Genomics of inherited neuromuscular diseases in Sub-Saharan Africa

Alves, Sergio

Genomics of inherited neuromuscular diseases in Sub-Saharan Africa

Thesis / Dissertation

2026

Publisher

University of Cape Town

Department

Department of Medicine

Faculty

Faculty of Health Sciences

Abstract

Introduction: Inherited muscle diseases (IMD) are a clinically and genetically heterogeneous group of disorders causing variable muscle weakness. In South Africa, accurate diagnosis is hindered by limited access to genetic testing, resulting in prolonged diagnostic odysseys and many patients remaining without a definitive diagnosis. Between 2020 and 2025, probands were enrolled in the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) study to provide definitive molecular diagnoses through comprehensive genetic testing unavailable locally Aim: To describe the phenotypic and genetic findings of a South African IMD cohort who underwent locally available genetic testing, if appropriate, and locally unavailable genetic testing. Methods: Patients with suspected IMD attending Groote Schuur Hospital, University of Cape Town, were phenotyped and categorised by predominant weakness pattern: limb-girdle, distal, extraocular muscle (EOM), myotonia-related, myasthenic-like with fatigable weakness and periodic or exercise-related muscle symptoms. Tier 1 testing included locally available testing for Dystrophinopathies (DMD), Myotonic Dystrophy type 1 (DM1) and mitochondrial DNA (mtDNA) screening if clinically indicated. Thereafter, undiagnosed patients proceeded to tier 2 testing which included PABPN1 repeat expansion testing (Oculopharyngeal Muscular Dystrophy, OPMD) or D4Z4 contraction testing (Facioscapulohumeral Muscular Dystrophy, FSHD1) if clinically indicated or next generation sequencing (NGS). Results: Of 89 probands with suspected IMD, 55 (62%) obtained genetic diagnoses although only 16 (18%) were solved via tier 1 testing. Locally solved cases included 8 dystrophinopathies (88% with childhood onset), 5 DM1 (none with African ancestry) and 3 adults with EOM paralysis due to a single large mtDNA deletion. Despite locally available dystrophinopathy screening, median diagnostic delay was 10 years. Tier 2 testing provided diagnoses for 53% (39/73) of cases remaining undiagnosed or untested by tier 1. Targeted testing identified FSHD1 (n=8) and OPMD (n=5) in 13 of 17 cases tested, with OPMD predominating in older adults (>50 years). Notably, FSHD1 was absent in patients of African ancestry. NGS, the most frequently employed tier 2 modality, resulted in genetic diagnoses in 41% of those tested (26/64). Frequently identified conditions via NGS included Myotonia Congenita (CLCN1, n=4), Desminopathies (DES, n=3) and a large heterozygous NEB deletion in three South African admixed families with autosomal dominant inheritance of a distal myopathy. Of seven cases with a prioritised variant of uncertain significance (VUS) in diseaseassociated genes, six (7%) were reportable and probably solved, while one was inconclusive and considered possibly solved. Eight probands harboured variants novel to ClinVar, with four classified as VUS. Conclusion: This study represents the largest adult single-centre heterogeneous IMD cohort reported in a diverse South African population. Despite limited tier 1 testing, an overall diagnostic yield of 62% was achieved with tier 2 testing contributing 53% of diagnoses. Prolonged diagnostic delays despite available dystrophinopathy screening suggest barriers beyond laboratory access. This study characterises a unique South African mutational landscape including ancestry-dependent disease distribution in which FSHD1 and DM1 predominated in European, and less so in admixed ancestry patients, but were absent in those of African ancestry. These findings underscore the inadequacy of current IMD testing in South Africa and the need for expanded genomic testing capacity.