X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia

Summary

X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia (MONDO:0010455) is a disease caused by MAGT1 (GenCC Strong), with 4 cohort genes and 1 clinical trial. Top therapeutic interventions include magnesium and l-threonic acid.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MAGT1 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 279
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia
Mondo ID	MONDO:0010455
OMIM	300853
Orphanet	317476
DOID	DOID:0080319
NCIT	C126336
SNOMED CT	711481001
UMLS	C3275445
MedGen	477076
GARD	0010907
Is cancer (heuristic)	no

Also known as: Cid due to MAGT1 deficiency · combined immunodeficiency due to MAGT1 deficiency · immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia, X-linked recessive · immunodeficiency, X-linked, with magnesium defect, Epstein-Barr VIRUS infection, and neoplasia · X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia · X-linked magnesium deficiency with Epstein-Barr virus infection and neoplasia · XMEN

Data availability: 279 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia

Related subtypes (32): ataxia telangiectasia, combined immunodeficiency due to ZAP70 deficiency, combined immunodeficiency due to moesin deficiency, Wiskott-Aldrich syndrome, MHC class I deficiency, combined immunodeficiency due to STK4 deficiency, combined immunodeficiency due to MALT1 deficiency, combined immunodeficiency due to OX40 deficiency, combined immunodeficiency due to CD3gamma deficiency, combined immunodeficiency due to CTPS1 deficiency, combined immunodeficiency due to CRAC channel dysfunction, severe combined immunodeficiency, non-SCID combined immunodeficiency, combined immunodeficiency due to RELA haploinsufficiency, combined immunodeficiency due to GINS1 deficiency, combined immunodeficiency syndrome, combined immunodeficiency due to POLE2 deficiency, autosomal recessive combined immunodeficiency due to complete IL6ST deficiency, autosomal recessive combined immunodeficiency due to partial IL6ST deficiency, autosomal dominant combined immunodeficiency due to partial IL6ST deficiency, autosomal recessive combined immunodeficiency due to IL6R deficiency, autosomal dominant combined immunodeficiency due to ERBIN deficiency, combined immunodeficiency due to TBX1 deficiency, RAC2-related combined immunodeficiency-bronchiectasis-cancer-predisposing syndrome, combined immunodeficiency due to dimerization defective IKAROS mutation, late-onset combined immunodeficiency due to ICOSL deficiency, combined immunodeficiency-hypogammaglobulinemia-skeletal anomalies syndrome due to IKBKA deficiency, early-onset combined immunodeficiency with low ig due to dominant negative IKAROS mutation, combined immunodeficiency with low Ig due to BCL10 deficiency, IRF4-related combined immunodeficiency, NFATC1-related combined immunodeficiency, POLD3-related combined immunodeficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

279 retrieved; paginated sample, class counts are floors:

116 uncertain significance, 76 likely benign, 28 pathogenic, 24 benign, 18 likely pathogenic, 14 conflicting classifications of pathogenicity, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2427018	NC_000023.10:g.(?77084697)(77268629_?)del	ATP7A	Pathogenic	criteria provided, single submitter
419298	NM_001367916.1(MAGT1):c.14G>A (p.Trp5Ter)	LOC130068460	Pathogenic	criteria provided, single submitter
1074386	NM_001367916.1(MAGT1):c.490G>T (p.Glu164Ter)	MAGT1	Pathogenic	criteria provided, single submitter
1074984	NM_001367916.1(MAGT1):c.507G>A (p.Trp169Ter)	MAGT1	Pathogenic	criteria provided, single submitter
1220528	NM_001367916.1(MAGT1):c.678dup (p.Val227fs)	MAGT1	Pathogenic	no assertion criteria provided
1220529	NM_001367916.1(MAGT1):c.707G>A (p.Trp236Ter)	MAGT1	Pathogenic	no assertion criteria provided
1458559	NM_001367916.1(MAGT1):c.909T>A (p.Cys303Ter)	MAGT1	Pathogenic	criteria provided, single submitter
1527846	NM_001367916.1(MAGT1):c.484dup (p.Ser162fs)	MAGT1	Pathogenic	criteria provided, multiple submitters, no conflicts
2120336	NM_001367916.1(MAGT1):c.751_752dup (p.Gly252fs)	MAGT1	Pathogenic	criteria provided, single submitter
2808207	NM_001367916.1(MAGT1):c.462T>A (p.Tyr154Ter)	MAGT1	Pathogenic	criteria provided, single submitter
2844435	NM_001367916.1(MAGT1):c.607_610del (p.Val203fs)	MAGT1	Pathogenic	criteria provided, single submitter
29981	NM_001367916.1(MAGT1):c.826_826+9del	MAGT1	Pathogenic	no assertion criteria provided
29982	NM_001367916.1(MAGT1):c.313C>T (p.Arg105Ter)	MAGT1	Pathogenic	criteria provided, multiple submitters, no conflicts
3245416	NC_000023.10:g.(?77126285)(77126442_?)del	MAGT1	Pathogenic	criteria provided, single submitter
3728820	NM_001367916.1(MAGT1):c.502dup (p.Arg168fs)	MAGT1	Pathogenic	criteria provided, single submitter
4071550	NM_001367916.1(MAGT1):c.493C>T (p.Gln165Ter)	MAGT1	Pathogenic	criteria provided, single submitter
4726786	NM_001367916.1(MAGT1):c.418del (p.Ile140fs)	MAGT1	Pathogenic	criteria provided, single submitter
539316	NM_001367916.1(MAGT1):c.127C>T (p.Gln43Ter)	MAGT1	Pathogenic	criteria provided, single submitter
578831	NM_001367916.1(MAGT1):c.348dup (p.Ala117fs)	MAGT1	Pathogenic	criteria provided, single submitter
625837	NM_001367916.1(MAGT1):c.895C>T (p.Arg299Ter)	MAGT1	Pathogenic	criteria provided, multiple submitters, no conflicts
625838	NM_001367916.1(MAGT1):c.842T>G (p.Leu281Ter)	MAGT1	Pathogenic	criteria provided, single submitter
649134	NM_001367916.1(MAGT1):c.641_642insGA (p.Phe214fs)	MAGT1	Pathogenic	criteria provided, single submitter
662023	NM_001367916.1(MAGT1):c.676_680del (p.Phe226fs)	MAGT1	Pathogenic	criteria provided, single submitter
689408	NM_001367916.1(MAGT1):c.502del (p.Arg168fs)	MAGT1	Pathogenic	no assertion criteria provided
689409	NM_001367916.1(MAGT1):c.616C>T (p.Arg206Ter)	MAGT1	Pathogenic	criteria provided, multiple submitters, no conflicts
689410	NM_001367916.1(MAGT1):c.459dup (p.Tyr154fs)	MAGT1	Pathogenic	no assertion criteria provided
844382	NM_001367916.1(MAGT1):c.272+1G>C	MAGT1	Pathogenic	criteria provided, single submitter
976322	NM_001367916.1(MAGT1):c.948G>A (p.Trp316Ter)	MAGT1	Pathogenic	criteria provided, single submitter
3245438	NC_000023.10:g.(?77112986)(77112986_?)del		Likely pathogenic	criteria provided, single submitter
1220530	NM_001367916.1(MAGT1):c.-2dup	LOC130068460	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MAGT1	Strong	X-linked	X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAGT1	Orphanet:317476	XMEN
COX7B	Orphanet:2556	Microphthalmia with linear skin defects syndrome
ATP7A	Orphanet:139557	X-linked distal spinal muscular atrophy type 3
ATP7A	Orphanet:198	Occipital horn syndrome
ATP7A	Orphanet:388	Hirschsprung disease
ATP7A	Orphanet:565	Menkes disease
ATRX	Orphanet:100075	Neuroendocrine tumor of stomach
ATRX	Orphanet:231401	Alpha-thalassemia-myelodysplastic syndrome
ATRX	Orphanet:847	X-linked alpha-thalassemia-intellectual disability syndrome
ATRX	Orphanet:96253	Cushing disease

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MAGT1	HGNC:28880	ENSG00000102158	Q9H0U3	Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit MAGT1	gencc,clinvar
COX7B	HGNC:2291	ENSG00000131174	P24311	Cytochrome c oxidase subunit 7B, mitochondrial	clinvar
ATP7A	HGNC:869	ENSG00000165240	Q04656	Copper-transporting ATPase 1	clinvar
ATRX	HGNC:886	ENSG00000085224	P46100	Transcriptional regulator ATRX	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAGT1	Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit MAGT1	Accessory component of the STT3B-containing form of the N-oligosaccharyl transferase (OST) complex which catalyzes the transfer of a high mannose oligosaccharide from a lipid-linked oligosaccharide donor to an asparagine residue within an…
COX7B	Cytochrome c oxidase subunit 7B, mitochondrial	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
ATP7A	Copper-transporting ATPase 1	ATP-driven copper (Cu(+)) ion pump that plays an important role in intracellular copper ion homeostasis.
ATRX	Transcriptional regulator ATRX	Involved in transcriptional regulation and chromatin remodeling.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	2	4.1×	0.149
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MAGT1	Other/Unknown	no		MAGT1/OST3/OST6, Thioredoxin-like_sf
COX7B	Other/Unknown	no		Cyt_c_oxidase_suVIIB, Cyt_c_oxidase_suVIIB_dom_sf
ATP7A	Transcription factor	no	7.2.2.8	P_typ_ATPase, HMA_dom, HMA_Cu_ion-bd
ATRX	Transcription factor	no		SNF2_N, Helicase_C-like, Znf_FYVE_PHD

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus epididymis	1
esophagus squamous epithelium	1
palpebral conjunctiva	1
apex of heart	1
biceps brachii	1
heart right ventricle	1
buccal mucosa cell	1
trabecular bone tissue	1
upper leg skin	1
calcaneal tendon	1
colonic epithelium	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAGT1	282	ubiquitous	marker	palpebral conjunctiva, corpus epididymis, esophagus squamous epithelium
COX7B	295	ubiquitous	marker	heart right ventricle, apex of heart, biceps brachii
ATP7A	275	ubiquitous	marker	buccal mucosa cell, trabecular bone tissue, upper leg skin
ATRX	294	ubiquitous	marker	endothelial cell, calcaneal tendon, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATRX	5,796
ATP7A	3,901
MAGT1	1,824
COX7B	1,135

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP7A	Q04656	22
ATRX	P46100	12
COX7B	P24311	3
MAGT1	Q9H0U3	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 40. Enrichment computed across 4 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Alternative Lengthening of Telomeres (ALT)	1	2855.0×	0.005	ATRX
Defective Inhibition of DNA Recombination at Telomere	1	2855.0×	0.005	ATRX
Diseases of Telomere Maintenance	1	2855.0×	0.005	ATRX
Defective Inhibition of DNA Recombination at Telomere Due to DAXX Mutations	1	1427.5×	0.006	ATRX
Defective Inhibition of DNA Recombination at Telomere Due to ATRX Mutations	1	1427.5×	0.006	ATRX
Ion influx/efflux at host-pathogen interface	1	713.8×	0.009	ATP7A
PD-L1(CD274) glycosylation and translocation to plasma membrane	1	129.8×	0.033	MAGT1
Miscellaneous transport and binding events	1	109.8×	0.033	MAGT1
Translation of Structural Proteins	1	102.0×	0.033	MAGT1
Diseases of mitotic cell cycle	1	98.5×	0.033	ATRX
Telomere Maintenance	1	92.1×	0.033	ATRX
Innate Immune System	2	12.8×	0.033	MAGT1, ATP7A
Transport of small molecules	2	12.6×	0.033	MAGT1, ATP7A
Detoxification of Reactive Oxygen Species	1	75.1×	0.036	ATP7A
Late SARS-CoV-2 Infection Events	1	73.2×	0.036	MAGT1
Maturation of spike protein	1	66.4×	0.036	MAGT1
Complex IV assembly	1	57.1×	0.036	COX7B
Antimicrobial peptides	1	56.0×	0.036	ATP7A
Chromosome Maintenance	1	52.9×	0.036	ATRX
Maturation of DENV proteins	1	52.9×	0.036	MAGT1
Ion transport by P-type ATPases	1	51.9×	0.036	ATP7A
Cytoprotection by HMOX1	1	46.0×	0.039	COX7B
Inhibition of DNA recombination at telomere	1	42.0×	0.041	ATRX
Cellular response to chemical stress	1	35.7×	0.046	ATP7A
TP53 Regulates Metabolic Genes	1	32.4×	0.048	COX7B
Disease	2	6.5×	0.048	MAGT1, ATRX
Immune System	2	6.5×	0.048	MAGT1, ATP7A
Ion channel transport	1	24.0×	0.057	ATP7A
Respiratory electron transport	1	23.8×	0.057	COX7B
SARS-CoV-2 Infection	1	20.1×	0.065	MAGT1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
post-embryonic forelimb morphogenesis	1	2106.5×	0.008	ATRX
obsolete negative regulation of catecholamine metabolic process	1	2106.5×	0.008	ATP7A
negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric	1	2106.5×	0.008	ATRX
obsolete L-tryptophan metabolic process	1	1404.3×	0.008	ATP7A
epinephrine metabolic process	1	1404.3×	0.008	ATP7A
copper ion export	1	1404.3×	0.008	ATP7A
obsolete tyrosine metabolic process	1	1053.2×	0.008	ATP7A
catecholamine metabolic process	1	1053.2×	0.008	ATP7A
magnesium ion transmembrane transport	1	1053.2×	0.008	MAGT1
T-helper cell differentiation	1	842.6×	0.008	ATP7A
chromosome organization involved in meiotic cell cycle	1	842.6×	0.008	ATRX
positive regulation of nuclear cell cycle DNA replication	1	702.2×	0.009	ATRX
meiotic spindle organization	1	601.9×	0.009	ATRX
copper ion import	1	601.9×	0.009	ATP7A
pyramidal neuron development	1	526.6×	0.009	ATP7A
norepinephrine biosynthetic process	1	526.6×	0.009	ATP7A
copper ion transport	1	421.3×	0.009	ATP7A
serotonin metabolic process	1	421.3×	0.009	ATP7A
subtelomeric heterochromatin formation	1	383.0×	0.009	ATRX
norepinephrine metabolic process	1	383.0×	0.009	ATP7A
elastic fiber assembly	1	383.0×	0.009	ATP7A
protein localization to chromosome, telomeric region	1	383.0×	0.009	ATRX
positive regulation of melanin biosynthetic process	1	351.1×	0.009	ATP7A
cellular response to hydroxyurea	1	351.1×	0.009	ATRX
regulation of oxidative phosphorylation	1	300.9×	0.009	ATP7A
magnesium ion transport	1	300.9×	0.009	MAGT1
detoxification of copper ion	1	280.9×	0.009	ATP7A
Sertoli cell development	1	280.9×	0.009	ATRX
removal of superoxide radicals	1	263.3×	0.009	ATP7A
cerebellar Purkinje cell differentiation	1	263.3×	0.009	ATP7A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAGT1	0	0
COX7B	0	0
ATP7A	0	0
ATRX	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ATP7A	11	Binding:11
MAGT1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP7A	7.2.2.8, 7.2.2.9	P-type Cu+ transporter, P-type Cu2+ transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	MAGT1, COX7B, ATP7A, ATRX

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MAGT1	1	—
COX7B	0	—
ATP7A	11	—
ATRX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02496676	PHASE1/PHASE2	COMPLETED	Magnesium Supplementation in People With XMEN Syndrome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MAGNESIUM	3	1
L-THREONIC ACID	2	1