Submission Details

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 relationships between MAGT1 disruption and X-linked intellectual disability were reported until 2017 (Brigida et al., PMID: 27770395). These authors 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 January 4th, 2023 (SOP Version 9). Note that the relationship between MAGT1 and XMEN will be evaluated separately by another gene curation expert panel.