IL10-related early-onset inflammatory bowel disease

Summary

IL10-related early-onset inflammatory bowel disease (MONDO:0016542) is a disease caused by IL10 (GenCC Strong), with 5 cohort genes. The dominant Reactome pathway is Interleukin-10 signaling (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IL10 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		80	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	IL10-related early-onset inflammatory bowel disease
Mondo ID	MONDO:0016542
Orphanet	238569
UMLS	C4749850
MedGen	1661450
GARD	0013016
Is cancer (heuristic)	no

Also known as: autosomal recessive early-onset IBD · autosomal recessive early-onset inflammatory bowel disease · IL10-related early-onset IBD · IL10-related early-onset inflammatory bowel disease · immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome

Data availability: 9 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › IL10-related early-onset inflammatory bowel disease

Related subtypes (40): B cell deficiency, complement deficiency, phagocyte bactericidal dysfunction, trichohepatoenteric syndrome, hepatic veno-occlusive disease-immunodeficiency syndrome, immunodeficiency with defective T-cell response to interleukin 1, Say-Barber-Miller syndrome, familial isolated congenital asplenia, X-linked immunoneurologic disorder, ectodermal dysplasia and immune deficiency, immunodeficiency 33, immunodeficiency 47, combined immunodeficiency due to moesin deficiency, immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein, properdin deficiency, X-linked, combined immunodeficiency with faciooculoskeletal anomalies, recurrent infections associated with rare immunoglobulin isotypes deficiency, immunodeficiency 28, autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity, immunodeficiency 37, immunodeficiency 39, BENTA disease, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, immunodeficiency 49, chronic mucocutaneous candidiasis, hereditary hemophagocytic lymphohistiocytosis, immunoglobulin heavy chain deficiency, immuno-osseous dysplasia, lymphoproliferative syndrome, T-cell immunodeficiency with epidermodysplasia verruciformis, Aicardi-Goutieres syndrome, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, inflammatory bowel disease-recurrent sinopulmonary infections syndrome, A20 haploinsufficiency, NK cell deficiency, T cell and NK cell immunodeficiency, dendritic cell deficiency, immunodysregulation with variable immunodeficiency and autoimmunity, immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency, STAT5 haploinsufficiency

Subtypes (2): inflammatory bowel disease 25, inflammatory bowel disease 28

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

9 retrieved; paginated sample, class counts are floors:

3 likely pathogenic, 2 uncertain significance, 2 pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
598789	NM_001354930.2(RIPK1):c.1278C>A (p.Tyr426Ter)	RIPK1	Pathogenic	no assertion criteria provided
598790	NM_001354930.2(RIPK1):c.954del (p.Met318fs)	RIPK1	Pathogenic/Likely pathogenic	no assertion criteria provided
598791	NM_001354930.2(RIPK1):c.1802G>A (p.Cys601Tyr)	RIPK1	Pathogenic	no assertion criteria provided
487577	NM_000660.7(TGFB1):c.133C>T (p.Arg45Cys)	LOC130064510	Likely pathogenic	criteria provided, single submitter
488345	NM_000660.7(TGFB1):c.328C>T (p.Arg110Cys)	LOC130064510	Likely pathogenic	criteria provided, single submitter
488346	NM_000660.7(TGFB1):c.1159T>C (p.Cys387Arg)	TGFB1	Likely pathogenic	criteria provided, single submitter
598788	NM_001354930.2(RIPK1):c.1934C>T (p.Thr645Met)	RIPK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1525940	NM_000572.3(IL10):c.323A>G (p.His108Arg)	IL10	Uncertain significance	criteria provided, single submitter
598787	NM_001354930.2(RIPK1):c.1844T>C (p.Ile615Thr)	RIPK1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 9 · 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
IL10	Strong	Autosomal recessive	IL10-related early-onset inflammatory bowel disease	5
IL10RA	Strong	Autosomal recessive	inflammatory bowel disease 28	4
IL10RB	Strong	Autosomal recessive	inflammatory bowel disease 25	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IL10	Orphanet:117	Behçet disease
IL10	Orphanet:238569	Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome
IL10	Orphanet:536	Systemic lupus erythematosus
IL10RA	Orphanet:238569	Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome
IL10RB	Orphanet:238569	Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome
RIPK1	Orphanet:529977	Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome
TGFB1	Orphanet:1328	Camurati-Engelmann disease
TGFB1	Orphanet:565788	Infantile inflammatory bowel disease with neurological involvement
TGFB1	Orphanet:586	Cystic fibrosis

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IL10	HGNC:5962	ENSG00000136634	P22301	Interleukin-10	gencc,clinvar
IL10RA	HGNC:5964	ENSG00000110324	Q13651	Interleukin-10 receptor subunit alpha	gencc
IL10RB	HGNC:5965	ENSG00000243646	Q08334	Interleukin-10 receptor subunit beta	gencc
RIPK1	HGNC:10019	ENSG00000137275	Q13546	Receptor-interacting serine/threonine-protein kinase 1	clinvar
TGFB1	HGNC:11766	ENSG00000105329	P01137	Transforming growth factor beta-1 proprotein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL10	Interleukin-10	Major immune regulatory cytokine that acts on many cells of the immune system where it has profound anti-inflammatory functions, limiting excessive tissue disruption caused by inflammation.
IL10RA	Interleukin-10 receptor subunit alpha	Cell surface receptor for the cytokine IL10 that participates in IL10-mediated anti-inflammatory functions, limiting excessive tissue disruption caused by inflammation.
IL10RB	Interleukin-10 receptor subunit beta	Shared cell surface receptor required for the activation of five class 2 cytokines: IL10, IL22, IL26, IL28, and IFNL1.
RIPK1	Receptor-interacting serine/threonine-protein kinase 1	Serine-threonine kinase which is a key regulator of TNF-mediated apoptosis, necroptosis and inflammatory pathways.
TGFB1	Transforming growth factor beta-1 proprotein	Transforming growth factor beta-1 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of TGF-beta-1, respectively.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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
Antibody/Immunoglobulin	2	11.7×	0.033
Kinase	1	5.5×	0.252
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IL10	Other/Unknown	no		IL-10, 4_helix_cytokine-like_core, IL-10_CS
IL10RA	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, FN3_sf
IL10RB	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, Interferon/interleukin_rcp_dom
RIPK1	Kinase	yes	2.7.10.2	Death_dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
TGFB1	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGFb1

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	3
leukocyte	3
monocyte	2
cartilage tissue	1
gall bladder	1
vermiform appendix	1
mononuclear cell	1
placenta	1
right lobe of liver	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IL10	158	broad	marker	vermiform appendix, gall bladder, cartilage tissue
IL10RA	234	broad	marker	granulocyte, leukocyte, mononuclear cell
IL10RB	142	ubiquitous	marker	placenta, monocyte, leukocyte
RIPK1	238	ubiquitous	marker	granulocyte, sural nerve, right lobe of liver
TGFB1	204	ubiquitous	marker	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TGFB1	7,596
IL10	6,185
RIPK1	4,129
IL10RA	2,462
IL10RB	1,554

Intra-cohort edges

A	B	Sources
IL10	IL10RA	biogrid_interaction, intact, string_interaction
IL10	IL10RB	intact, string_interaction
IL10RA	IL10RB	biogrid_interaction, string_interaction

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RIPK1	Q13546	39
TGFB1	P01137	20
IL10	P22301	9
IL10RA	Q13651	7
IL10RB	Q08334	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 84. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-10 signaling	3	139.8×	6e-05	IL10, IL10RA, IL10RB
Influenza Virus Induced Apoptosis	1	1142.0×	0.014	TGFB1
TGFBR2 MSI Frameshift Mutants in Cancer	1	1142.0×	0.014	TGFB1
Loss of Function of TGFBR2 in Cancer	1	761.3×	0.014	TGFB1
TGFBR2 Kinase Domain Mutants in Cancer	1	761.3×	0.014	TGFB1
SARS-CoV-1-mediated effects on programmed cell death	1	761.3×	0.014	RIPK1
TGFBR1 LBD Mutants in Cancer	1	571.0×	0.014	TGFB1
Microbial modulation of RIPK1-mediated regulated necrosis	1	571.0×	0.014	RIPK1
Loss of Function of TGFBR1 in Cancer	1	456.8×	0.014	TGFB1
Loss of Function of SMAD2/3 in Cancer	1	380.7×	0.014	TGFB1
Signaling by TGF-beta Receptor Complex in Cancer	1	380.7×	0.014	TGFB1
SMAD2/3 Phosphorylation Motif Mutants in Cancer	1	380.7×	0.014	TGFB1
TGFBR1 KD Mutants in Cancer	1	380.7×	0.014	TGFB1
TLR3-mediated TICAM1-dependent programmed cell death	1	380.7×	0.014	RIPK1
Defective RIPK1-mediated regulated necrosis	1	380.7×	0.014	RIPK1
Interleukin-4 and Interleukin-13 signaling	2	41.1×	0.014	IL10, TGFB1
RUNX3 regulates CDKN1A transcription	1	326.3×	0.015	TGFB1
TGFBR3 regulates TGF-beta signaling	1	285.5×	0.016	TGFB1
TRIF-mediated programmed cell death	1	253.8×	0.017	RIPK1
RUNX3 regulates p14-ARF	1	228.4×	0.017	TGFB1
CD163 mediating an anti-inflammatory response	1	228.4×	0.017	IL10
Regulation by c-FLIP	1	207.6×	0.017	RIPK1
CASP8 activity is inhibited	1	207.6×	0.017	RIPK1
Dimerization of procaspase-8	1	207.6×	0.017	RIPK1
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	175.7×	0.019	RIPK1
Caspase activation via Death Receptors in the presence of ligand	1	152.3×	0.021	RIPK1
Dengue virus modulates apoptosis	1	142.8×	0.021	RIPK1
RIP-mediated NFkB activation via ZBP1	1	134.3×	0.021	RIPK1
TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)	1	134.3×	0.021	TGFB1
TICAM1, RIP1-mediated IKK complex recruitment	1	120.2×	0.023	RIPK1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
interleukin-10-mediated signaling pathway	3	842.6×	8e-07	IL10, IL10RA, IL10RB
positive regulation of receptor signaling pathway via JAK-STAT	3	259.3×	2e-05	IL10, IL10RA, IL10RB
regulation of synapse organization	2	259.3×	0.002	IL10, IL10RA
liver regeneration	2	204.3×	0.003	IL10, TGFB1
columnar/cuboidal epithelial cell maturation	1	3370.4×	0.004	TGFB1
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1	3370.4×	0.004	TGFB1
negative regulation of chronic inflammatory response to antigenic stimulus	1	3370.4×	0.004	IL10
positive regulation of microglia differentiation	1	3370.4×	0.004	TGFB1
regulation of interleukin-23 production	1	3370.4×	0.004	TGFB1
negative regulation of cytokine activity	1	3370.4×	0.004	IL10
branch elongation involved in mammary gland duct branching	1	3370.4×	0.004	TGFB1
ripoptosome assembly	1	3370.4×	0.004	RIPK1
regulation of response to wounding	1	3370.4×	0.004	IL10
positive regulation of miRNA processing	1	3370.4×	0.004	RIPK1
negative regulation of T cell proliferation	2	132.2×	0.004	IL10, TGFB1
extrinsic apoptotic signaling pathway	2	122.6×	0.004	RIPK1, TGFB1
positive regulation of miRNA transcription	2	116.2×	0.004	IL10, TGFB1
negative regulation of autophagy	2	103.7×	0.004	IL10, IL10RA
cellular response to virus	2	80.2×	0.004	TGFB1, IL10RB
positive regulation of tumor necrosis factor production	2	61.3×	0.006	RIPK1, TGFB1
chronic inflammatory response to antigenic stimulus	1	1685.2×	0.006	IL10
negative regulation of interleukin-18 production	1	1685.2×	0.006	IL10
embryonic liver development	1	1685.2×	0.006	TGFB1
positive regulation of primary miRNA processing	1	1685.2×	0.006	TGFB1
positive regulation of inflammatory response	2	58.1×	0.006	RIPK1, TGFB1
negative regulation of inflammatory response	2	54.8×	0.006	IL10, IL10RA
cytokine-mediated signaling pathway	2	52.2×	0.006	IL10RA, IL10RB
negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target	1	1123.5×	0.007	TGFB1
response to inactivity	1	1123.5×	0.007	IL10
response to carbon monoxide	1	1123.5×	0.007	IL10

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 3

Druggability breadth: 5 of 5 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
RIPK1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RIPK1	24	4
TGFB1	1	2
IL10	0	0
IL10RA	0	0
IL10RB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	RIPK1
FEDRATINIB	4	RIPK1
AXITINIB	4	RIPK1
SORAFENIB	4	RIPK1
DABRAFENIB	4	RIPK1
PAZOPANIB	4	RIPK1
NINTEDANIB	4	RIPK1
SUNITINIB	4	RIPK1
QUIZARTINIB	4	RIPK1
CRIZOTINIB	4	RIPK1
LINIFANIB	3	RIPK1
DOVITINIB	3	RIPK1
FORETINIB	2	RIPK1
SU-014813	2	RIPK1
REBASTINIB	2	RIPK1
FEXAGRATINIB	2	RIPK1
GSK2982772	2	RIPK1
ECLITASERTIB	2	RIPK1
FLIZASERTIB	2	RIPK1
OCADUSERTIB	2	RIPK1
RAF-265	2	RIPK1
TOZASERTIB	2	RIPK1
VACTOSERTIB	2	TGFB1
KW-2449	1	RIPK1
AST-487	1	RIPK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RIPK1	400	Binding:391, ADMET:7, Functional:2
TGFB1	9	Binding:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RIPK1	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RIPK1	400

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

25 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)
PONATINIB	4	RIPK1
FEDRATINIB	4	RIPK1
AXITINIB	4	RIPK1
SORAFENIB	4	RIPK1
DABRAFENIB	4	RIPK1
PAZOPANIB	4	RIPK1
NINTEDANIB	4	RIPK1
SUNITINIB	4	RIPK1
QUIZARTINIB	4	RIPK1
CRIZOTINIB	4	RIPK1
LINIFANIB	3	RIPK1
DOVITINIB	3	RIPK1
FORETINIB	2	RIPK1
SU-014813	2	RIPK1
REBASTINIB	2	RIPK1
FEXAGRATINIB	2	RIPK1
GSK2982772	2	RIPK1
ECLITASERTIB	2	RIPK1
FLIZASERTIB	2	RIPK1
OCADUSERTIB	2	RIPK1
RAF-265	2	RIPK1
TOZASERTIB	2	RIPK1
VACTOSERTIB	2	TGFB1
KW-2449	1	RIPK1
AST-487	1	RIPK1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RIPK1
B	Phased (≥1) drug, not yet approved	1	TGFB1
C	Druggable family + PDB, no drug	2	IL10RA, IL10RB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	IL10

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)
IL10	0	—
IL10RA	0	—
IL10RB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.