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

Frontiers in Neurology

Neurology

Gang Wu¹  Michael Benatar²  Mary M. Reilly³  Christopher J. Record³  Jana Vandrovcova⁴  Lindsay A. Wilson⁴  Michael Hanna⁵  Elizabeth Steyn⁶  Kireshnee Naidu⁶  Niki Floudiotis⁶  Amokelani C. Mahungu⁷  Melissa Nel⁷  Jeannine M. Heckmann⁷  Jo M. Wilmshurst⁸  Sharika Raga⁸ 

[1] Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, United States;Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States;Department of Neuromuscular Disease, Queen Square UCL Institute of Neurology and the National Hospital of Neurology and Neurosurgery, London, United Kingdom;Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, United Kingdom;Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, United Kingdom;NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London, United Kingdom;Neurology Research Group, Division of Neurology, Department of Medicine, University of Cape Town, Cape Town, South Africa;Neurology Research Group, Division of Neurology, Department of Medicine, University of Cape Town, Cape Town, South Africa;Neuroscience Institute, University of Cape Town, Cape Town, South Africa;Neuroscience Institute, University of Cape Town, Cape Town, South Africa;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;

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

DOI  :  10.3389/fneur.2023.1239725

 received in 2023-06-13, accepted in 2023-08-02,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionLimited 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.MethodsAfter 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.ResultsOf 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.DiscussionIn 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.

【 授权许可】

Unknown   
Copyright © 2023 Mahungu, Steyn, Floudiotis, Wilson, Vandrovcova, Reilly, Record, Benatar, Wu, Raga, Wilmshurst, Naidu, Hanna, Nel and Heckmann.