Atypical Phenotype of Predominant Autoimmune Cytopenia and Impaired Perforin Expression in XMEN Syndrome

X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia (XMEN) is caused by a pathogenic variant in the magnesium transporter 1 (MAGT1) gene. The defect leads to impaired N-glycosylation which affects various immune processes. In this study, we described the disease course, clinical features and laboratory parameters observed in six patients from three families diagnosed with XMEN syndrome. They exhibit heterogeneous clinical manifestation while displaying typical laboratory signs of the disease, including decreased surface expression of NKG2D and CD28 on CD8⁺ T-cells and NK cells, as well as defects in the N-glycosylation of transferrin. We identified two novel variants in the cohort: a frameshift variant c.444dup in exon 3, and a splicing variant c.998-20_1008del. Notably, a patient with the c.444dup variant presented with severe autoimmune cytopenia as an isolated manifestation of the disease, while his younger brother, carrying the same variant, exhibited predominantly mild skin infections. These findings illustrate varying degrees of severity in penetrance and highlight that some patients may exhibit only partial symptoms. Furthermore, our study confirmed defects in perforin expression in XMEN syndrome. We observed a significant reduction in perforin expression within CD8⁺ T-cells and NK cells which may lead to increased susceptibility to recurrent infections and autoimmune complications frequently observed in XMEN patients.