TY - JOUR
T1 - Revealing the Mutational Spectrum in Southern Africans with Amyotrophic Lateral Sclerosis
AU - Nel, Melissa
AU - Mahungu, Amokelani C.
AU - Monnakgotla, Nomakhosazana
AU - Botha, Gerrit R.
AU - Mulder, Nicola J.
AU - Wu, Gang
AU - Rampersaud, Evadnie
AU - Van Blitterswijk, Marka
AU - Wuu, Joanne
AU - Cooley, Anne
AU - Myers, Jason
AU - Rademakers, Rosa
AU - Taylor, J. Paul
AU - Benatar, Michael
AU - Heckmann, Jeannine M.
N1 - Funding Information:
The Article Processing Charge was funded by the authors.
Funding Information:
The authors thank Dr. C. Albertyn for cognitive phenotyping of the ALS cases. The authors thank the Africa Wits-INDEPTH partnership for Genomics studies (AWI-Gen), a Human Heredity and Health in Africa (H3A) Consortium study, for providing variant frequency information for South African control subjects. The authors also thank the Southern African Human Genome Programme (SAHGP) participants. The South African WGS data set was generated by the national SAHGP initiative funded by the Department of Science and Technology of South Africa. The authors acknowledge the use of the Ilifu cloud computing facility ( ilifu.ac.za ), a partnership between the University of Cape Town, the University of the Western Cape, the University of Stellenbosch, Sol Plaatje University, the Cape Peninsula University of Technology, and the South African Radio Astronomy Observatory. The Ilifu facility is supported by contributions from the Inter-University Institute for Data Intensive Astronomy (IDIA—a partnership between the University of Cape Town, the University of Pretoria, and the University of the Western Cape), the Computational Biology division at UCT, and the Data Intensive Research Initiative of South Africa (DIRISA). JMH and AM receive funding from the National Research Foundation of South Africa. MN is the recipient of a CReATe scholar award and a Carnegie Developing Emerging Academic Leaders (DEAL) award. This publication was made possible (in part) by a grant from Carnegie Corporation of New York and a L'Oréal-UNESCO For Women in Science South African Young Talents Award. The statements made and views expressed are solely the responsibility of the authors.
Publisher Copyright:
© 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
PY - 2022/2/12
Y1 - 2022/2/12
N2 - Background and ObjectivesTo perform the first screen of 44 amyotrophic lateral sclerosis (ALS) genes in a cohort of African genetic ancestry individuals with ALS using whole-genome sequencing (WGS) data.MethodsOne hundred three consecutive cases with probable/definite ALS (using the revised El Escorial criteria), and self-categorized as African genetic ancestry, underwent WGS using various Illumina platforms. As population controls, 238 samples from various African WGS data sets were included. Our analysis was restricted to 44 ALS genes, which were curated for rare sequence variants and classified according to the American College of Medical Genetics guidelines as likely benign, uncertain significance, likely pathogenic, or pathogenic variants.ResultsThirteen percent of 103 ALS cases harbored pathogenic variants; 5 different SOD1 variants (N87S, G94D, I114T, L145S, and L145F) in 5 individuals (5%, 1 familial case), pathogenic C9orf72 repeat expansions in 7 individuals (7%, 1 familial case) and a likely pathogenic ANXA11 (G38R) variant in 1 individual. Thirty individuals (29%) harbored ≥1 variant of uncertain significance; 10 of these variants had limited pathogenic evidence, although this was insufficient to permit confident classification as pathogenic.DiscussionOur findings show that known ALS genes can be expected to identify a genetic cause of disease in >11% of sporadic ALS cases of African genetic ancestry. Similar to European cohorts, the 2 most frequent genes harboring pathogenic variants in this population group are C9orf72 and SOD1.
AB - Background and ObjectivesTo perform the first screen of 44 amyotrophic lateral sclerosis (ALS) genes in a cohort of African genetic ancestry individuals with ALS using whole-genome sequencing (WGS) data.MethodsOne hundred three consecutive cases with probable/definite ALS (using the revised El Escorial criteria), and self-categorized as African genetic ancestry, underwent WGS using various Illumina platforms. As population controls, 238 samples from various African WGS data sets were included. Our analysis was restricted to 44 ALS genes, which were curated for rare sequence variants and classified according to the American College of Medical Genetics guidelines as likely benign, uncertain significance, likely pathogenic, or pathogenic variants.ResultsThirteen percent of 103 ALS cases harbored pathogenic variants; 5 different SOD1 variants (N87S, G94D, I114T, L145S, and L145F) in 5 individuals (5%, 1 familial case), pathogenic C9orf72 repeat expansions in 7 individuals (7%, 1 familial case) and a likely pathogenic ANXA11 (G38R) variant in 1 individual. Thirty individuals (29%) harbored ≥1 variant of uncertain significance; 10 of these variants had limited pathogenic evidence, although this was insufficient to permit confident classification as pathogenic.DiscussionOur findings show that known ALS genes can be expected to identify a genetic cause of disease in >11% of sporadic ALS cases of African genetic ancestry. Similar to European cohorts, the 2 most frequent genes harboring pathogenic variants in this population group are C9orf72 and SOD1.
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U2 - 10.1212/NXG.0000000000000654
DO - 10.1212/NXG.0000000000000654
M3 - Article
AN - SCOPUS:85125131958
VL - 8
JO - Neurology: Genetics
JF - Neurology: Genetics
SN - 2376-7839
IS - 1
M1 - e654
ER -