Abstract
Inborn Errors of Immunity (IEIs) are rare genetic disorders affecting immune function. Humoral IEIs, the most commonly diagnosed subtype, are characterised by antibody deficiencies. There is limited data regarding the variation of genes associated with humoral IEI in Africa with implications for designing genetic assays for testing for these diseases. This study aimed to assess the genetic variation in genes which are commonly associated with humoral IEI in African populations. Using the African Genome Variation Database (AGVD) which contain genotype frequencies from African populations. We analysed genotype frequency data from the African Genome Variation Database (AGVD), covering diverse African populations, to identify variants in 23 genes associated with humoral IEIs. Variants were annotated using Ensembl’s Variant Effect Predictor and classified for clinical significance with ClinVar. For variants absent in ClinVar, predictive tools (SIFT, PolyPhen-2) were used. A total of 815 variants were identified; 335 were present in African populations, and 219 were unique to African populations. Most were missense mutations, 4 variants identified in TCF3 and RAG1/2 were classified as pathogenic or likely pathogenic. Additionally, 144 variants (43%) were not listed in ClinVar; of these, 53 were predicted to be deleterious. Some variants exhibited high genotype frequencies (e.g., up to 0.67 in CR2), suggesting possible adaptive functions or population-specific relevance.
Data availability
The data analysed in this study are available from the AGVD (https://nyame.h3abionet.org/accounts/login/?next=/refresh). Access to the data requires the creation of a user account on the AGVD website.
Abbreviations
- IEIs:
-
Inborn errors of immunity
- CVID:
-
Common variable immunodeficiency
- BTK:
-
Brutton’s kinase
- AGVD:
-
African genome variation database
- VEP:
-
Variant effect predictor
- ACMG:
-
American College of Medical Genetics and Genomics
- AMP:
-
Association of pathology
- VUS:
-
Variant of uncertain significance
- SIFT:
-
Sorting intolerance from tolerance
- EBV:
-
Epstein barr virus
References
Ahmed Meelad, R. et al. Impact of primary immunodeficiency diseases on the life experiences of patients in Malaysia from the caregivers’ perspective: A qualitative study. Front. Pediatr. 10, 846393 (2022).
Hansen, A. T. et al. Diagnostic vaccination in clinical practice. Front. Immunol. 12, 717873 (2021).
Stray-Pedersen, A. et al. Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders. J. Allergy Clin. Immunol. 139 (1), 232–245 (2017).
Slade, C. A. et al. Delayed diagnosis and complications of predominantly antibody deficiencies in a cohort of Australian adults. Front. Immunol. 9, 694 (2018).
Kebudi, R., Kiykim, A. & Sahin, M. K. Primary immunodeficiency and cancer in children: A review of the literature. Curr. Pediatr. Rev. 15 (4), 245–250 (2019).
Abolhassani, H. et al. Global systematic review of primary immunodeficiency registries. Expert Rev. Clin. Immunol. 16 (7), 717–732 (2020).
Bousfiha, A. A. et al. Primary immunodeficiency diseases worldwide: More common than generally thought. J. Clin. Immunol. 33 (1), 1–7 (2013).
Engelbrecht, C. et al. Clinical utility of whole exome sequencing and targeted panels for the identification of inborn errors of immunity in a Resource-Constrained setting. Front. Immunol. 12, 665621 (2021).
Erjaee, A. et al. Primary immunodeficiency in Africa—A review. South. Afr. Med. J. 109 (8b), 3 (2019).
Tangye, S. G. et al. Human inborn errors of immunity: 2022 update on the classification from the international union of immunological societies expert committee. J. Clin. Immunol. 42, 1473–1507 (2022).
Cereser, L. et al. High-resolution computed tomography findings in humoral primary immunodeficiencies and correlation with pulmonary function tests. World J. Radiol. 10 (11), 172–183 (2018).
Jorgensen, G. H. et al. Clinical symptoms in adults with selective IgA deficiency: A case-control study. J. Clin. Immunol. 33 (4), 742–747 (2013).
Harriman, G. R. et al. Targeted deletion of the IgA constant region in mice leads to IgA deficiency with alterations in expression of other Ig isotypes. J. Immunol. 162 (5), 2521–2529 (1999).
Edwards, E. S. J. et al. Predominantly Antibody-Deficient patients with Non-infectious complications have reduced Naive B, Treg, Th17, and Tfh17 cells. Front. Immunol. 10, 2593 (2019).
Sayers, E. W. et al. Database resources of the national center for biotechnology information. Nucleic Acids Res. 48 (D1), D9–D16 (2020).
Perez, E. M. et al. Genetics of inborn errors of immunity: Diagnostic strategies and new approaches to CNV detection. Eur. J. Clin. Invest. 54 (6), e14191 (2024).
Glanzmann, B. et al. Inborn errors of immunity in South Africa: Genetics and the expanding universe. Curr. Allergy Clin. Immunol. 37 (1), 5–10 (2024).
Choudhury, A. et al. High-depth African genomes inform human migration and health. Nature 586 (7831), 741–748 (2020).
Todt, D. An African genome variation database and its applications in human diversity and health. (2021).
McLaren, W. et al. The ensembl variant effect predictor. Genome Biol. 17 (1), 122 (2016).
Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet. Med. 17 (5), 405–424 (2015).
Masson, E. et al. Expanding ACMG variant classification guidelines into a general framework. Hum. Genomics. 16 (1), 31 (2022).
Ng, P. C. & Henikoff, S. Predicting deleterious amino acid substitutions. Genome Res. 11 (5), 863–874 (2001).
Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nat. Methods. 7 (4), 248–249 (2010).
Sibomana, O. Genetic diversity landscape in African population: A review of implications for personalized and precision medicine. Pharmgenomics Pers. Med. 17, 487–496 (2024).
Similuk, M. & Kuijpers, T. Nature and nurture: Understanding phenotypic variation in inborn errors of immunity. Front. Cell. Infect. Microbiol. 13, 1183142 (2023).
Kim, V. H. D. et al. Inborn errors of immunity (primary immunodeficiencies). Allergy Asthma Clin. Immunol. 20 (Suppl 3), 76 (2025).
Boisson, B. et al. A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells. J. Clin. Invest. 123 (11), 4781–4785 (2013).
Qureshi, S., Sheikh, M. D. A. & Qamar, F. N. Autosomal recessive Agammaglobulinemia—First case with a novel TCF3 mutation from Pakistan. Clin. Immunol. 198, 100–101 (2019).
Boast, B. et al. TCF3 haploinsufficiency defined by immune, clinical, gene-dosage, and murine studies. J. Allergy Clin. Immunol. 152 (3), 736–747 (2023).
Braams, M., Pike-Overzet, K. & Staal, F. J. T. The recombinase activating genes: Architects of immune diversity during lymphocyte development. Front. Immunol. 14, 1210818 (2023).
Mat Ripen, A. et al. Whole exome sequencing identifies compound heterozygous variants of CR2 gene in monozygotic twin patients with common variable immunodeficiency. SAGE Open Med. 8, 2050312120922652 (2020).
Dudley, J. T. et al. Human genomic disease variants: A neutral evolutionary explanation. Genome Res. 22 (8), 1383–1394 (2012).
Thiel, J. et al. Genetic CD21 deficiency is associated with hypogammaglobulinemia. J. Allergy Clin. Immunol. 129 (3), 801–810 (2012).
Shannon-Lowe, C. & Rowe, M. Epstein-Barr virus infection of polarized epithelial cells via the basolateral surface by memory B cell-mediated transfer infection. PLoS Pathog. 7 (5), e1001338 (2011).
Fingeroth Joyce, D. et al. CD21-Dependent infection of an epithelial cell Line, 293, by Epstein-Barr virus. J. Virol. 73 (3), 2115–2125 (1999).
Hammerl, L. et al. The burden of Burkitt lymphoma in Africa. Infect. Agent Cancer 14, 17 (2019).
Funding
This research was funded by the National Institutes of Health, grant number: 5UH3HG007438–05.
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L.H. and E.M. were responsible for study design, data analysis and collection and writing of the original draft. A.M. and N.M. provided assistance with data analysis and access and assisted with preparation of the original draft. All authors reviewed the manuscript.
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Hlongwa, L., Meintjes, A., Mulder, N. et al. Uncovering genetic variation in humoral inborn errors of immunity in African populations: insights from the African genome variation database. Sci Rep (2026). https://doi.org/10.1038/s41598-026-39612-2
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DOI: https://doi.org/10.1038/s41598-026-39612-2
