# Modifier-Sensitive Phenotypic Divergence in XMEN Disease (MAGT1 Deficiency): Neurodegenerative and Immuno-Hematologic Trajectories

## TL;DR

XMEN disease caused by MAGT1 mutations shows varied symptoms between siblings, including neurodegeneration and immune issues, highlighting the role of modifier genes in disease expression.

## Contribution

The study reveals intrafamilial clinical heterogeneity in XMEN disease and proposes a new conceptual framework for neurological classifications.

## Key findings

- Two siblings with MAGT1 deficiency showed divergent phenotypes: one with neurodegeneration and the other with immuno-hematologic complications.
- Shared B-cell defects but distinct T-cell differentiation patterns were observed between the siblings.
- A novel association of EBV-positive Hodgkin lymphoma and thrombotic microangiopathy was identified in XMEN disease.

## Abstract

Background: X-linked immunodeficiency with magnesium defect, Epstein–Barr 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.