hyper-IgM syndrome type 1

Summary

hyper-IgM syndrome type 1 (MONDO:0010626) is a disease caused by CD40LG (GenCC Definitive), with 3 cohort genes and 4 clinical trials.

At a glance

• Causal gene: CD40LG (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 294
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyper-IgM syndrome type 1
Mondo ID	MONDO:0010626
OMIM	308230
Orphanet	101088
DOID	DOID:0060022, DOID:6620
NCIT	C61244
SNOMED CT	403835002
UMLS	C0398689
MedGen	96019
GARD	0000073
NORD	1261
Is cancer (heuristic)	no

Also known as: HIGM · HIGM1 · hyper IgM immunodeficiency, X-linked · hyper IgM syndrome · hyper IgM syndrome 1 · Hyper IgM Syndromes · hyper-IgM syndrome due to CD40 ligand deficiency · hyper-IgM syndrome due to CD40L deficiency · hyper-IgM syndrome type 1 · hyper-IgM syndrome, X-linked · hyperimmunoglobulin M syndrome · IHIS · immunodeficiency with hyper IgM type 1 · immunodeficiency with hyper-IgM, type 1 · immunodeficiency, X-linked, with hyper-IgM, X-linked recessive · X-linked hyper IgM syndrome · X-linked hyper-IgM syndrome · XHIGM · XHIM

Data availability: 294 ClinVar variants · 4 GenCC gene-disease records · 6 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › hyper-IgM syndrome type 1

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

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

294 retrieved; paginated sample, class counts are floors:

79 likely benign, 73 pathogenic, 71 uncertain significance, 27 benign, 20 likely pathogenic, 15 conflicting classifications of pathogenicity, 5 pathogenic/likely pathogenic, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11158	NM_000074.2(CD40LG):c.[384T>A;386A>G]		Pathogenic	no assertion criteria provided
1458589	NC_000023.10:g.(?135067662)(136652229_?)del	ADGRG4	Pathogenic	criteria provided, single submitter
1070421	NM_000074.3(CD40LG):c.346+5G>A	CD40LG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070422	NM_000074.3(CD40LG):c.470del (p.Asn157fs)	CD40LG	Pathogenic	criteria provided, single submitter
1071618	NM_000074.3(CD40LG):c.15C>A (p.Tyr5Ter)	CD40LG	Pathogenic	criteria provided, single submitter
1074317	NM_000074.3(CD40LG):c.346+1G>A	CD40LG	Pathogenic	criteria provided, single submitter
11157	NM_000074.3(CD40LG):c.703G>C (p.Ala235Pro)	CD40LG	Pathogenic	no assertion criteria provided
11159	NM_000074.3(CD40LG):c.680G>T (p.Gly227Val)	CD40LG	Pathogenic	no assertion criteria provided
11160	NM_000074.3(CD40LG):c.464T>C (p.Leu155Pro)	CD40LG	Pathogenic	criteria provided, single submitter
11161	CD40LG, THR211ASP	CD40LG	Pathogenic	no assertion criteria provided
11162	NM_000074.3(CD40LG):c.107T>G (p.Met36Arg)	CD40LG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11163	NM_000074.3(CD40LG):c.419G>A (p.Trp140Ter)	CD40LG	Pathogenic	no assertion criteria provided
11166	NM_000074.3(CD40LG):c.412_419del	CD40LG	Pathogenic	no assertion criteria provided
11167	CD40LG, 10-BP DEL	CD40LG	Pathogenic	no assertion criteria provided
11168	NM_000074.3(CD40LG):c.368C>A (p.Ala123Glu)	CD40LG	Pathogenic	criteria provided, single submitter
11169	NM_000074.3(CD40LG):c.189dup (p.Val64fs)	CD40LG	Pathogenic	no assertion criteria provided
11170	NG_007280.1:g.5145_5146insAluAluYb8inv	CD40LG	Pathogenic	no assertion criteria provided
1327990	NM_000074.3(CD40LG):c.166G>T (p.Glu56Ter)	CD40LG	Pathogenic	criteria provided, single submitter
1381599	NM_000074.3(CD40LG):c.156+2T>C	CD40LG	Pathogenic	criteria provided, single submitter
1402799	NM_000074.3(CD40LG):c.409+1G>C	CD40LG	Pathogenic	criteria provided, single submitter
1405864	NM_000074.3(CD40LG):c.385G>T (p.Glu129Ter)	CD40LG	Pathogenic	criteria provided, single submitter
1413373	NM_000074.3(CD40LG):c.598A>T (p.Arg200Ter)	CD40LG	Pathogenic	criteria provided, single submitter
1423116	NM_000074.3(CD40LG):c.289-1G>A	CD40LG	Pathogenic	criteria provided, single submitter
1444168	NM_000074.3(CD40LG):c.478C>T (p.Gln160Ter)	CD40LG	Pathogenic	criteria provided, multiple submitters, no conflicts
1454482	NC_000023.10:g.(?135730388)(135737600_?)del	CD40LG	Pathogenic	criteria provided, single submitter
1687523	NM_000074.3(CD40LG):c.158_161del	CD40LG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803793	NM_000074.3(CD40LG):c.229del (p.Arg77fs)	CD40LG	Pathogenic	no assertion criteria provided
1996844	NM_000074.3(CD40LG):c.43del (p.Thr15fs)	CD40LG	Pathogenic	criteria provided, single submitter
1997026	NM_000074.3(CD40LG):c.268C>T (p.Gln90Ter)	CD40LG	Pathogenic	criteria provided, multiple submitters, no conflicts
2013065	NM_000074.3(CD40LG):c.431del (p.Gly144fs)	CD40LG	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
CD40LG	Definitive	X-linked	hyper-IgM syndrome type 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CD40LG	Orphanet:101088	X-linked hyper-IgM syndrome
CD40	Orphanet:101090	Hyper-IgM syndrome type 3

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CD40LG	HGNC:11935	ENSG00000102245	P29965	CD40 ligand	gencc,clinvar
CD40	HGNC:11919	ENSG00000101017	P25942	Tumor necrosis factor receptor superfamily member 5	clinvar
ADGRG4	HGNC:18992	ENSG00000156920	Q8IZF6	Adhesion G-protein coupled receptor G4	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.
CD40	Tumor necrosis factor receptor superfamily member 5	Receptor for TNFSF5/CD40LG.
ADGRG4	Adhesion G-protein coupled receptor G4	Orphan adhesion G-protein coupled receptor (aGPCR).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
GPCR	1	8.0×	0.240
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CD40LG	Other/Unknown	no		CD40L, TNF_dom, Tumour_necrosis_fac-like_dom
CD40	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_5, TNFRSF5_N
ADGRG4	GPCR	yes		GPS, GPCR_2_secretin-like, PTX_dom

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lymph node	2
blood	1
granulocyte	1
right lung	1
spleen	1
buccal mucosa cell	1
duodenum	1
jejunal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CD40LG	124	tissue_specific	marker	granulocyte, lymph node, blood
CD40	242	ubiquitous	marker	lymph node, right lung, spleen
ADGRG4	55	tissue_specific	marker	buccal mucosa cell, duodenum, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD40	3,765
CD40LG	3,072
ADGRG4	768

Intra-cohort edges

A	B	Sources
CD40	CD40LG	biogrid_interaction, intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CD40	P25942	14
CD40LG	P29965	8
ADGRG4	Q8IZF6	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 evidence-associated genes (2 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 2 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	2	671.8×	1e-05	CD40LG, CD40
TNFR2 non-canonical NF-kB pathway	2	181.3×	9e-05	CD40LG, CD40
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	2	87.2×	3e-04	CD40LG, CD40
Cytokine Signaling in Immune system	1	20.4×	0.073	CD40LG
Adaptive Immune System	1	14.9×	0.079	CD40LG
Immune System	1	6.5×	0.148	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
CD40 signaling pathway	2	1123.5×	4e-05	CD40LG, CD40
positive regulation of endothelial cell apoptotic process	2	488.5×	1e-04	CD40LG, CD40
B cell proliferation	2	321.0×	2e-04	CD40LG, CD40
positive regulation of interleukin-12 production	2	261.3×	2e-04	CD40LG, CD40
platelet activation	2	178.3×	4e-04	CD40LG, CD40
response to cobalamin	1	2808.7×	0.003	CD40
positive regulation of protein kinase C signaling	1	1872.4×	0.003	CD40
positive regulation of interleukin-4-mediated signaling pathway	1	1872.4×	0.003	CD40
B cell mediated immunity	1	1404.3×	0.003	CD40
cellular response to erythropoietin	1	1404.3×	0.003	CD40
positive regulation of canonical NF-kappaB signal transduction	2	48.4×	0.003	CD40LG, CD40
cell surface receptor signaling pathway	2	42.7×	0.003	CD40LG, ADGRG4
regulation of immunoglobulin production	1	802.5×	0.004	CD40LG
immune response-regulating cell surface receptor signaling pathway	1	624.1×	0.005	CD40
positive regulation of isotype switching to IgG isotypes	1	510.7×	0.006	CD40
inflammatory response	2	25.1×	0.006	CD40LG, CD40
isotype switching	1	280.9×	0.010	CD40LG
defense response to protozoan	1	200.6×	0.013	CD40
positive regulation of interleukin-4 production	1	187.2×	0.013	CD40LG
response to type II interferon	1	175.5×	0.013	CD40
leukocyte cell-cell adhesion	1	156.0×	0.013	CD40LG
B cell activation	1	151.8×	0.013	CD40
positive regulation of extrinsic apoptotic signaling pathway	1	151.8×	0.013	CD40LG
positive regulation of interleukin-10 production	1	133.8×	0.014	CD40LG
positive regulation of blood vessel endothelial cell migration	1	130.6×	0.014	CD40
T cell costimulation	1	124.8×	0.014	CD40LG
positive regulation of B cell proliferation	1	114.6×	0.015	CD40
cell surface receptor signaling pathway via JAK-STAT	1	96.8×	0.017	CD40
cellular response to interleukin-1	1	93.6×	0.017	CD40
positive regulation of T cell proliferation	1	86.4×	0.018	CD40LG

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
CD40	0	0
ADGRG4	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
CD40	10	Binding:10
CD40LG	8	Binding:8

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	ADGRG4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CD40LG, CD40

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CD40LG	8	—
CD40	10	—
ADGRG4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01884311	PHASE3	COMPLETED	Pharmacokinetics (PK) and Safety of Subgam-VF in Primary Immunodeficiency Diseases
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT00004341	Not specified	UNKNOWN	Study of Genetic and Molecular Defects in Primary Immunodeficiency Disorders
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies