Investigating the ancestral origin of pathogenic variants in South African patients with neurological disorders

Kinghorn, Erin Kathleen

Investigating the ancestral origin of pathogenic variants in South African patients with neurological disorders

Thesis / Dissertation

2026

Publisher

University of Cape Town

Department

Department of Medicine

Faculty

Faculty of Health Sciences

Abstract

The genetic basis of inherited neurological disorders has been largely elucidated in European populations, informing the design of genetic test panels and gene-targeted therapies. While genetic studies on inherited neurological disorders in Africa are limited, local initiatives are expanding our understanding of the genetic spectrum underlying these disorders through the use of exome and genome sequencing. Among South African patients with amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder of complex aetiology that includes genetic factors, the European-predominant C9orf72 hexanucleotide repeat expansions (HRE) and SOD1 pathogenic variants were the most frequent, explaining ~7% and 4% of cases, respectively. Among South African patients with inherited neuropathy (a group of neuromuscular disorders (NMD), a notable finding was the enrichment of biallelic, putative pathogenic variants in the MPV17 gene which have not previously been implicated in this phenotype. South Africa harbours individuals with a rich genetic architecture due to contributions from various ancestral populations. One of the most unique populations in Southern Africa is the multiway admixed population which has received ancestral contributions from five distinct populations including; Bantu-speaking African (~30%), KhoeSan (~30%), European (~20%), East Asian (~10%) and Southeast Asian (~10%) populations. This has led to complicated genetic admixture with heterogeneous patterns of associated traits and linkage disequilibrium. However, sub-setting the South African patient samples by continental ancestry subgroups (Admixed, African and European) revealed distinct patterns; the presence of C9orf72 HRE and MPV17 pathogenic variants was highest in individuals with predominantly European and African ancestry respectively, while SOD1 pathogenic variants were observed across all groups. These ancestry-associated patterns of variant distribution highlight the importance of considering population structure when interpreting genetic findings and suggest that both global and local ancestry may influence the frequency and origin of pathogenic variants. This raised key questions about the ancestry-specific contribution to disease risk and the possibility of population-specific founder effects. This study thus aimed to investigate the relationship between genetic variants and global ancestry in South African patients with ALS and NMD, determine the local ancestry of pathogenic variants in C9orf72 HRE and SOD1 pathogenic variants and explore the possibility of a founder effect for MPV17 variants observed in NMD patients. To investigate global ancestry, ADMIXTURE was run on all patients (ALS & NMD, n=180). This analysis confirmed the population structure of the ALS subset to be multiway admixed and predominantly African in the NMD subset of patients. Local ancestry was inferred using RFMix in the subset of ALS patients harbouring C9orf72 HRE (n=12) and SOD1 pathogenic variants (n=7). This revealed that C9orf72 HRE in South African ALS patients is largely European derived (7/12, 58%) while the local ancestry of SOD1 pathogenic variants is globally diverse: African (2/6, 33%), SouthEast Asian (2/6, 33%) and European (2/6, 33%). Lastly, to investigate a potential founder effect, ASCEND and Haploview were used in the subset of NMD patients harbouring MPV17 variants (n=12). Haploview was applied to construct linkage disequilibrium (LD)plots and define haplotype blocks, enabling the visualization of SNP correlations and the identification of genomic regions in strong LD surrounding the MPV17 variants. To assess the robustness of the founder effect analysis, two independent runs using different reference panels were performed. Both runs yielded consistent results, with similar estimates of founder intensity (0.7% and 0.4%) for the MPV17 p.Gln36Ter variant. The relatively low founder intensities observed in both runs suggest a weak but detectable founder effect and suggest that the variant likely originated from a shared ancestral haplotype within African populations. The results of this study provide important evidence to guide genetic testing strategies for both ALS and NMDs in African populations. In ALS, the findings highlight the importance of screening genes such as SOD1, especially in settings where C9orf72 HRE are uncommon. The detection of a potential founder effect involving the MPV17 p.Gln36Ter variant in the NMD cohort further underscores the need to consider ancestry and population history when interpreting rare variants. Together, these results demonstrate the value of ancestry-informed approaches in improving variant prioritization and in uncovering both global and population-specific contributors to inherited neuropathies in Africa.

Keywords

neurology

ancestry

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