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Analysis of South African families with familial Parkinson’s Disease
Braun, A. 2025. Analysis of South African Families with Familial Parkinson’s Disease. Unpublished masters thesis. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/81c49840-1c00-4d2e-9162-902a34020c8d
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Stellenbosch : Stellenbosch University
2025
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| _version_ | 1867613938414256128 |
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| access_status_str | Open Access |
| author | Braun, Abigail |
| author2 | Bardien, Soraya |
| author_browse | Bardien, Soraya Braun, Abigail |
| author_facet | Bardien, Soraya Braun, Abigail |
| author_sort | Braun, Abigail |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Braun, A. 2025. Analysis of South African Families with Familial Parkinson’s Disease. Unpublished masters thesis. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/81c49840-1c00-4d2e-9162-902a34020c8d |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/132085 |
| institution | Stellenbosch University (South Africa) |
| last_indexed | 2026-06-10T12:44:05.289Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/132085 Analysis of South African families with familial Parkinson’s Disease Braun, Abigail Bardien, Soraya Moosa, Shahida Sparks, Anel Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics. Nervous system -- Diseases -- South Africa Parkinson's disease -- Genetic aspects -- South Africa High-throughput nucleotide sequencing Families -- South Africa UCTD Braun, A. 2025. Analysis of South African Families with Familial Parkinson’s Disease. Unpublished masters thesis. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/81c49840-1c00-4d2e-9162-902a34020c8d Thesis (MSc)--Stellenbosch University, 2025. ENGLISH ABSTRACT: Globally, neurological diseases are the leading cause of overall disease burden. Parkinson’s disease (PD) has been ranked the 11th leading neurological disease contributing to the global burden of disability and premature death. PD is a common, neurodegenerative disease (NDD), with debilitating motor and non-motor symptoms. Although treatments exist to alleviate these symptoms, PD remains incurable. PD has a multifaceted aetiology involving ageing, the environment, gut microbiome, epigenetics, and as yet undiscovered factors. In particular, genetic causes have been well established to result in PD neuropathology. In recent years, 22 genes have been linked with the disorder, with seven of these being strongly associated (SNCA, PRKN, PINK1, DJ-1, LRRK2, VPS35, and GBA). However, since the majority of research focussing on the genetics of PD has been done using individuals of European ancestry, it remains plausible that novel pathogenic variants in these seven genes, as well as additional genes that have not yet been linked to PD, are present in Sub-Saharan Africa (SSA) populations. SSA populations are particularly distinguished by their great level of genetic diversity, but remain understudied and underrepresented in PD research. With the advent of next generation sequencing (NGS) technologies, such as whole exome sequencing (WES) and whole genome sequencing (WGS), it is possible to generate masses of data in a limited period. However, as few researchers in the SSA region can access NGS resources it is important that we collaborate with larger, international Consortia to study the genetic underpinnings of SSA individuals affected by monogenic disorders such as familial PD. Hence, in the present study, we collaborated with the Global Parkinson’s Genetics Program (GP2) Consortium to investigate the genetic aetiology of 10 South African (SA) families with PD. Data from 19 solved SA families were used as positive controls. We received NeuroBooster Array (NBA) data on 59 individuals, and WGS data on five affected individuals from two unsolved families, from the GP2 Consortium. The South African Medical Research Council (SAMRC) Genomics Platform provided us with WES data on 16 individuals from five of the families. Moreover, we screened the 10 probands for the LRRK2 p.Gly2019Ser variant using High-Resolution Melt (HRM) experiments (validated with Sanger sequencing) and investigated copy number variations (CNVs) using a Multiplex Ligation-dependent Probe Amplification (MLPA) assay. A single family was found to carry an α-Synuclein (SNCA) whole gene duplication. Furthermore, analysis of WES data focussing on coding regions of NDD-related genes prioritised several repeat expansions in two families, but these were later shown to be within normal ranges. Analyses of the other three families did not yield any candidate variants. Therefore, WGS data were analysed to investigate possible pathogenic variants in intronic regions of NDD-related genes for two families. The WGS data revealed 15 candidate variants in four genes (NUS1, LRRK2, PSEN1, and ANO3) in one family, and one candidate variant in one gene (RIC3) in another family. However, as there were some limitations to the present study, we were not able to investigate these candidate variants further. Even so, this study emphasises the importance of screening unsolved, familial PD cases, in individuals of SSA ancestry to find novel genetic variants associated with the aetiology of the disorder. As our population remains underrepresented in PD research, it is critical that we focus resources on ascertaining the reason for their disease phenotypes in an attempt to gain a better understanding of the complex pathology of the disorder. In turn, this will allow us to diagnose people of SSA descent presenting with familial PD faster, predict disease in future generations, and create variant-specific treatments. Nevertheless, future genetic studies focussing on underrepresented populations (URPs) is needed to unravel the genetic causes of PD in familial cases in these regions. AFRIKAANSE OPSOMMING: Neurologiese siektes is wêreldwyd die hoof-oorsaak van die algehele siektelas. Parkinson se siekte (PD) is die 11de grootste bydraer tot die neurologiese siekte lys. PD is ‘n algemene neurodegeneratiewe siekte (NDD) met aftakelende motor en nie-motor simptome. Alhoewel daar behandeling bestaan wat hierdie simptome kan verlig, is die siekte ongeneeslik. PD is ‘n multifaktoriale siekte wat veroorsaak word deur veroudering, die omgewing, ingewand- mikrobioom en epigenetika, asook faktore wat tot dusver onbekend is. In die besonder is genetiese oorsake al geredelik vasgestel as 'n oorsaak van PD neuropatalogie. In onlangse jare is 22 gene aan die siekte gekoppel, met sewe van hierdie gene wat ‘n sterk assosiasie toon (SNCA, PRKN, PINK1, DJ-1, LRRK2, VPS35 en GBA). Aangesien die meerderheid navorsing op die genetika van PD op mense van Europese herkoms gedoen is, kan dit egter aangeneem word dat nuwe patogeniese variante in hierdie sewe gene, asook ander gene, wat nog nie aan PD gekoppel is nie, kan voorkom in individue in Afrika, Suid van die Sahara (SSA). SSA populasies kan in die besonder onderskei word deur hul hoë vlak van genetiese diversiteit, maar die SSA populasie is steeds onderbestudeer asook onderverteenwoordig in PD navorsing. Met die koms van volgende generasie volgordebepalingstegnologie (NGS), soos heel-eksoom olgordebepaling (WES) en heelgenoom-volgordebepaling (WGS) is dit moontlik om massas data in 'n beperkte tyd te genereer. Aangesien min navorsers in die SSA area toegang tot hierdie hulpbronne kan kry, is dit egter belangrik dat ons met groter internasionale konsortia saamwerk om die genetiese boustene van SSA individue geaffekteer deur monogeniese siektes (soos familiële PD) te bestudeer. Dus, in hierdie studie het ons saam met die Global Parkinson’s Genetics Program (GP2) Consortium gewerk om die genetiese etiologie van 10 Suid-Afrikaanse (SA) families met PD te ondersoek. Data van 19 SA families wat opgelos is, het gedien as positiewe kontroles. Ons het NeuroBooster Array (NBA) data van 59 individue, asook WGS data van vyf geaffekteerde individue van twee families wat nog onopgelos is, van die GP2 konsortium ontvang. Die Suid-Afrikaanse Mediese Navorsingsraad (SAMRC) se Genomiese Platform het ons met WES data van 16 individue van vyf onopgeloste families voorsien. Buiten hierdie, het ons 10 mutasie-negatiewe families gesif vir die LRRK2 p.G2019S variant met behulp van High-Resolution Melt (HRM) eksperimente (gevalideer met Sanger-volgordebepaling), asook kopié-getal variante (CNVs) met die gebruik van Multiplex Ligation-dependent Probe Amplification (MLPA) analise. Masters 2025-05-22T13:38:04Z 2025-05-22T13:38:04Z 2025-03 Thesis https://scholar.sun.ac.za/handle/10019.1/132085 Stellenbosch University ix, 154 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Nervous system -- Diseases -- South Africa Parkinson's disease -- Genetic aspects -- South Africa High-throughput nucleotide sequencing Families -- South Africa UCTD Braun, Abigail Analysis of South African families with familial Parkinson’s Disease |
| title | Analysis of South African families with familial Parkinson’s Disease |
| title_full | Analysis of South African families with familial Parkinson’s Disease |
| title_fullStr | Analysis of South African families with familial Parkinson’s Disease |
| title_full_unstemmed | Analysis of South African families with familial Parkinson’s Disease |
| title_short | Analysis of South African families with familial Parkinson’s Disease |
| title_sort | analysis of south african families with familial parkinson s disease |
| topic | Nervous system -- Diseases -- South Africa Parkinson's disease -- Genetic aspects -- South Africa High-throughput nucleotide sequencing Families -- South Africa UCTD |
| url | https://scholar.sun.ac.za/handle/10019.1/132085 |
| work_keys_str_mv | AT braunabigail analysisofsouthafricanfamilieswithfamilialparkinsonsdisease |