combined immunodeficiency due to RELA haploinsufficiency

Summary

combined immunodeficiency due to RELA haploinsufficiency (MONDO:0035694) is a disease caused by RELA (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RELA (GenCC Definitive)
• Cohort genes: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	combined immunodeficiency due to RELA haploinsufficiency
Mondo ID	MONDO:0035694
Orphanet	596759
UMLS	C5680288
MedGen	1843216
GARD	0022392
Is cancer (heuristic)	no

Also known as: CID due to RELA haploinsufficiency

Data availability: 1 GenCC gene-disease record.

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 RELA haploinsufficiency

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 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 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
RELA	Definitive	Autosomal dominant	combined immunodeficiency due to RELA haploinsufficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RELA	Orphanet:530792	RELA fusion-positive ependymoma
RELA	Orphanet:596759	Combined immunodeficiency due to RELA haploinsufficiency

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
RELA	HGNC:9955	ENSG00000173039	Q04206	Transcription factor p65	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RELA	Transcription factor p65	NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as infl…

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RELA	Transcription factor	no		NFkB/Dor, IPT_dom, p53-like_TF_DNA-bd_sf

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
mucosa of stomach	1
popliteal artery	1
tibial artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RELA	295	ubiquitous	marker	mucosa of stomach, popliteal artery, tibial artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RELA	8,449

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RELA	Q04206	88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 94. 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
p75NTR signals via NF-kB	1	1903.3×	0.008	RELA
CLEC7A/inflammasome pathway	1	1903.3×	0.008	RELA
DEx/H-box helicases activate type I IFN and inflammatory cytokines production	1	1631.4×	0.008	RELA
IkBA variant leads to EDA-ID	1	1631.4×	0.008	RELA
Regulation of NFE2L2 gene expression	1	1427.5×	0.008	RELA
Interleukin-1 processing	1	1268.9×	0.008	RELA
Inflammasomes	1	1142.0×	0.008	RELA
Cell recruitment (pro-inflammatory response)	1	1142.0×	0.008	RELA
ZBP1(DAI) mediated induction of type I IFNs	1	1038.2×	0.008	RELA
Regulated proteolysis of p75NTR	1	1038.2×	0.008	RELA
SUMOylation of immune response proteins	1	951.7×	0.008	RELA
NF-kB is activated and signals survival	1	878.5×	0.008	RELA
Diseases of Immune System	1	878.5×	0.008	RELA
Diseases associated with the TLR signaling cascade	1	878.5×	0.008	RELA
Downstream signaling events of B Cell Receptor (BCR)	1	815.7×	0.008	RELA
RIP-mediated NFkB activation via ZBP1	1	671.8×	0.008	RELA
The NLRP3 inflammasome	1	671.8×	0.008	RELA
CD209 (DC-SIGN) signaling	1	519.1×	0.010	RELA
TCR signaling	1	496.5×	0.010	RELA
TRAF6 mediated NF-kB activation	1	456.8×	0.010	RELA
Purinergic signaling in leishmaniasis infection	1	423.0×	0.010	RELA
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1	356.9×	0.010	RELA
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	356.9×	0.010	RELA
Signaling by the B Cell Receptor (BCR)	1	346.1×	0.010	RELA
Nuclear events mediated by NFE2L2	1	335.9×	0.010	RELA
TAK1-dependent IKK and NF-kappa-B activation	1	300.5×	0.010	RELA
Response of endothelial cells to shear stress	1	300.5×	0.010	RELA
Cytosolic sensors of pathogen-associated DNA	1	285.5×	0.010	RELA
Fc epsilon receptor (FCERI) signaling	1	271.9×	0.010	RELA
Interleukin-1 family signaling	1	271.9×	0.010	RELA

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
prolactin signaling pathway	1	8426.0×	0.004	RELA
positive regulation of miRNA metabolic process	1	5617.3×	0.004	RELA
toll-like receptor TLR6:TLR2 signaling pathway	1	4213.0×	0.004	RELA
postsynapse to nucleus signaling pathway	1	3370.4×	0.004	RELA
cellular response to peptidoglycan	1	2808.7×	0.004	RELA
cellular response to nicotine	1	2106.5×	0.004	RELA
response to UV-B	1	1872.4×	0.004	RELA
negative regulation of protein sumoylation	1	1532.0×	0.004	RELA
nucleotide-binding oligomerization domain containing 2 signaling pathway	1	1532.0×	0.004	RELA
cellular response to lipoteichoic acid	1	1532.0×	0.004	RELA
response to muramyl dipeptide	1	1404.3×	0.004	RELA
positive regulation of leukocyte adhesion to vascular endothelial cell	1	1404.3×	0.004	RELA
defense response to tumor cell	1	1296.3×	0.004	RELA
cellular response to hepatocyte growth factor stimulus	1	1123.5×	0.004	RELA
vascular endothelial growth factor signaling pathway	1	1053.2×	0.004	RELA
cellular response to interleukin-6	1	991.3×	0.004	RELA
cellular response to angiotensin	1	936.2×	0.004	RELA
positive regulation of amyloid-beta formation	1	887.0×	0.004	RELA
non-canonical NF-kappaB signal transduction	1	842.6×	0.004	RELA
interleukin-1-mediated signaling pathway	1	802.5×	0.004	RELA
response to muscle stretch	1	766.0×	0.004	RELA
negative regulation of miRNA transcription	1	624.1×	0.005	RELA
toll-like receptor 4 signaling pathway	1	526.6×	0.005	RELA
response to interleukin-1	1	510.7×	0.005	RELA
negative regulation of non-canonical NF-kappaB signal transduction	1	510.7×	0.005	RELA
positive regulation of vascular endothelial growth factor production	1	495.6×	0.005	RELA
negative regulation of cytokine production involved in inflammatory response	1	421.3×	0.006	RELA
negative regulation of extrinsic apoptotic signaling pathway	1	421.3×	0.006	RELA
positive regulation of interleukin-12 production	1	391.9×	0.006	RELA
hair follicle development	1	383.0×	0.006	RELA

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RELA	INDOPROFEN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RELA	17	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INDOPROFEN	4	RELA
VAMOROLONE	4	RELA
BORTEZOMIB	4	RELA
DEXAMETHASONE	4	RELA
SULFASALAZINE	4	RELA
GEFITINIB	4	RELA
CURCUMIN	3	RELA
RESVERATROL	3	RELA
IXAZOMIB	3	RELA
WITHANOLIDE D	3	RELA
TRIPTOLIDE	3	RELA
FRENTIZOLE	2	RELA
LAPACHONE	2	RELA
SANGUINARIUM	2	RELA
URSOLIC ACID	2	RELA
AS-602868	1	RELA
WITHAFERIN A	1	RELA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RELA	422	Binding:417, Functional:4, ADMET:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
RELA	422

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

17 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.

Compound	Max phase	Cohort target (bioactivity)
INDOPROFEN	4	RELA
VAMOROLONE	4	RELA
BORTEZOMIB	4	RELA
DEXAMETHASONE	4	RELA
SULFASALAZINE	4	RELA
GEFITINIB	4	RELA
CURCUMIN	3	RELA
RESVERATROL	3	RELA
IXAZOMIB	3	RELA
WITHANOLIDE D	3	RELA
TRIPTOLIDE	3	RELA
FRENTIZOLE	2	RELA
LAPACHONE	2	RELA
SANGUINARIUM	2	RELA
URSOLIC ACID	2	RELA
AS-602868	1	RELA
WITHAFERIN A	1	RELA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RELA
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.