Ancestral origin of amyotrophic lateral sclerosis pathogenic variants in South Africa

<ns3:p>Background and objectives Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with diverse genetic causes. While the <ns3:italic>C9orf72</ns3:italic> hexanucleotide repeat expansion (HRE) and <ns3:italic>SOD1</ns3:italic> variants are common in European and Asian populations respectively, their prevalence and ancestral origins in African populations remain underexplored. This study investigated the local ancestry of <ns3:italic>C9orf72</ns3:italic> HRE and <ns3:italic>SOD1</ns3:italic> pathogenic variants previously identified in South African ALS patients. Methods Whole-genome sequencing was conducted on 168 ALS patients recruited from Groote Schuur Hospital in Cape Town, South Africa. Global ancestry was inferred using ADMIXTURE, and local ancestry at variant loci was determined using RFMix to determine their ancestral origin. Results Twelve patients, including eight with admixed ancestry, carried <ns3:italic>C9orf72</ns3:italic> HRE. In 10 of these (83%), the local ancestry at the <ns3:italic>C9orf72</ns3:italic> locus was European, consistent with the Finnish risk haplotype. One African-ancestry patient carried the HRE with African flanking haplotypes, which only partially matched the Finnish risk variants. In contrast, <ns3:italic>SOD1</ns3:italic> pathogenic variants were found in seven patients, with diverse local ancestry: African (43%), Southeast Asian (29%) and European (29%). Discussion These findings support the rarity of <ns3:italic>C9orf72</ns3:italic> HRE in African-ancestry individuals and suggest its European origin in most admixed South African patients. The identification of <ns3:italic>SOD1</ns3:italic> variants of African ancestral origin highlights the relevance of <ns3:italic>SOD1</ns3:italic> as a genetic risk factor for ALS in Africa. Despite a limited sample size, this study emphasizes the importance of expanding genomic research across African populations to better understand ALS genetics. Such efforts will be crucial for accurate genetic testing, counselling and inclusive access to gene-based therapies.</ns3:p>