MAGT1

Inheritance Pattern: XL

Disease ID:MONDO:0010413

Submitter: G2P

Inheritance Pattern: XL

Disease ID:MONDO:0100284

Submitter: ClinGen

*MAGT1* was first reported in relation to X-linked intellectual disability in 2008 (Molinari et al., PMID: 18455129). The authors reported a missense variant that co-segregated with X-linked non-syndromic intellectual disability in a family. However, this variant was later found to be common in the general population and unlikely to be disease-causing (PMID: 23871722). Truncating variants in *MAGT1* are a well-known cause of X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN). Of note, none of the reported males with truncating variants and the immunodeficiency phenotype had intellectual disability (Li et al. 2011, PMID: 21796205; Chaigne-Delalande et al., 2013, PMID: 23846901; Li et al., 2014, PMID: 24550228; Dhalla et al., 2014, PMID: 25504528; Ravell et al., 2020, PMID: 31714901), questioning the implication of *MAGT1* in neurodevelopmental disorders. No other cases with *MAGT1* disruption and X-linked intellectual disability were reported until 2017, when Brigida et al. (PMID: 27770395) reported a patient with a large deletion in the *MAGT1* gene with immunological phenotypes characteristic of XMEN disease, along with cognitive and language delay. However, the patient's neurological manifestations may be explained by disruption of the *ATRX* gene, involved in X-linked alpha thalassaemia intellectual disability syndrome, since the deletion extended into the promoter. In 2019, Blommaert et al. (PMID: 31036665) reported *MAGT1* variants in two unrelated male individuals with intellectual disability and a glycosylation defect. The variants, including a missense and a nonsense variant, were detected via an in-house congenital disorder of glycosylation gene panel. Given that no other causes of intellectual disability were ruled out with exome or genome sequencing, it is not possible to conclude that the *MAGT1* variants are responsible for the intellectual disability observed in these individuals. Furthermore, this same nonsense variant was also found in two other individuals who had XMEN disease with the characteristic immunological phenotype but did not have intellectual disability (PMID: 31714901). No experimental evidence linking variation in the *MAGT1* gene to intellectual disability was identified in the literature. In summary, the evidence supporting the relationship between *MAGT1* and X-linked intellectual disability has been disputed. More evidence is needed to either support or entirely refute the role *MAGT1* plays in this disease. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 1, 2023 (SOP Version 9). Note that the relationship between *MAGT1* and XMEN will be evaluated separately by another gene curation expert panel.

Inheritance Pattern: XL

Disease ID:MONDO:0010455

Submitter: ClinGen

*MAGT1* was first reported in relation to X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia (i.e., XMEN) in 2011 (Li FY, et al., PMID: 21796205). XMEN is a congenital disorder of glycosylation presenting as combined immunodeficiency. This is a heterogeneous disorder typically characterized by increased susceptibility to Epstein-Barr virus and associated lymphomas (e.g., Hodgkin lymphoma and Burkitt lymphoma), increased susceptibility to otitis media and sinopulmonary infections, an increased naïve B cell population, a decreased CD4+:CD8+ T cell ratio, decreased NKG2D expression on CD8+ T and natural killer cells, and defective N-linked glycosylation (PMID: 21796205, 23846901, 30470981, 31815737, 31865525, 32451662, 35145548, 35182234, 35264785, 38041964). Phenotypic features of patients with XMEN may also overlap with autoimmune lymphoproliferative syndrome including autoimmune cytopenias and an increased population of TCR alpha-beta double-negative T cells (PMID: 24550228, 25956530). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia (OMIM: 300853) and X-linked intellectual disability (OMIM: 301031). The split curation for X-linked intellectual disability has been curated separately. Seven variants (frameshift, nonsense, missense) that have been reported in 7 probands in 5 publications (PMIDs: 21796205, 30470981, 31865525, 35145548, 35264785) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by animal models, expression studies, and ex vivo and in vitro functional assays (PMIDs: 19717468, 23846901, 29051561, 29581357, 33051095, 34086870). Bone marrow transplant and hematopoietic stem cell transplant appear to be curative options for patients with XMEN (PMIDs: 30470981, 38143450, 38578340). In addition, promise is shown for CAR T-cell therapy based on treatment of patients, gene-editing of *MAGT1* with CRISPR based on experiments in patient cells, and expression of TUSC3 based on in vitro studies (PMID: 34086870, 37086924, 38578340). Notably, magnesium supplementation does not appear to have significant therapeutic effects (PMID: 34655400). In summary, there is definitive evidence supporting the relationship between *MAGT1* and X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Primary Immune Regulatory Disorders on the meeting date November 28, 2025 (SOP Version 11).

Inheritance Pattern: XL

Disease ID:MONDO:0010455

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0010455

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: Unknown

Disease ID:MONDO:0010455

Submitter: Orphanet