Doctoral Degrees (Molecular Biology and Human Genetics)

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Browsing Doctoral Degrees (Molecular Biology and Human Genetics) by Author "Bayley, Samantha Lee"

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    Hyperphosphatasia with mental retardation syndrome in South Africa: identifying a recurring PGAP3 variant
    (Stellenbosch : Stellenbosch University, 2021-10) Bayley, Samantha Lee; Moosa, Shahida; Kinnear, Craig; Moller, Marlo ; Uren, Caitlin; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics.
    ENGLISH ABSTRACT: Rare diseases (RDs) may individually be rare, but cumulatively affect up to 6% of the population. In Africa, research and diagnostics for RDs have not been prioritised. Therefore, most African patients with RDs remain undiagnosed. Intra-continental and inter-continental migration have caused African genomes to become highly diverse. Thus, African genomes hold a multitude of unique variants that have not been identified in other populations. Increased research is needed to identify disease-causing variants in these populations. Hyperphosphatasia with Mental Retardation Syndrome (HPMRS) is a rare disease and the only report on this syndrome in southern Africa forms the basis of this thesis. The HPMRS phenotype presents with severe global developmental delay, facial dysmorphic features, and seizures. This thesis investigates whether the pathogenic PGAP3 (NM_0033419.5): c.G557C, p.Arg186Thr variant identified in the preliminary research is recurring in the Xhosa population and the likelihood that this is caused by a founder effect. To evaluate the hypothesis that the PGAP3 variant is recurring due to a founder effect in the Xhosa population, Sanger sequencing and genotyping on the InfiniumTM H3Africa Consortium Array v1 were completed on a total of 15 patients. Genotyping array data were evaluated to determine the relatedness of the patients, local ancestry of the variant, and runs of homozygosity. The carrier frequency was identified in a separate collection of 267 Xhosa individuals. This investigation identified ten unrelated patients as homozygous for the pathogenic PGAP3 variant; therefore, confirming the diagnosis of HPMRS type four. The genotyping results show that the variant is of Bantu-speaking African ancestry and that this variant is within a long run of homozygosity in all the diagnosed patients. The estimated carrier frequency for this variant is 1 in 134 individuals in the Xhosa population. To conclude, the results demonstrate that the PGAP3 variant is a recurring variant that is probably caused by a founder effect. To definitively determine if a founder effect is a true cause, the runs of homozygosity over the variant in the patients should be sequenced. Accordingly, clinicians should consider HPMRS to be more frequent in the Xhosa population due to the presence of this recurring pathogenic PGAP3 variant. This thesis provided valuable information on HPMRS specifically in South Africa and research concerning founder effects in a South African population.