# Case Report: Novel MAGT1 pathogenic variant with significant atopy, hypogammaglobulinemia and viral skin infections

## TL;DR

A 6-year-old boy with a novel MAGT1 gene variant was diagnosed with XMEN disease after a detailed clinical and genetic investigation.

## Contribution

A novel MAGT1 pathogenic variant was identified and functionally analyzed using AlphaFold to understand its impact on protein structure and function.

## Key findings

- A novel hemizygous MAGT1 variant (c.580dup) was found to cause XMEN disease.
- AlphaFold analysis revealed structural disruptions affecting MAGT1's interaction with the OST-B complex.
- The patient exhibited hallmark features of XMEN disease including NKG2D deficiency and glycosylation defects.

## Abstract

X-linked MAGT1 deficiency with increased susceptibility to EBV-infection and N-linked glycosylation (XMEN) disease is an inborn error of immunity (IEI) affecting the Magnesium Transporter 1 (MAGT1) gene. In this report, we present the diagnostic odyssey for a patient harboring a novel MAGT1 variant resulting in XMEN disease.

A 6y old male child of Caucasian ancestry presented at the immunology clinic in our hospital with a history of recurrent upper respiratory tract infections, as well as significant atopy and viral skin lesions. Genetic testing identified a novel, hemizygous pathogenic variant in the magnesium transporter 1 (MAGT1) gene (c.580dup; p.Ser194Phefs*3). Follow-up testing by flow cytometry revealed the canonical disruption in Natural Killer Group 2D (NKG2D) surface expression on CD8 T cells and NK cells, and clinical testing for congenital disorders of glycosylation (CDG) additionally verified the hallmark defect in glycosylation that underpins XMEN disease. Subsequent in silico analyses using AlphaFold provided an in-depth view of the resulting aberrant protein structural variant and its inability to tether itself to the OST-B complex, a pre-requisite for optimal enzymatic activity of the MAGT1 protein. Disease management included infection control and prophylaxis, steroids and immunotherapy for the patient’s asthma and atopy, topical antiviral treatment for the warts and molluscum, as well as biannual EBV load monitoring (the patient is EBV negative).

This case illustrates how a synergistic multi-disciplinary team approach established a diagnosis of XMEN disease in a patient with an atypical clinical presentation. This case also highlights a growing trend where established diagnostic tools such as flow-cytometry and genomics can be complemented with newer, sophisticated analytical approaches such as AlphaFold to further elucidate the functionally crippling effects of novel variants described in the setting of IEI.