Clinical Phenotypes and Immunological Characteristics of 18 Egyptian LRBA Deficiency Patients

LPS-responsive beige-like anchor (LRBA) deficiency is an autosomal recessive primary immunodeficiency disorder, OMIM (#614700). LRBA deficiency patients suffer from variable manifestations including recurrent infections, immune dysregulation, autoimmunity, cytopenias, and enteropathy. This study describes different clinical phenotypes and immunological characteristics of 18 LRBA deficiency patients diagnosed from Egypt. T and B lymphocyte subpopulations, LRBA, and cytotoxic T lymphocyte-associated protein 4 (CTLA4) expression were evaluated in resting and stimulated T cells using flow cytometry. Next-generation sequencing was used to identify mutations in the LRBA gene. LRBA deficiency patients had significantly lower B cells and increased percentage of memory T cells. CTLA4 levels were lower in LRBA-deficient T regulatory cells in comparison to healthy donors at resting conditions and significantly increased upon stimulation of T cells. We identified 11 novel mutations in LRBA gene ranging from large deletions to point mutations. Finally, we were able to differentiate LRBA-deficient patients from healthy control and common variable immunodeficiency patients using a simple flow cytometry test performed on whole blood and without need to prior stimulation. LRBA deficiency has heterogeneous phenotypes with poor phenotype-genotype correlation since the same mutation may manifest differently even within the same family. Low LRBA expression, low numbers of B cells, increased numbers of memory T cells, and defective CTLA4 expression (which increase to normal level upon T cell stimulation) are useful laboratory tests to establish the diagnosis of LRBA deficiency. Screening of the siblings of affected patients is very important as patients may be asymptomatic at the beginning of the disease course.This article is available to RD&E staff via NHS OpenAthens (subject to any publisher embargo). Click on the Publisher URL, and log in with NHS OpenAthens if prompted.Genetic sequencing for four patients was supported by the Jeffrey Modell Foundation through their genetic sequencing pilot program and through the Deutsche Forschungsgemeinschaft (DFG) under Germany’s Excellence Strategy (CIBSS – EXC-2189 – Project ID 390939984, and RESIST – EXC 2155 – Project ID 39087428); through the E-rare program of the EU, managed by the DFG, grant code GR1617/14-1/iPAD; and through the “Netzwerke Seltener Erkrankungen” of the German Ministry of Education and Research (BMBF), grant code: GAIN_ 01GM1910A received by BG.published version, accepted version (12 month embargo