Hyperphosphatasia with mental retardation syndrome in South Africa: identifying a recurring PGAP3 variant
| dc.contributor.advisor | Moosa, Shahida | en_ZA |
| dc.contributor.advisor | Kinnear, Craig | en_ZA |
| dc.contributor.advisor | Möller, Marlo | en_ZA |
| dc.contributor.advisor | Uren, Caitlin | en_ZA |
| dc.contributor.author | Bayley, Samantha Lee | en_ZA |
| dc.contributor.other | Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics. | en_ZA |
| dc.date.accessioned | 2021-11-05T13:18:50Z | en_ZA |
| dc.date.accessioned | 2022-02-22T10:23:09Z | en_ZA |
| dc.date.available | 2022-07-05T03:00:20Z | en_ZA |
| dc.date.issued | 2021-10 | en_ZA |
| dc.description | Thesis (MSc)--Stellenbosch University, 2021. | en_ZA |
| dc.description.abstract | 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. | en_ZA |
| dc.description.abstract | AFRIKAANSE OPSOMMING: Seldsame siektes (RD's) kan individueel skaars wees, maar kumulatief beïnvloed hulle tot 6% van die bevolking. In Afrika is navorsing en diagnostiek vir RD's nie geprioritiseer nie, dus bly die meeste Afrika-pasiënte met RD's ongediagnoseerd. Intra-kontinentale en inter-kontinentale migrasie het gelei tot ‘n hoogs uiteenlopende Afrika genoom. Afrika genome bevat dus ‘n menigte unieke variante wat nog nooit vantevore in ander populasies geïdentifiseer is nie. ‘n Toename in navorsing is dus nodig om siekte-veroorsakende variante in dié populasies te identifiseer. Hiperfosfotasië met verstandelike gestremdheidsindroom is ‘n seldsame siekte, en die enigste verslag oor hierdie sindroom in Suidelike Afrika is die vorige navorsing wat hierdie tesis vooraf gegaan het. Hierdie sindroom bied 'n fenotipe van ernstige liggaamswye ontwikkelingsvertraging, gesigs-deformasie asook stuipe. Hierdie tesis ondersoek of die patogeniese PGAP3 (NM_0033419.5): c.G557C, p.Arg186Thr variant wat in die voorlopige navorsing geidentifiseer is, herhalend in die Xhosa bevolking is asook wat die waarskynlikheid is dat dit deur ‘n stigter-effek veroorsaak is. Om die hipotese te ondersoek dat die PGAP3 variant herhalend voorkom in die Xhosa bevolking en ook as gevolg van ‘n stigters-effek is, is Sanger-volgorde en genotipering op die InfiniumTM H3Africa Consortium Array v1 op ‘n totaal van 15 pasiënte uitgevoer. Die genotipering data is geëvalueer om vas te stel wat die verwantskap van die pasiënte is, die plaaslike afkoms van die variante, asook om die lope van homosigositeit te bepaal. Die draer frekwensie was in ‘n afsonderlike groep van 267 Xhosa individue geidentifiseer. Hierdie ondersoek het tien onverwante pasiënte as homosigote vir die PGAP3 variant geidentifiseer en die pasiënte kon dus met Hiperfosfotasië met verstandelike gestremdheidsindroom tipe vier gediagnoseer word. Die genotipering resultate dui aan dat die variant van die Bantu-sprekende Afrika afkoms is, en dat die variant binne ‘n lang loop van homosigositeit in al die gediagnoseerde pasiënte gevind is. Die beraamde draer frekwensie van die variant is 1 in elke 134 individue binne die Xhosa bevolking. In afsluiting dui die resultate aan dat die PGAP3 variant ‘n herhalende variant is wat heel waarskynlik deur die stigters-effek veroorsaak is. Om akkuraat te bepaal of die stigters-effek die ware oorsaak is, moet die lope van homosigositeit oor die variant in die pasiënte opgevolg word met volgordebepaling. Dokters moet gevolglik bewus wees daarvan dat Hiperfosfotasië met verstandelike gestremdheidsindroom meer gereeld kan voorkom in die Xhosa bevolking as gevolg van die herhalende aanwesigheid van die PGAP3 variant. Hierdie tesis het waardevolle inligting verskaf oor HPMRS spesifiek in Suid -Afrika en navorsing oor die ‘n stigter-effek in 'n Suid -Afrikaanse bevolking. | af_ZA |
| dc.description.version | Masters | en_ZA |
| dc.embargo.terms | 2022-07-01 | en_ZA |
| dc.format.extent | xiv, 97 pages : illustrations | en_ZA |
| dc.identifier.uri | http://hdl.handle.net/10019.1/124286 | en_ZA |
| dc.language.iso | en_ZA | en_ZA |
| dc.publisher | Stellenbosch : Stellenbosch University | en_ZA |
| dc.rights.holder | Stellenbosch University | en_ZA |
| dc.subject.lcsh | Rare diseases -- South Africa | en_ZA |
| dc.subject.lcsh | Intellectual disability -- South Africa | en_ZA |
| dc.subject.lcsh | Precision medicine | en_ZA |
| dc.title | Hyperphosphatasia with mental retardation syndrome in South Africa: identifying a recurring PGAP3 variant | en_ZA |
| dc.type | Thesis | en_ZA |