combined immunodeficiency due to OX40 deficiency

Summary

combined immunodeficiency due to OX40 deficiency (MONDO:0014268) is a disease with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 351

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Identifiers

Disease identifiers

Field	Value
Canonical name	combined immunodeficiency due to OX40 deficiency
Mondo ID	MONDO:0014268
OMIM	615593
Orphanet	431149
DOID	DOID:0111935
SNOMED CT	766879006
UMLS	C3810053
MedGen	816383
GARD	0017710
Is cancer (heuristic)	no

Also known as: combined immunodeficiency with childhood-onset Kaposi sarcoma · combined immunodeficiency with impaired immunity to HHV-8 · combined immunodeficiency with impaired immunity to human herpes virus 8 · IMD16 · immunodeficiency 16 · immunodeficiency type 16

Data availability: 351 ClinVar variants · 4 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 › combined immunodeficiency due to OX40 deficiency

Related subtypes (32): ataxia telangiectasia, combined immunodeficiency due to ZAP70 deficiency, X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia, 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 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

351 retrieved; paginated sample, class counts are floors:

183 uncertain significance, 141 likely benign, 15 benign, 5 benign/likely benign, 5 conflicting classifications of pathogenicity, 1 pathogenic, 1 no classifications from unflagged records

ClinVar	Variant (HGVS)	Gene	Classification	Review
1412663	NC_000001.10:g.(?861322)(3768971_?)del	ARHGEF16	Pathogenic	criteria provided, single submitter
2918189	NM_003327.4(TNFRSF4):c.41C>T (p.Ala14Val)	TNFRSF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3971409	NM_003327.4(TNFRSF4):c.17G>A (p.Arg6Gln)	TNFRSF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
573043	NM_003327.4(TNFRSF4):c.494T>C (p.Ile165Thr)	TNFRSF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
854797	NM_003327.4(TNFRSF4):c.614G>C (p.Arg205Pro)	TNFRSF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
966997	NM_003327.4(TNFRSF4):c.801G>C (p.Gln267His)	TNFRSF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1020063	NC_000001.10:g.(?1146915)(1168668_?)dup	B3GALT6	Uncertain significance	criteria provided, single submitter
2424672	NC_000001.10:g.(?1146935)(1168648_?)dup	B3GALT6	Uncertain significance	criteria provided, single submitter
3247835	NC_000001.10:g.(?955553)(1168648_?)dup	C1orf159	Uncertain significance	criteria provided, single submitter
2767265	NM_003327.4(TNFRSF4):c.146-84_328del	LOC129929100	Uncertain significance	criteria provided, single submitter
1003348	NM_003327.4(TNFRSF4):c.239C>T (p.Pro80Leu)	TNFRSF4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1003989	NM_003327.4(TNFRSF4):c.371A>G (p.Asp124Gly)	TNFRSF4	Uncertain significance	criteria provided, single submitter
1011115	NM_003327.4(TNFRSF4):c.7G>A (p.Val3Met)	TNFRSF4	Uncertain significance	criteria provided, single submitter
1015210	NM_003327.4(TNFRSF4):c.509del (p.Asp170fs)	TNFRSF4	Uncertain significance	criteria provided, single submitter
1017107	NM_003327.4(TNFRSF4):c.332C>T (p.Ala111Val)	TNFRSF4	Uncertain significance	criteria provided, single submitter
1035860	NM_003327.4(TNFRSF4):c.485C>T (p.Ser162Leu)	TNFRSF4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1038803	NM_003327.4(TNFRSF4):c.767G>C (p.Gly256Ala)	TNFRSF4	Uncertain significance	criteria provided, single submitter
1051616	NM_003327.4(TNFRSF4):c.332C>A (p.Ala111Glu)	TNFRSF4	Uncertain significance	criteria provided, single submitter
1055797	NM_003327.4(TNFRSF4):c.121C>T (p.Arg41Trp)	TNFRSF4	Uncertain significance	criteria provided, single submitter
1060187	NM_003327.4(TNFRSF4):c.490G>A (p.Ala164Thr)	TNFRSF4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1061258	NM_003327.4(TNFRSF4):c.638G>C (p.Arg213Pro)	TNFRSF4	Uncertain significance	criteria provided, single submitter
1064159	NM_003327.4(TNFRSF4):c.722G>A (p.Arg241Gln)	TNFRSF4	Uncertain significance	criteria provided, single submitter
1353532	NM_003327.4(TNFRSF4):c.322C>T (p.Arg108Cys)	TNFRSF4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1363409	NM_003327.4(TNFRSF4):c.299C>T (p.Thr100Met)	TNFRSF4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1367100	NM_003327.4(TNFRSF4):c.6C>G (p.Cys2Trp)	TNFRSF4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1367327	NM_003327.4(TNFRSF4):c.812A>G (p.His271Arg)	TNFRSF4	Uncertain significance	criteria provided, single submitter
1383055	NM_003327.4(TNFRSF4):c.504C>G (p.Asp168Glu)	TNFRSF4	Uncertain significance	criteria provided, single submitter
1385033	NM_003327.4(TNFRSF4):c.40G>A (p.Ala14Thr)	TNFRSF4	Uncertain significance	criteria provided, single submitter
1386340	NM_003327.4(TNFRSF4):c.253A>G (p.Thr85Ala)	TNFRSF4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1388596	NM_003327.4(TNFRSF4):c.476G>A (p.Ser159Asn)	TNFRSF4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · 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
TNFRSF4	Supportive	Autosomal recessive	combined immunodeficiency due to OX40 deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNFRSF4	Orphanet:431149	Combined immunodeficiency due to OX40 deficiency
B3GALT6	Orphanet:536467	B3GALT6-related spondylodysplastic Ehlers-Danlos syndrome
B3GALT6	Orphanet:642099	Spondyloepimetaphyseal dysplasia with joint laxity, Beighton type

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
TNFRSF4	HGNC:11918	ENSG00000186827	P43489	Tumor necrosis factor receptor superfamily member 4	gencc,clinvar
ARHGEF16	HGNC:15515	ENSG00000130762	Q5VV41	Rho guanine nucleotide exchange factor 16	clinvar
B3GALT6	HGNC:17978	ENSG00000176022	Q96L58	Beta-1,3-galactosyltransferase 6	clinvar
C1orf159	HGNC:26062	ENSG00000131591	Q96HA4	Uncharacterized protein C1orf159	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNFRSF4	Tumor necrosis factor receptor superfamily member 4	Receptor for TNFSF4/OX40L/GP34.
ARHGEF16	Rho guanine nucleotide exchange factor 16	Guanyl-nucleotide exchange factor of the RHOG GTPase stimulating the exchange of RHOG-associated GDP for GTP.
B3GALT6	Beta-1,3-galactosyltransferase 6	Beta-1,3-galactosyltransferase that transfers galactose from UDP-galactose to substrates with a terminal beta-linked galactose residue.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Scaffold/PPI	1	4.3×	0.441
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNFRSF4	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_4, TNFRSF4_N
ARHGEF16	Scaffold/PPI	no		DH_dom, SH3_domain, PH_domain
B3GALT6	Enzyme (other)	yes	2.4.1.134	Glyco_trans_31
C1orf159	Other/Unknown	no		DUF4501

Expression context

Cohort genes with no expression data: 0.

2 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
apex of heart	1
granulocyte	1
primordial germ cell in gonad	1
ileal mucosa	1
metanephros cortex	1
mucosa of transverse colon	1
Brodmann (1909) area 23	1
cartilage tissue	1
endothelial cell	1
left testis	1
lower esophagus mucosa	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNFRSF4	160	broad	marker	apex of heart, granulocyte, primordial germ cell in gonad
ARHGEF16	199	broad	marker	mucosa of transverse colon, metanephros cortex, ileal mucosa
B3GALT6	236	ubiquitous	yes	Brodmann (1909) area 23, endothelial cell, cartilage tissue
C1orf159	169	ubiquitous	yes	left testis, right testis, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNFRSF4	1,779
ARHGEF16	1,269
B3GALT6	797
C1orf159	409

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNFRSF4	P43489	8
ARHGEF16	Q5VV41	1
B3GALT6	Q96L58	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C1orf159	Q96HA4	49.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Chondroitin sulfate/dermatan sulfate metabolism	1	317.2×	0.032	B3GALT6
Diseases associated with glycosaminoglycan metabolism	1	253.8×	0.032	B3GALT6
Defective B3GALT6 causes EDSP2 and SEMDJL1	1	190.3×	0.032	B3GALT6
Heparan sulfate/heparin (HS-GAG) metabolism	1	181.3×	0.032	B3GALT6
Glycosaminoglycan-protein linkage region biosynthesis	1	131.3×	0.032	B3GALT6
TNFs bind their physiological receptors	1	131.3×	0.032	TNFRSF4
Glycosaminoglycan metabolism	1	73.2×	0.041	B3GALT6
Cell death signalling via NRAGE, NRIF and NADE	1	73.2×	0.041	ARHGEF16
p75 NTR receptor-mediated signalling	1	62.4×	0.041	ARHGEF16
NRAGE signals death through JNK	1	61.4×	0.041	ARHGEF16
RHOG GTPase cycle	1	49.4×	0.041	ARHGEF16
Death Receptor Signaling	1	46.4×	0.041	ARHGEF16
G alpha (12/13) signalling events	1	45.9×	0.041	ARHGEF16
Diseases of glycosylation	1	43.8×	0.041	B3GALT6
Metabolism of carbohydrates and carbohydrate derivatives	1	40.1×	0.041	B3GALT6
Diseases of metabolism	1	26.8×	0.058	B3GALT6
CDC42 GTPase cycle	1	24.1×	0.060	ARHGEF16
RHO GTPase cycle	1	20.0×	0.068	ARHGEF16
GPCR downstream signalling	1	14.5×	0.089	ARHGEF16
Signaling by GPCR	1	13.4×	0.091	ARHGEF16
Signaling by Rho GTPases	1	11.4×	0.099	ARHGEF16
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	11.2×	0.099	ARHGEF16
Disease	1	4.4×	0.231	B3GALT6
Metabolism	1	3.9×	0.247	B3GALT6
Signal Transduction	1	3.4×	0.267	ARHGEF16

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
glycosaminoglycan-protein linkage region biosynthetic process	1	1404.3×	0.012	B3GALT6
dermatan sulfate proteoglycan biosynthetic process	1	561.7×	0.012	B3GALT6
regulation of Cdc42 protein signal transduction	1	468.1×	0.012	ARHGEF16
glycosaminoglycan biosynthetic process	1	280.9×	0.012	B3GALT6
proteoglycan biosynthetic process	1	280.9×	0.012	B3GALT6
activation of GTPase activity	1	244.2×	0.012	ARHGEF16
chondroitin sulfate proteoglycan biosynthetic process	1	208.1×	0.012	B3GALT6
heparan sulfate proteoglycan biosynthetic process	1	187.2×	0.012	B3GALT6
positive regulation of immunoglobulin production	1	160.5×	0.012	TNFRSF4
T cell proliferation	1	127.7×	0.014	TNFRSF4
positive regulation of B cell proliferation	1	114.6×	0.014	TNFRSF4
positive regulation of protein localization to plasma membrane	1	90.6×	0.016	ARHGEF16
protein O-linked glycosylation	1	74.9×	0.018	B3GALT6
cell chemotaxis	1	61.7×	0.021	ARHGEF16
regulation of actin cytoskeleton organization	1	52.5×	0.023	ARHGEF16
immune response	1	15.7×	0.070	TNFRSF4
inflammatory response	1	12.6×	0.082	TNFRSF4
negative regulation of transcription by RNA polymerase II	1	5.9×	0.160	TNFRSF4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNFRSF4	0	0
ARHGEF16	0	0
B3GALT6	0	0
C1orf159	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
B3GALT6	2.4.1.134	galactosylxylosylprotein 3-beta-galactosyltransferase

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	1	B3GALT6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	TNFRSF4, ARHGEF16, C1orf159

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)
TNFRSF4	0	—
ARHGEF16	0	—
B3GALT6	0	—
C1orf159	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.