# Uncovering genetic variation in humoral inborn errors of immunity in African populations: insights from the African genome variation database

## TL;DR

This study explores genetic variations linked to immune disorders in African populations using a genome database, revealing new insights into antibody-related immune conditions.

## Contribution

The study identifies population-specific genetic variants associated with humoral IEIs in African populations, many of which are not previously documented in ClinVar.

## Key findings

- 815 variants were identified in 23 genes, with 219 unique to African populations.
- Four pathogenic variants were found in TCF3 and RAG1/2 genes.
- 144 variants (43%) were not listed in ClinVar, with 53 predicted to be deleterious.

## 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.

The online version contains supplementary material available at 10.1038/s41598-026-39612-2.