemophilia B population.

BACKGROUND: Haemophilia B is characterised by a deficiency of factor IX (FIX) protein due to genetic variants in the FIX gene (F9). Genetic testing may have a vital role in effectively managing haemophilia B. However, in many developing countries, comprehensive genetic variant detection is unavailable. This study aimed to address the lack of genetic data in our country by conducting genetic variant detection on people affected by haemophilia B in our region. METHODS: Twenty-one participants were screened with a direct Sanger sequencing method to identify variants in the F9 gene. The identified variants were then compared to previously published variants and/or to a reference database. RESULTS AND DISCUSSION: A total of ten F9 genetic changes were detected, with five of them being novel. These identified variants were distributed across different domains of the FIX protein. Only one participant had a history of inhibitor formation against FIX replacement therapy. Notably, this participant had two distinct genetic changes present adjacent to each other. Thus, we hypothesise that the presence of multiple variants within the same functional region of the gene may increase the risk for inhibitor development. CONCLUSION: The discovery of novel pathogenic variations in the F9 gene highlights the importance of genetic analysis in specific geographical regions. The possible link between a complex variant and inhibitor formation illustrates the potential role that genetic screening has as a pre-treatment tool in predicting treatment reactions and outcomes.

Molecular characterisation of NPM1 and FLT3-ITD mutations in a central South African adult de novo acute myeloid leukaemia cohort.

BACKGROUND: Recognition of molecular abnormalities in acute myeloid leukaemia (AML) has improved our understanding of its biology. NPM1 and FLT3-ITD mutations are recurrent in AML and clinically significant. NPM1 mutations are associated with a favourable prognosis, while FLT3-ITD mutations are an independent poor prognostic factor in AML. OBJECTIVE: This study described the prevalence and molecular characteristics of the NPM1 and FLT3-ITD mutations in a newly diagnosed AML patient cohort in central South Africa. METHODS: The study included 40 de novo AML patients. An NPM1 and FLT3-ITD multiplex polymerase chain reaction assay was optimised to screen patients for the respective mutations and were confirmed using Sanger sequencing. The prevalence of the NPM1 and FLT3-ITD mutations were determined, and mutation-specific characteristics were described in relation to patients' demographic information and AML classifications. RESULTS: The patients' median age was 38.5 years, with 77.5% (n = 31) of patients being self-proclaimed Black Africans. AML with recurrent genetic abnormalities was most prevalent (57.5%; n = 23), of which acute promyelocytic leukaemia (APL) was most common (40.0%; n = 16). None of the patients had the NPM1 mutation. FLT3-ITD was present in 37.5% (6/16) of APL patients and in one (20.0%) of five AML patients with a t(8;21) translocation. Most patients had an FLT3-ITD allele ratio of ≥ 50% and ITD lengths of > 39 bp. CONCLUSION: FLT3-ITD mutations were mainly found in APL cases at a similar prevalence as reported in the literature. High FLT3-ITD allele ratios and long ITD lengths predominated. No NPM1 mutations were detected.

HLA major allele group frequencies in a diverse population of the Free State Province, South Africa.

BACKGROUND: Human Leucocyte Antigens (HLA) play a vital role in disease pathogenesis and transplant rejection. HLA-typing is a useful tool in predicting disease progression and to identify potential organ donors. Due to human migration and known ethnic variation, frequent targeted HLA sequencing of specific populations is crucial to increase their representation in global reference panels. MATERIALS AND METHODS: We performed a retrospective file audit of all HLA-typings done in our setting from 2005-2019. We discuss data for the major HLA-A, HLA-B, HLA-C, and HLA-DRB1 allele groups. RESULTS: Overall, the most common allele groups were HLA-A∗02, HLA-B∗15, HLA-C∗07 and HLA-DRB1∗03. For the African descent group, the most common alleles were HLA-A∗30, HLA-B∗15, HLA-C∗07 and HLA-DRB1∗03. For the European descent group, the most common alleles were HLA-A∗02, HLA-B∗07, HLA-C∗07 and HLA-DRB1∗15. For the mixed ancestry group, the most common allele groups were HLA-A∗02, HLA-B∗15, HLA-C∗02 and HLA-DRB1∗13. HLA-B∗44 was identified as the most common allele group in patients with renal failure. DISCUSSION AND CONCLUSION: The significant variation within the HLA frequencies between the different ethnic groups highlights the value of population-specific HLA-typing. Furthermore, the identification of HLA-B∗44 as a prominent HLA in our renal failure population warrants in-depth investigation of this group.