The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia

Amokelani C Mahungu; Elizabeth Steyn; Niki Floudiotis; Lindsay A Wilson; Jana Vandrovcova; Mary M Reilly; Christopher J Record; Michael Benatar; Gang Wu; Sharika Raga; Jo M Wilmshurst; Kireshnee Naidu; Michael Hanna; Melissa Nel; Jeannine M Heckmann

doi:10.3389/fneur.2023.1239725

The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia

Front Neurol. 2023 Aug 29:14:1239725. doi: 10.3389/fneur.2023.1239725. eCollection 2023.

Authors

Amokelani C Mahungu^{1

2}, Elizabeth Steyn¹, Niki Floudiotis¹, Lindsay A Wilson³, Jana Vandrovcova³, Mary M Reilly⁴, Christopher J Record⁴, Michael Benatar⁵, Gang Wu⁶, Sharika Raga^{2

7}, Jo M Wilmshurst^{2

7}, Kireshnee Naidu¹, Michael Hanna^{3

8}, Melissa Nel^{1

2}, Jeannine M Heckmann^{1

2}

Affiliations

¹ Neurology Research Group, Division of Neurology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
² Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
³ Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, United Kingdom.
⁴ Department of Neuromuscular Disease, Queen Square UCL Institute of Neurology and the National Hospital of Neurology and Neurosurgery, London, United Kingdom.
⁵ Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States.
⁶ Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, United States.
⁷ Division of Paediatric Neurology, Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa.
⁸ NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London, United Kingdom.

Abstract

Introduction: Limited diagnostics are available for inherited neuromuscular diseases (NMD) in South Africa and (excluding muscle disease) are mainly aimed at the most frequent genes underlying genetic neuropathy (GN) and spastic ataxias in Europeans. In this study, we used next-generation sequencing to screen 61 probands with GN, hereditary spastic paraplegia (HSP), and spastic ataxias for a genetic diagnosis.

Methods: After identifying four GN probands with PMP22 duplication and one spastic ataxia proband with SCA1, the remaining probands underwent whole exome (n = 26) or genome sequencing (n = 30). The curation of coding/splice region variants using gene panels was guided by allele frequencies from internal African-ancestry control genomes (n = 537) and the Clinical Genome Resource's Sequence Variant Interpretation guidelines.

Results: Of 32 GN probands, 50% had African-genetic ancestry, and 44% were solved: PMP22 (n = 4); MFN2 (n = 3); one each of MORC2, ATP1A1, ADPRHL2, GJB1, GAN, MPZ, and ATM. Of 29 HSP probands (six with predominant ataxia), 66% had African-genetic ancestry, and 48% were solved: SPG11 (n = 3); KIF1A (n = 2); and one each of SPAST, ATL1, SPG7, PCYT2, PSEN1, ATXN1, ALDH18A1, CYP7B1, and RFT1. Structural variants in SPAST, SPG11, SPG7, MFN2, MPZ, KIF5A, and GJB1 were excluded by computational prediction and manual visualisation.

Discussion: In this preliminary cohort screening panel of disease genes using WES/WGS data, we solved ~50% of cases, which is similar to diagnostic yields reported for global cohorts. However, the mutational profile among South Africans with GN and HSP differs substantially from that in the Global North.

Keywords: African; Charcot-Marie-Tooth disease; diversity and inclusion; equity; hereditary spastic paraplegia; whole exome sequencing; whole genome sequencing.

Grants and funding

AM received funding from the UCT Neurology Research Group, the National Research Foundation of South Africa (NRF), and the University of Cape Town. This research was funded in whole or in part by the Wellcome Trust [226519/Z/22/Z] (MN). For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. The costs incurred for storing VCF files in the NHGRI AnVIL were supported by the Google Cloud Research Credits program with the award GCP19980904 (MN). This publication was made possible (in part) by grants from the South African Medical Research Council (SAMRC), the Gabriel Grant Foundation, and the Carnegie Corporation of New York (MN), and the statements made and views expressed are solely the responsibility of the authors. This work was supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) (MR/S005021/1) and the National Institutes of Neurological Diseases and Stroke and the Office of Rare Diseases (U54NS065712, 1UOINS109403-01, and R21TROO3034) (CR and MR). KN was supported by a fellowship from The Guarantors of Brain (UK Charity 1197319), and SR was supported by a fellowship from the ICGNMD.