{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T11:01:42Z","timestamp":1774263702749,"version":"3.50.1"},"reference-count":35,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T00:00:00Z","timestamp":1774051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: X-linked immunodeficiency with magnesium defect, Epstein\u2013Barr virus (EBV) infection, and neoplasia (XMEN) disease is a rare inborn error of immunity caused by loss-of-function mutations in MAGT1, leading to impaired N-linked glycosylation. Although chronic EBV viremia is a hallmark of XMEN disease, the mechanisms underlying its marked clinical heterogeneity remain poorly understood. Methods: We performed an in-depth clinical, immunological, and genetic characterization of two siblings carrying a pathogenic MAGT1 variant (c.369_370insCC; p.Gly124fs), validated and deposited in ClinVar (SCV007293792). Assessments included whole-exome sequencing, multiparametric flow cytometry focusing on NKG2D expression, and longitudinal clinical follow-up. Results: Despite shared absence of NKG2D expression, the siblings exhibited strikingly divergent phenotypes. One sibling developed progressive neurodegeneration with central nervous system atrophy. The other presented with a complex immuno-hematologic phenotype, including EBV-positive Hodgkin lymphoma, recurrent autoimmune cytopenias, and lymphoma-associated thrombotic microangiopathy, representing a novel clinical association in XMEN disease. Comparative immunophenotyping revealed shared defects in B-cell maturation but distinct T-cell differentiation patterns. To contextualize neurological variability, we propose a descriptive, hypothesis-generating three-category conceptual classification comprising early-onset neurodevelopmental forms, adult-onset neurodegenerative manifestations, and secondary immune-mediated or vascular involvement of the nervous system. Conclusions: These findings demonstrate profound intrafamilial heterogeneity in XMEN disease and suggest a model in which modifier-sensitive factors influence organ-specific disease expression. The observation of lymphoma-associated thrombotic microangiopathy and the proposed descriptive neurological classification provide a conceptual framework that may help guide tailored, multidisciplinary surveillance beyond the primary genetic defect.<\/jats:p>","DOI":"10.3390\/jcm15062395","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T09:48:42Z","timestamp":1774259322000},"page":"2395","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modifier-Sensitive Phenotypic Divergence in XMEN Disease (MAGT1 Deficiency): Neurodegenerative and Immuno-Hematologic Trajectories"],"prefix":"10.3390","volume":"15","author":[{"given":"Ragip Fatih","family":"Kural","sequence":"first","affiliation":[{"name":"Division of Allergy and Immunology, Department of Internal Medicine, Ege University Faculty of Medicine, Izmir 35100, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9627-4281","authenticated-orcid":false,"given":"Zuleyha","family":"Galata","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Internal Medicine, Ege University Faculty of Medicine, Izmir 35100, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reyhan","family":"Gumusburun","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Internal Medicine, Ege University Faculty of Medicine, Izmir 35100, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ceyda","family":"Tunakan Dalgic","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Internal Medicine, Ege University Faculty of Medicine, Izmir 35100, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7722-506X","authenticated-orcid":false,"given":"Nur","family":"Soyer","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Internal Medicine, Ege University Faculty of Medicine, Izmir 35100, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2564-7420","authenticated-orcid":false,"given":"Havva","family":"Yaz\u0131c\u0131","sequence":"additional","affiliation":[{"name":"Division of Pediatric Metabolism, Department of Pediatrics, Ege University Faculty of Medicine, Izmir 35100, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayse Nur","family":"Yuceyar","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ege University Faculty of Medicine, Izmir 35100, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asl\u0131","family":"Subas\u0131oglu","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Atat\u00fcrk Training and Research Hospital, Izmir Katip Celebi University, Izmir 35360, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irem","family":"Evcili","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center (IBG), Dokuz Eyl\u00fcl University, Izmir 35330, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bilgi","family":"Gungor","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center (IBG), Dokuz Eyl\u00fcl University, Izmir 35330, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kas\u0131m","family":"Okan","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Internal Medicine, Ege University Faculty of Medicine, Izmir 35100, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9145-1506","authenticated-orcid":false,"given":"Mehmet","family":"Soylu","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Ege University Faculty of Medicine, Izmir 35100, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cihat","family":"Uzunkopru","sequence":"additional","affiliation":[{"name":"Department of Neurology, Atat\u00fcrk Training and Research Hospital, Izmir Katip Celebi University, Izmir 35360, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omur","family":"Ardeniz","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Internal Medicine, Ege University Faculty of Medicine, Izmir 35100, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/nature10246","article-title":"Second messenger role for Mg2+ revealed by human T-cell immunodeficiency","volume":"475","author":"Li","year":"2011","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1182\/blood-2013-11-538686","article-title":"XMEN disease: A new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus","volume":"123","author":"Li","year":"2014","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1126\/science.1240094","article-title":"Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through 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