hyper-IgM syndrome

Summary

hyper-IgM syndrome (MONDO:0003947) is a disease (an umbrella term covering 5 Mondo subtypes) with 1 cohort gene and 5 clinical trials. Top therapeutic interventions include human immunoglobulin g and fludarabine phosphate.

At a glance

• Umbrella term: 5 Mondo subtypes
• Cohort genes: 1
• ClinVar variants: 1
• Clinical trials: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyper-IgM syndrome
Mondo ID	MONDO:0003947
MeSH	D053306
OMIM	308230
DOID	DOID:0080544
NCIT	C3990, C84783
SNOMED CT	82286005
UMLS	C0272236
MedGen	124420
GARD	0023748
Is cancer (heuristic)	no

Also known as: immunodeficiency with hyper-IgM

Data availability: 1 ClinVar variant · 6 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › B cell deficiency › hyperimmunoglobulin syndrome › hyper-IgM syndrome

Related subtypes (1): hyper-IgE syndrome

Subtypes (5): hyper-IgM syndrome type 1, hyper-IgM syndrome type 2, hyper-IgM syndrome type 3, hyper-IgM syndrome type 5, hyper-IgM syndrome type 4

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
928859	NM_000074.3(CD40LG):c.347-1G>A	CD40LG	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CD40LG	Orphanet:101088	X-linked hyper-IgM syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CD40LG	HGNC:11935	ENSG00000102245	P29965	CD40 ligand	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CD40LG	CD40 ligand	Cytokine that acts as a ligand to CD40/TNFRSF5.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CD40LG	Other/Unknown	no		CD40L, TNF_dom, Tumour_necrosis_fac-like_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
granulocyte	1
lymph node	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CD40LG	124	tissue_specific	marker	granulocyte, lymph node, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD40LG	3,072

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CD40LG	P29965	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	671.8×	0.009	CD40LG
TNFR2 non-canonical NF-kB pathway	1	181.3×	0.017	CD40LG
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	87.2×	0.023	CD40LG
Cytokine Signaling in Immune system	1	40.8×	0.037	CD40LG
Adaptive Immune System	1	29.8×	0.040	CD40LG
Immune System	1	13.0×	0.077	CD40LG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of immunoglobulin production	1	2407.4×	0.005	CD40LG
CD40 signaling pathway	1	1685.2×	0.005	CD40LG
isotype switching	1	842.6×	0.005	CD40LG
positive regulation of endothelial cell apoptotic process	1	732.7×	0.005	CD40LG
positive regulation of interleukin-4 production	1	561.7×	0.005	CD40LG
B cell proliferation	1	481.5×	0.005	CD40LG
leukocyte cell-cell adhesion	1	468.1×	0.005	CD40LG
positive regulation of extrinsic apoptotic signaling pathway	1	455.5×	0.005	CD40LG
positive regulation of interleukin-10 production	1	401.2×	0.005	CD40LG
positive regulation of interleukin-12 production	1	391.9×	0.005	CD40LG
T cell costimulation	1	374.5×	0.005	CD40LG
platelet activation	1	267.5×	0.006	CD40LG
positive regulation of T cell proliferation	1	259.3×	0.006	CD40LG
B cell differentiation	1	218.9×	0.006	CD40LG
obsolete positive regulation of NF-kappaB transcription factor activity	1	205.5×	0.006	CD40LG
integrin-mediated signaling pathway	1	160.5×	0.008	CD40LG
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.016	CD40LG
cell surface receptor signaling pathway	1	64.1×	0.017	CD40LG
inflammatory response	1	37.7×	0.028	CD40LG
negative regulation of apoptotic process	1	34.8×	0.029	CD40LG

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CD40LG	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CD40LG	8	Binding:8

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	CD40LG

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CD40LG	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	2
Not specified	2
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01289847	PHASE4	COMPLETED	A Study to Find Out How Safe and Effective Gammaplex® is in Young People With Primary Immunodeficiency
NCT00278954	PHASE3	COMPLETED	Efficacy, Safety and Pharmacokinetics of Gammaplex in Primary Immunodeficiency Diseases.
NCT01963143	PHASE3	COMPLETED	Bioequivalence Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Gammaplex® 10 and Gammaplex® 5% in Primary Immunodeficiency Diseases
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT00266513	Not specified	TERMINATED	Studies of Disorders in Antibody Production and Related Primary Immunodeficiency States

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
HUMAN IMMUNOGLOBULIN G	4	2
FLUDARABINE PHOSPHATE	4	1