Systematic Analysis of LRBA pathogenic variants and the association with functional protein domains and clinical presentation

LRBA deficiency is an inborn error of immunity initially associated with Common Variable Immunodeficiency (IDCV). Patients show biallelic variants leading to null protein expression in most of them. The clinical phenotype is heterogeneous, predominately hypogammaglobulinemia, recurrent infections, and autoimmunity. Around one hundred LRBA pathogenic variants are reported and the associated syndromes are growing, so this project aims to define the association between the clinical phenotype and the nature of variants.
We reviewed reported LRBA variants from 2012 to 2023 and performed a database of clinical findings and laboratory parameters. From this data, we analyzed the localization of variants and the relationship with the presentation of autoimmunity, numbers of B cells, memory B cells, regulatory T cells, and immunoglobulins IgG, IgM, and IgA.
The variants that generate a premature stop codon are associated with an earlier clinical presentation. The central systems affected by autoimmunity are the gastrointestinal and hematological components. There is not a clear association between the position of the variants and the type of autoimmunity, however, there is a considerable number of missense variants in patients who only present autoimmune cytopenias. Variants that lead to a premature stop codon are associated with reduced numbers of total B cells and regulatory T cells; with regards to memory B cells, we did not find a clear association with the type of variant. The main isotype of reduced immunoglobulins were IgA and IgG. Variants causing a premature stop codon were associated with a higher concentration of IgG, suggesting a possible autoimmune origin.
There was no clear association between the phenotype and the distribution of variants through the protein, however, there was a difference between the variants that lead to a truncated protein or a missense variant. Stop codon variants generate a more severe phenotype.

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