A Novel Homozygous CRACR2A Variant Underlying CRACR2A-Associated Immunodeficiency in a Tunisian Patient

Abstract

The calcium release-activated calcium modulator-2A (CRACR2A) protein plays a critical role in regulating store-operated calcium entry (SOCE) through CRAC channels, a process essential for numerous cellular functions, particularly T cell activation. Herein, we report the first Tunisian patient harboring a homozygous CRACR2A mutation. The patient is a 45-year-old female, born to consanguineous parents, who presented with lymph node and urinary tuberculosis, as well as recurrent fungal infections, including oral, genital, and urinary candidiasis, raising suspicion of an inborn error of immunity (IEI). HIV serology was negative. Immunophenotypic analysis revealed profound CD4+ and CD8+ T cell lymphopenia associated with a markedly decreased percentage of naïve CD4 T lymphocytes (CD4+ naïve T cells: 17.3%, normal: 33–66%). Lymphocyte proliferation to phytohemagglutinin (PHA) was impaired, and functional studies of IL-12/IFN-γ and TH17 pathways studies were normal, excluding other primary immunodeficiencies (PIDs). Whole-exome sequencing identified a homozygous missense variant in CRACR2A (c.1058G>A, p.Gly353Glu), predicted as disease-causing by MutationTaster. This variation was confirmed by Sanger sequencing. To the best of our knowledge, only one case of CRACR2A deficiency has been reported in the literature. The previously reported Asian patient presented with chronic diarrhea and recurrent pulmonary infections since adolescence, associated with severe hypogammaglobulinemia, progressive CD4 T cell lymphopenia, and a reduced proliferative response to mitogens, consistent with a late-onset combined immunodeficiency (LOCID). CRACR2A deficiency is presumed to result in functional impairment of T lymphocytes. Further immunological investigations are needed to better characterize the impact of the novel variant described herein. In conclusion, we describe the first Tunisian patient with a homozygous CRACR2A mutation, making her the second reported case worldwide. This finding broadens the clinical and immunological spectrum of CRACR2A-associated immunodeficiency and contributes to expanding the catalogue of genetic variants underlying this rare inborn error of immunity.