Hirschsprung disease, susceptibility to, 4

Summary

Hirschsprung disease, susceptibility to, 4 (MONDO:0013384) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 70

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Hirschsprung disease, susceptibility to, 4
Mondo ID	MONDO:0013384
OMIM	613712
UMLS	C3150975
MedGen	462325
Is cancer (heuristic)	no

Also known as: EDN3 Hirschsprung disease · Hirschsprung disease caused by mutation in EDN3 · Hirschsprung disease, susceptibility to, 4 · Hirschsprung disease, susceptibility to, type 4 · HSCR4

Data availability: 70 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › Hirschsprung disease, susceptibility to › Hirschsprung disease, susceptibility to, 4

Related subtypes (8): Hirschsprung disease, susceptibility to, 1, Hirschsprung disease, susceptibility to, 2, Hirschsprung disease, susceptibility to, 5, Hirschsprung disease, susceptibility to, 6, Hirschsprung disease, susceptibility to, 7, Hirschsprung disease, susceptibility to, 8, Hirschsprung disease, susceptibility to, 9, Hirschsprung disease, susceptibility to, 3

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

70 retrieved; paginated sample, class counts are floors:

45 uncertain significance, 11 likely benign, 9 benign, 2 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
16648	NM_207034.3(EDN3):c.262dup (p.Ala88fs)	EDN3	risk factor	no assertion criteria provided
16646	NM_207034.3(EDN3):c.49G>A (p.Ala17Thr)	EDN3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
339123	NM_207034.3(EDN3):c.293C>A (p.Thr98Lys)	EDN3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1803101	NM_207034.3(EDN3):c.377C>G (p.Pro126Arg)	EDN3	Uncertain significance	criteria provided, single submitter
339116	NM_207034.3(EDN3):c.-164G>A	EDN3	Uncertain significance	criteria provided, single submitter
339117	NM_207034.3(EDN3):c.-120C>T	EDN3	Uncertain significance	criteria provided, single submitter
339118	NM_207034.3(EDN3):c.-85G>A	EDN3	Uncertain significance	criteria provided, single submitter
339121	NM_207034.3(EDN3):c.43T>G (p.Ser15Ala)	EDN3	Uncertain significance	criteria provided, multiple submitters, no conflicts
339122	NM_207034.3(EDN3):c.257A>G (p.Glu86Gly)	EDN3	Uncertain significance	criteria provided, single submitter
339125	NM_207034.3(EDN3):c.543-7C>T	EDN3	Uncertain significance	criteria provided, single submitter
339126	NM_207034.3(EDN3):c.688C>T (p.Arg230Cys)	EDN3	Uncertain significance	criteria provided, multiple submitters, no conflicts
339127	NM_207034.3(EDN3):c.689G>A (p.Arg230His)	EDN3	Uncertain significance	criteria provided, multiple submitters, no conflicts
339129	NM_207034.3(EDN3):c.*96G>A	EDN3	Uncertain significance	criteria provided, single submitter
339135	NM_207034.3(EDN3):c.*143C>T	EDN3	Uncertain significance	criteria provided, single submitter
339136	NM_207034.3(EDN3):c.*144C>T	EDN3	Uncertain significance	criteria provided, single submitter
339137	NM_207034.3(EDN3):c.*145C>A	EDN3	Uncertain significance	criteria provided, single submitter
339139	NM_207034.3(EDN3):c.*147C>G	EDN3	Uncertain significance	criteria provided, single submitter
339144	NM_207034.3(EDN3):c.*571A>G	EDN3	Uncertain significance	criteria provided, single submitter
339145	NM_207034.3(EDN3):c.*585C>T	EDN3	Uncertain significance	criteria provided, single submitter
339146	NM_207034.3(EDN3):c.*586G>A	EDN3	Uncertain significance	criteria provided, single submitter
339148	NM_207034.3(EDN3):c.*679A>G	EDN3	Uncertain significance	criteria provided, single submitter
339149	NM_207034.3(EDN3):c.*756C>T	EDN3	Uncertain significance	criteria provided, single submitter
339152	NM_207034.3(EDN3):c.*904A>G	EDN3	Uncertain significance	criteria provided, single submitter
339157	NM_207034.3(EDN3):c.*1111G>A	EDN3	Uncertain significance	criteria provided, single submitter
339158	NM_207034.3(EDN3):c.*1147A>G	EDN3	Uncertain significance	criteria provided, single submitter
339159	NM_207034.3(EDN3):c.*1255C>T	EDN3	Uncertain significance	criteria provided, single submitter
339160	NM_207034.3(EDN3):c.*1271A>G	EDN3	Uncertain significance	criteria provided, single submitter
339162	NM_207034.3(EDN3):c.*1398C>T	EDN3	Uncertain significance	criteria provided, single submitter
3892384	NM_207034.3(EDN3):c.646A>C (p.Met216Leu)	EDN3	Uncertain significance	criteria provided, single submitter
523332	NM_207034.3(EDN3):c.143AGACTGTGGCTGGCCCTGGCGAGG[3] (p.48ETVAGPGE[3])	EDN3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · 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
EDN3	Limited	Autosomal dominant	Hirschsprung disease, susceptibility to, 4	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EDN3	Orphanet:388	Hirschsprung disease
EDN3	Orphanet:661	Congenital central hypoventilation syndrome
EDN3	Orphanet:897	Waardenburg-Shah syndrome

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
EDN3	HGNC:3178	ENSG00000124205	P14138	Endothelin-3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EDN3	Endothelin-3	Endothelins are endothelium-derived vasoconstrictor peptides.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EDN3	Other/Unknown	no		Endothln-like_toxin, Endothelin_toxin_CS, Endothelin

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
jejunal mucosa	1
penis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EDN3	175	broad	marker	penis, jejunal mucosa, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EDN3	1,376

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EDN3	P14138	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.017	EDN3
Peptide ligand-binding receptors	1	74.2×	0.017	EDN3
G alpha (q) signalling events	1	57.4×	0.017	EDN3

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
regulation of developmental pigmentation	1	5617.3×	0.002	EDN3
vein smooth muscle contraction	1	4213.0×	0.002	EDN3
regulation of systemic arterial blood pressure by endothelin	1	2808.7×	0.002	EDN3
intracellular magnesium ion homeostasis	1	2808.7×	0.002	EDN3
peptide hormone secretion	1	2808.7×	0.002	EDN3
positive regulation of hormone secretion	1	1685.2×	0.003	EDN3
positive regulation of leukocyte chemotaxis	1	1296.3×	0.003	EDN3
positive regulation of potassium ion transmembrane transport	1	991.3×	0.003	EDN3
positive regulation of smooth muscle contraction	1	936.2×	0.003	EDN3
vasoconstriction	1	887.0×	0.003	EDN3
regulation of vasoconstriction	1	802.5×	0.003	EDN3
melanocyte differentiation	1	802.5×	0.003	EDN3
positive regulation of heart rate	1	702.2×	0.003	EDN3
positive regulation of mitotic nuclear division	1	543.6×	0.004	EDN3
blood circulation	1	510.7×	0.004	EDN3
axon extension	1	495.6×	0.004	EDN3
neural crest cell migration	1	337.0×	0.005	EDN3
neutrophil chemotaxis	1	285.6×	0.006	EDN3
positive regulation of cell differentiation	1	267.5×	0.006	EDN3
establishment of localization in cell	1	160.5×	0.009	EDN3
intracellular calcium ion homeostasis	1	145.3×	0.010	EDN3
potassium ion transmembrane transport	1	135.9×	0.010	EDN3
cell population proliferation	1	102.8×	0.013	EDN3
axon guidance	1	90.6×	0.014	EDN3
regulation of gene expression	1	83.4×	0.014	EDN3
positive regulation of MAPK cascade	1	80.6×	0.014	EDN3
cell-cell signaling	1	69.6×	0.016	EDN3
cell surface receptor signaling pathway	1	64.1×	0.017	EDN3
positive regulation of cell population proliferation	1	33.6×	0.031	EDN3
signal transduction	1	16.1×	0.062	EDN3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EDN3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	EDN3

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)
EDN3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.