Inflammatory skin and bowel disease, neonatal, 1

Summary

Inflammatory skin and bowel disease, neonatal, 1 (MONDO:0013693) is a disease caused by ADAM17 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: ADAM17 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 533

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	inflammatory skin and bowel disease, neonatal, 1
Mondo ID	MONDO:0013693
OMIM	614328
DOID	DOID:0061192
UMLS	C3280501
MedGen	482131
GARD	0018429
Is cancer (heuristic)	no

Also known as: ADAM17 neonatal inflammatory skin and bowel disease · inflammatory skin and bowel disease, neonatal, 1 · inflammatory skin and bowel disease, neonatal, type 1 · neonatal inflammatory skin and bowel disease caused by mutation in ADAM17 · NISBD1

Data availability: 533 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 › inflammatory bowel disease › neonatal inflammatory skin and bowel disease › inflammatory skin and bowel disease, neonatal, 1

Related subtypes (1): inflammatory skin and bowel disease, neonatal, 2

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

533 retrieved; paginated sample, class counts are floors:

261 likely benign, 208 uncertain significance, 23 benign, 18 pathogenic, 11 benign/likely benign, 7 likely pathogenic, 4 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1452811	NM_003183.6(ADAM17):c.1467_1468del (p.Cys489_Asp490delinsTer)	ADAM17	Pathogenic	criteria provided, single submitter
1459451	NM_003183.6(ADAM17):c.987_988dup (p.Ser330fs)	ADAM17	Pathogenic	criteria provided, single submitter
1908951	NM_003183.6(ADAM17):c.1951C>T (p.Arg651Ter)	ADAM17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2092587	NM_003183.6(ADAM17):c.619+1del	ADAM17	Pathogenic	criteria provided, single submitter
2424648	NC_000002.11:g.(?9645275)(9650280_?)del	ADAM17	Pathogenic	criteria provided, single submitter
2424649	NC_000002.11:g.(?9663358)(9666393_?)del	ADAM17	Pathogenic	criteria provided, single submitter
2745572	NM_003183.6(ADAM17):c.1305_1306del (p.Met435fs)	ADAM17	Pathogenic	criteria provided, single submitter
2767335	NC_000002.12:g.9523337_9523340del	ADAM17	Pathogenic	criteria provided, single submitter
2812323	NM_003183.6(ADAM17):c.1151del (p.Gly383_Leu384insTer)	ADAM17	Pathogenic	criteria provided, single submitter
2830713	NM_003183.6(ADAM17):c.1015dup (p.Thr339fs)	ADAM17	Pathogenic	criteria provided, single submitter
30374	NM_003183.6(ADAM17):c.603_606del (p.Asp201fs)	ADAM17	Pathogenic	no assertion criteria provided
3255337	NM_003183.6(ADAM17):c.308dup (p.Asn103fs)	ADAM17	Pathogenic	criteria provided, single submitter
3610015	NM_003183.6(ADAM17):c.631C>T (p.Arg211Ter)	ADAM17	Pathogenic	criteria provided, single submitter
3661120	NM_003183.6(ADAM17):c.1352C>G (p.Ser451Ter)	ADAM17	Pathogenic	criteria provided, single submitter
4766309	NM_003183.6(ADAM17):c.714C>A (p.Tyr238Ter)	ADAM17	Pathogenic	criteria provided, single submitter
640542	NM_003183.6(ADAM17):c.1645del (p.Thr549fs)	ADAM17	Pathogenic	criteria provided, single submitter
852789	NM_003183.6(ADAM17):c.1975_1993+4del	ADAM17	Pathogenic	criteria provided, single submitter
857427	NM_003183.6(ADAM17):c.1793dup (p.Asn598fs)	ADAM17	Pathogenic	criteria provided, single submitter
1925904	NM_003183.6(ADAM17):c.1573dup (p.Cys525fs)	IAH1	Pathogenic	criteria provided, single submitter
1705353	NM_003183.6(ADAM17):c.1344+1G>A	ADAM17	Likely pathogenic	criteria provided, single submitter
2101430	NM_003183.6(ADAM17):c.1544+2T>C	ADAM17	Likely pathogenic	criteria provided, single submitter
2831726	NM_003183.6(ADAM17):c.1344+1G>T	ADAM17	Likely pathogenic	criteria provided, single submitter
2853995	NM_003183.6(ADAM17):c.361+1G>C	ADAM17	Likely pathogenic	criteria provided, single submitter
4291994	NM_003183.6(ADAM17):c.1930C>T (p.Arg644Ter)	ADAM17	Likely pathogenic	criteria provided, single submitter
4293786	NM_003183.6(ADAM17):c.769dup (p.Arg257fs)	ADAM17	Likely pathogenic	criteria provided, single submitter
4720642	NM_003183.6(ADAM17):c.843+1G>A	ADAM17	Likely pathogenic	criteria provided, single submitter
1033978	NM_003183.6(ADAM17):c.362-11T>C	ADAM17	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1432565	NM_003183.6(ADAM17):c.42C>A (p.Phe14Leu)	ADAM17	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
738562	NM_003183.6(ADAM17):c.1545-7_1545-5del	ADAM17	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
997097	NM_003183.6(ADAM17):c.851T>C (p.Ile284Thr)	ADAM17	Conflicting classifications of pathogenicity	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
ADAM17	Definitive	Autosomal recessive	inflammatory skin and bowel disease, neonatal, 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADAM17	Orphanet:294023	Neonatal erythroderma-autoinflammation-inflammatory bowel disease syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ADAM17	HGNC:195	ENSG00000151694	P78536	Disintegrin and metalloproteinase domain-containing protein 17	gencc,clinvar
IAH1	HGNC:27696	ENSG00000134330	Q2TAA2	Isoamyl acetate-hydrolyzing esterase 1 homolog	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADAM17	Disintegrin and metalloproteinase domain-containing protein 17	Transmembrane metalloprotease which mediates the ectodomain shedding of a myriad of transmembrane proteins including adhesion proteins, growth factor precursors and cytokines important for inflammation and immunity.
IAH1	Isoamyl acetate-hydrolyzing esterase 1 homolog	Probable lipase.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Protease	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADAM17	Protease	yes	3.4.24.86	Peptidase_M12B, Disintegrin_dom, MetalloPept_cat_dom_sf
IAH1	Other/Unknown	no		GDSL, SGNH_hydro_sf, Iah1-like

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	2
adrenal tissue	1
calcaneal tendon	1
pericardium	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADAM17	294	ubiquitous	marker	oocyte, adrenal tissue, calcaneal tendon
IAH1	256	ubiquitous	marker	secondary oocyte, oocyte, pericardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADAM17	3,140
IAH1	1,055

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ADAM17	P78536	33

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IAH1	Q2TAA2	93.67

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 38. Enrichment computed across 2 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
Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	2855.0×	0.006	ADAM17
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	1631.4×	0.006	ADAM17
Release of Hh-Np from the secreting cell	1	1427.5×	0.006	ADAM17
Signaling by NOTCH1 HD Domain Mutants in Cancer	1	1268.9×	0.006	ADAM17
CD163 mediating an anti-inflammatory response	1	1142.0×	0.006	ADAM17
Regulated proteolysis of p75NTR	1	1038.2×	0.006	ADAM17
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	761.3×	0.006	ADAM17
Growth hormone receptor signaling	1	475.8×	0.006	ADAM17
TNF signaling	1	423.0×	0.006	ADAM17
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	407.9×	0.006	ADAM17
Signaling by NOTCH1 in Cancer	1	407.9×	0.006	ADAM17
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	407.9×	0.006	ADAM17
Anti-inflammatory response favouring Leishmania parasite infection	1	393.8×	0.006	ADAM17
Leishmania parasite growth and survival	1	393.8×	0.006	ADAM17
Signaling by NOTCH1	1	356.9×	0.006	ADAM17
Activated NOTCH1 Transmits Signal to the Nucleus	1	356.9×	0.006	ADAM17
Nuclear signaling by ERBB4	1	346.1×	0.006	ADAM17
Signaling by EGFR	1	326.3×	0.006	ADAM17
Signaling by ERBB4	1	271.9×	0.007	ADAM17
Hedgehog ligand biogenesis	1	211.5×	0.008	ADAM17
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	196.9×	0.008	ADAM17
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	196.9×	0.008	ADAM17
p75 NTR receptor-mediated signalling	1	187.2×	0.008	ADAM17
Signaling by Hedgehog	1	184.2×	0.008	ADAM17
Collagen degradation	1	175.7×	0.008	ADAM17
Signaling by NOTCH	1	175.7×	0.008	ADAM17
Leishmania infection	1	163.1×	0.008	ADAM17
Parasitic Infection Pathways	1	163.1×	0.008	ADAM17
Death Receptor Signaling	1	139.3×	0.009	ADAM17
Degradation of the extracellular matrix	1	117.7×	0.011	ADAM17

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of mast cell apoptotic process	1	8426.0×	0.006	ADAM17
signal release	1	2808.7×	0.006	ADAM17
cellular response to high density lipoprotein particle stimulus	1	2808.7×	0.006	ADAM17
cytokine precursor processing	1	1685.2×	0.006	ADAM17
production of molecular mediator involved in inflammatory response	1	1203.7×	0.006	ADAM17
regulation of axon regeneration	1	1203.7×	0.006	ADAM17
Notch receptor processing	1	936.2×	0.006	ADAM17
germinal center formation	1	842.6×	0.006	ADAM17
ERBB2-EGFR signaling pathway	1	842.6×	0.006	ADAM17
neutrophil mediated immunity	1	702.2×	0.006	ADAM17
positive regulation of leukocyte chemotaxis	1	648.1×	0.006	ADAM17
amyloid precursor protein catabolic process	1	601.9×	0.006	ADAM17
positive regulation of T cell chemotaxis	1	561.7×	0.006	ADAM17
wound healing, spreading of epidermal cells	1	526.6×	0.006	ADAM17
positive regulation of tumor necrosis factor-mediated signaling pathway	1	526.6×	0.006	ADAM17
commissural neuron axon guidance	1	495.6×	0.006	ADAM17
positive regulation of vascular endothelial cell proliferation	1	421.3×	0.007	ADAM17
cell adhesion mediated by integrin	1	337.0×	0.008	ADAM17
membrane protein ectodomain proteolysis	1	324.1×	0.008	ADAM17
regulation of neuron migration	1	312.1×	0.008	ADAM17
positive regulation of epidermal growth factor receptor signaling pathway	1	247.8×	0.009	ADAM17
T cell differentiation in thymus	1	205.5×	0.009	ADAM17
spleen development	1	200.6×	0.009	ADAM17
cell motility	1	200.6×	0.009	ADAM17
positive regulation of G1/S transition of mitotic cell cycle	1	200.6×	0.009	ADAM17
positive regulation of blood vessel endothelial cell migration	1	195.9×	0.009	ADAM17
positive regulation of chemokine production	1	187.2×	0.009	ADAM17
negative regulation of cold-induced thermogenesis	1	172.0×	0.010	ADAM17
epidermal growth factor receptor signaling pathway	1	123.9×	0.013	ADAM17
lipid catabolic process	1	122.1×	0.013	IAH1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
ADAM17	PREDNISOLONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADAM17	8	4
IAH1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PREDNISOLONE	4	ADAM17
MARIMASTAT	3	ADAM17
PRINOMASTAT	3	ADAM17
CIPEMASTAT	2	ADAM17
ILOMASTAT	2	ADAM17
APRATASTAT	2	ADAM17
BATIMASTAT	2	ADAM17
CTS-1027	2	ADAM17

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ADAM17	288	Binding:257, Functional:25, ADMET:5, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADAM17	3.4.24.86	ADAM 17 endopeptidase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ADAM17	288

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

8 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)
PREDNISOLONE	4	ADAM17
MARIMASTAT	3	ADAM17
PRINOMASTAT	3	ADAM17
CIPEMASTAT	2	ADAM17
ILOMASTAT	2	ADAM17
APRATASTAT	2	ADAM17
BATIMASTAT	2	ADAM17
CTS-1027	2	ADAM17

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ADAM17
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	IAH1

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)
IAH1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.