C9orf72 repeat expansions in South Africans with amyotrophic lateral sclerosis

  • Author Footnotes
    1 These authors contributed equally.
    Melissa Nel
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Neurology research group, Department of Medicine, University of Cape Town, Cape Town, South Africa
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  • Author Footnotes
    1 These authors contributed equally.
    Gloudi M. Agenbag
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Division of Human Genetics, Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, University of Cape Town, Cape Town., South Africa
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  • Franclo Henning
    Affiliations
    Division of Neurology, Department of Medicine, University of Stellenbosch, Cape Town., South Africa
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  • Helen M. Cross
    Affiliations
    Division of Neurology, Department of Medicine, University of Cape Town, Cape Town, South Africa
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  • Alina Esterhuizen
    Affiliations
    Division of Human Genetics, Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, University of Cape Town, Cape Town., South Africa

    National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa
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  • Jeannine M. Heckmann
    Correspondence
    Corresponding author at: Neurology E8-74, Groote Schuur Hospital, Observatory 7925, Cape Town, South Africa.
    Affiliations
    Neurology research group, Department of Medicine, University of Cape Town, Cape Town, South Africa

    Division of Neurology, Department of Medicine, University of Cape Town, Cape Town, South Africa
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  • Author Footnotes
    1 These authors contributed equally.
Published:April 16, 2019DOI:https://doi.org/10.1016/j.jns.2019.04.026

      Highlights

      • 143 South Africans with ALS underwent C9orf72 repeat expansion genotyping.
      • Familial ALS was uncommon (2%) and these cases had normal C9orf72 alleles.
      • C9-expansions (>30 repeats) were found in 7% of cases with sporadic ALS.
      • C9-expansions were not found in 24 black Africans with ALS.

      Abstract

      The hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic variant found in individuals with sporadic amyotrophic lateral sclerosis (ALS), occurring at a frequency of between 7 and 11% in cohorts of European ancestry. While limited data suggest that C9-expansions (>30 repeats) are less frequent in African-Americans with ALS, there is no data on the frequency of C9-expansions among ALS subjects residing in Africa. We therefore investigated the frequency of this expansion mutation (using repeat-primed PCR) in a cohort of 143 South Africans (SA) with ALS. The cohort included different genetic ancestry subgroups who self-identified as black African (n = 24), Cape mixed-African (M/A) (n = 65), white European ancestry (n = 51), and Indian ancestry (n = 3). Three M/A individuals had a family history of ALS (2%) and all had normal C9orf72 alleles. Of the 140 individuals with sporadic ALS who were successfully genotyped, 10 (7%) carried pathogenic C9-expansions; four white and six M/A ancestry individuals, respectively. Our results highlight the importance of including Africans in genetic studies aimed at unravelling the genomic architecture in ALS and suggest pathogenetic mechanisms other than the C9orf72 expansion in black Africans with ALS.

      Keywords

      Abbreviations:

      ALS (Amyotrophic lateral sclerosis), FTD (Fronto-temporal dementia), SA (South Africa(n)), PLS (Primary lateral sclerosis), PMA (Progressive muscular atrophy), FA (Flail arm), M/A (Mixed-African), RP-PCR (Repeat primed polymerase chain reaction), ANOVA (Analysis of variance), US (United States), HD (Huntington's disease)
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