EDN3

Summary

EDN3 (endothelin 3, HGNC:3178) is a protein-coding gene on chromosome 20q13.32, encoding Endothelin-3 (P14138). Endothelins are endothelium-derived vasoconstrictor peptides.

The protein encoded by this gene is a member of the endothelin family. Endothelins are endothelium-derived vasoactive peptides involved in a variety of biological functions. The active form of this protein is a 21 amino acid peptide processed from the precursor protein. The active peptide is a ligand for endothelin receptor type B (EDNRB). The interaction of this endothelin with EDNRB is essential for development of neural crest-derived cell lineages, such as melanocytes and enteric neurons. Mutations in this gene and EDNRB have been associated with Hirschsprung disease (HSCR) and Waardenburg syndrome (WS), which are congenital disorders involving neural crest-derived cells. Altered expression of this gene is implicated in tumorigenesis. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 1908 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Waardenburg syndrome type 4B (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 16
• Clinical variants (ClinVar): 199 total — 5 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 54
• MANE Select transcript: NM_207034

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3178
Approved symbol	EDN3
Name	endothelin 3
Location	20q13.32
Locus type	gene with protein product
Status	Approved
Aliases	ET3
Ensembl gene	ENSG00000124205
Ensembl biotype	protein_coding
OMIM	131242
Entrez	1908

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 retained_intron

ENST00000311585, ENST00000337938, ENST00000371025, ENST00000371028, ENST00000395654, ENST00000644821, ENST00000671744, ENST00000672969, ENST00000867055, ENST00000867056

RefSeq mRNA: 8 — MANE Select: NM_207034 NM_001302455, NM_001302456, NM_001424361, NM_001424362, NM_001424363, NM_207032, NM_207033, NM_207034

CCDS: CCDS13477, CCDS13478, CCDS13479, CCDS77597

Canonical transcript exons

ENST00000337938 — 5 exons

Exon	Start	End
ENSE00000845872	59300611	59300864
ENSE00000845873	59301410	59301722
ENSE00000845874	59321017	59321193
ENSE00001352266	59322372	59322417
ENSE00003676907	59324331	59325992

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 92.61.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3467 / max 305.3100, expressed in 225 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185621	0.6166	134
185616	0.2997	93
185620	0.2200	84
185615	0.0741	29
185617	0.0484	15
185619	0.0265	13
209182	0.0237	11
185622	0.0170	9
185623	0.0116	7
185618	0.0090	3

Top tissues by expression

283 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
penis	UBERON:0000989	92.61	gold quality
jejunal mucosa	UBERON:0000399	91.97	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.65	gold quality
islet of Langerhans	UBERON:0000006	89.53	gold quality
duodenum	UBERON:0002114	89.46	gold quality
mammalian vulva	UBERON:0000997	88.98	gold quality
cervix squamous epithelium	UBERON:0006922	87.47	silver quality
ileal mucosa	UBERON:0000331	87.44	gold quality
rectum	UBERON:0001052	86.35	gold quality
parotid gland	UBERON:0001831	85.78	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.77	gold quality
mucosa of transverse colon	UBERON:0004991	85.46	gold quality
vagina	UBERON:0000996	85.42	gold quality
colonic mucosa	UBERON:0000317	85.31	gold quality
right lobe of thyroid gland	UBERON:0001119	84.97	gold quality
lower esophagus mucosa	UBERON:0035834	84.91	gold quality
thyroid gland	UBERON:0002046	84.57	gold quality
left lobe of thyroid gland	UBERON:0001120	84.31	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.95	gold quality
cervix epithelium	UBERON:0004801	83.95	silver quality
small intestine	UBERON:0002108	83.75	gold quality
mucosa of sigmoid colon	UBERON:0004993	83.45	gold quality
esophagus mucosa	UBERON:0002469	83.02	gold quality
saliva-secreting gland	UBERON:0001044	82.86	gold quality
transverse colon	UBERON:0001157	81.81	gold quality
minor salivary gland	UBERON:0001830	81.10	gold quality
pancreas	UBERON:0001264	79.96	gold quality
esophagus	UBERON:0001043	78.97	gold quality
body of pancreas	UBERON:0001150	77.39	gold quality
intestine	UBERON:0000160	77.24	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-ENAD-27	yes	495.86
E-GEOD-135922	yes	60.45
E-GEOD-81547	yes	11.77
E-MTAB-5061	yes	11.53
E-ANND-3	yes	4.31

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CTNNB1, ESR1, NFKB

Literature-anchored findings (GeneRIF, showing 29)

• Mutations are found in Hirschsprung’s disease in a Chinese population. (PMID:14669347)
• KEL6 red blood cells have endothelin-3-converting enzyme activity (PMID:16423827)
• neither polymorphism nor mutation was observed in EDN3 in Chinese Hirschprung disease patients (PMID:17554617)
• Endothelin-3 molecule is specifically upregulated in metastatic melanoma cells, showing that an abnormal autocrine stimulation pathway involving ET-3 is present in metastatic melanoma cells. (PMID:18346402)
• Endothelin signaling axis activates osteopontin expression through PI3 kinase pathway in A375 melanoma cells. (PMID:18722093)
• ET3 induced activation of IkappaB & MAPK in epithelial cells. ET3 is involved in regulating human colonic epithelial cell proliferation & survival, particularly for goblet cells. (PMID:18832450)
• In conclusion, Multiplex Ligation-dependent Probe Amplification assessment of rearrangements in the RET proto-oncogene and in 3 other associated genes, ZEB2, EDN3 and GDNF did not show any variants in 80 sporadic Hirschsprung disease patients. (PMID:19183406)
• EDN3, in contrast to EDN1 and EDN2, may act as natural tumour suppressor in the human mammary gland (PMID:19527488)
• Finding suggest that mutations in RET and NTRK3 acting together are necessary and sufficient for the appearance of Hirschsprung disease and that the EDN3 mutation acts as a phenotype modifier. (PMID:19556619)
• Report on spanish cases of Waardenburg syndrome type 4 with novel mutations in EDN3 and SOX 10 genes. (PMID:19764030)
• EDN3 may be considered as a common susceptibility gene for sporadic Hirschsprung disease in a low-penetrance fashion. (PMID:20009762)
• ET-1 and the ET-1/ET-3 ratio are elevated in cirrhotic patients with portopulmonary hypertension (PPHT) and that ET-1 is associated with a poor outcome irrespective of PPHT. (PMID:21813388)
• These data suggest that autocrine EDN3/EDNRB signaling is essential for maintaining GSCs. Incorporating END3/EDNRB-targeted therapies into conventional cancer treatments may have clinical implication for the prevention of tumor recurrence. (PMID:22013079)
• Studies revealed hypermethylation of EDN2 and EDN3 genes in human primary colon cancers and in a panel of human colon cancer cell lines. Epigenetic inactivation of ET-2 and ET-3 occurs frequently in both rat and human colon cancers. (PMID:22865632)
• A novel missense mutation in EDN3 and a deletion mutation in DMD has been found in the same Indian family members affected with Waardenburg syndrome and Duchenne muscular dystrophy. (PMID:22876130)
• plasma levels of big ET-2, and big ET-3 are markedly increased in patients with end stage renal disease on hemodialysis (PMID:22921304)
• Our data showed that almost all patients, regardless of individual characteristics such as gender or age, expressed the endothelin receptor genes, but did not express the genes for ET-3. (PMID:23515723)
• Down-regulated expression of ET3 attenuates the malignant behaviors of human melanoma cells partially by decreasing the expression of SPARC. (PMID:23904381)
• Waardenburg syndrome type II and mutations of EDNRB, EDN3 and SOX10 genes are responsible for Waardenburg syndrome type IV. (review) (PMID:24379252)
• EDN3 expression in left internal mammary arteries depends on tissue harvesting technique. (PMID:24647318)
• genome-wide association studies in population of women in China: Data suggest that EDN3 (endothelin 3) and EDNRB (endothelin receptor type B) play important roles in the molecular mechanisms underlying cervical cancer. (PMID:27863272)
• the critical physiological role of the KIT-ET3-NO pathway in fulfilling high demand (exceeding basal level) of endothelium-dependent NO generation for coping with atherosclerosis, pregnancy, and aging, is reported. (PMID:28880927)
• Association of endothelin genetic variants and hospitalized infection complications in end-stage renal disease (ESRD) patients. (PMID:31167651)
• Growth factor and receptor malfunctions associated with human genetic deafness. (PMID:31506927)
• The ratio of circulating endothelin-1 to endothelin-3 associated with TIMI risk and dynamic TIMI risk score in ST elevation acute myocardial infarction. (PMID:32315546)
• Insights into Endothelin-3 and Multiple Sclerosis. (PMID:32589590)
• miR27a3p regulates the inhibitory influence of endothelin 3 on the tumorigenesis of papillary thyroid cancer cells. (PMID:33537832)
• Endothelin-3 is epigenetically silenced in endometrioid endometrial cancer. (PMID:36542159)
• Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue. (PMID:39174539)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	edn3b	ENSDARG00000086669
mus_musculus	Edn3	ENSMUSG00000027524
rattus_norvegicus	Edn3	ENSRNOG00000007477

Paralogs (2): EDN1 (ENSG00000078401), EDN2 (ENSG00000127129)

Protein

Protein identifiers

Endothelin-3 — P14138 (reviewed: P14138)

Alternative names: Preproendothelin-3

All UniProt accessions (4): A0A2R8Y214, A0A5F9ZHX0, P14138, Q4FAT2

UniProt curated annotations — full annotation on UniProt →

Function. Endothelins are endothelium-derived vasoconstrictor peptides.

Subcellular location. Secreted.

Tissue specificity. Expressed in trophoblasts and placental stem villi vessels, but not in cultured placental smooth muscle cells.

Disease relevance. Hirschsprung disease 4 (HSCR4) [MIM:613712] A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. The disease is caused by variants affecting the gene represented in this entry. Waardenburg syndrome 4B (WS4B) [MIM:613265] A disorder characterized by the association of Waardenburg features (depigmentation and deafness) with the absence of enteric ganglia in the distal part of the intestine (Hirschsprung disease). The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the endothelin/sarafotoxin family.

Isoforms (3)

UniProt ID	Names	Canonical?
P14138-1	Long	yes
P14138-2	Short
P14138-3	3

RefSeq proteins (8): NP_001289384, NP_001289385, NP_001411290, NP_001411291, NP_001411292, NP_996915, NP_996916, NP_996917* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001928	Endothln-like_toxin	Domain
IPR019764	Endothelin_toxin_CS	Conserved_site
IPR020475	Endothelin	Family

Pfam: PF00322

UniProt features (18 total): sequence variant 4, region of interest 3, propeptide 2, disulfide bond 2, splice variant 2, signal peptide 1, helix 1, peptide 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6IGK	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P14138-F1	56.84	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 117–118 (cleavage; by kel)

Disulfide bonds (2): 99–107, 97–111

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-416476	G alpha (q) signalling events
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity

MSigDB gene sets: 359 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, MODULE_92, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, GOBP_REGULATION_OF_NUCLEAR_DIVISION, MODULE_64, GOBP_GROWTH, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CONTRACTION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_HORMONE_LEVELS

GO Biological Process (34): neural crest cell migration (GO:0001755), positive regulation of leukocyte chemotaxis (GO:0002690), regulation of systemic arterial blood pressure by endothelin (GO:0003100), intracellular calcium ion homeostasis (GO:0006874), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), cell-cell signaling (GO:0007267), axon guidance (GO:0007411), blood circulation (GO:0008015), cell population proliferation (GO:0008283), positive regulation of cell population proliferation (GO:0008284), positive regulation of heart rate (GO:0010460), regulation of gene expression (GO:0010468), intracellular magnesium ion homeostasis (GO:0010961), vein smooth muscle contraction (GO:0014826), regulation of vasoconstriction (GO:0019229), peptide hormone secretion (GO:0030072), melanocyte differentiation (GO:0030318), neutrophil chemotaxis (GO:0030593), vasoconstriction (GO:0042310), positive regulation of MAPK cascade (GO:0043410), positive regulation of cell differentiation (GO:0045597), positive regulation of mitotic nuclear division (GO:0045840), positive regulation of smooth muscle contraction (GO:0045987), positive regulation of hormone secretion (GO:0046887), regulation of developmental pigmentation (GO:0048070), axon extension (GO:0048675), establishment of localization in cell (GO:0051649), potassium ion transmembrane transport (GO:0071805), positive regulation of potassium ion transmembrane transport (GO:1901381), neuron differentiation (GO:0030182), regulation of cell migration (GO:0030334), neuron projection development (GO:0031175), blood vessel diameter maintenance (GO:0097746)

GO Molecular Function (3): signaling receptor binding (GO:0005102), hormone activity (GO:0005179), endothelin B receptor binding (GO:0031708)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1
MITF-M-regulated melanocyte development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular monoatomic cation homeostasis	2
cell communication	2
cellular process	2
signaling	2
blood vessel diameter maintenance	2
neural crest cell development	1
mesenchymal cell migration	1
positive regulation of leukocyte migration	1
regulation of leukocyte chemotaxis	1
leukocyte chemotaxis	1
positive regulation of chemotaxis	1
regulation of systemic arterial blood pressure by hormone	1
calcium ion homeostasis	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
axonogenesis	1
neuron projection guidance	1
circulatory system process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regulation of heart rate	1
positive regulation of heart contraction	1
gene expression	1
regulation of macromolecule biosynthetic process	1
magnesium ion homeostasis	1
phasic smooth muscle contraction	1
vascular associated smooth muscle contraction	1
vasoconstriction	1
regulation of blood circulation	1
peptide secretion	1
hormone secretion	1
nitrogen compound transport	1
pigment cell differentiation	1
granulocyte chemotaxis	1
neutrophil migration	1
protein binding	1
receptor ligand activity	1
bombesin receptor binding	1

Protein interactions and networks

STRING

1268 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EDN3	EDNRA	P25101	999
EDN3	EDNRB	P24530	999
EDN3	ECE1	P42892	936
EDN3	ECE2	P0DPD6	893
EDN3	SOX10	P56693	870
EDN3	GDNF	P39905	859
EDN3	EEF1AKMT4-ECE2	P0DPD8	827
EDN3	KEL	P23276	814
EDN3	RET	P07949	800
EDN3	PHOX2B	Q99453	784
EDN3	EDN1	P05305	725
EDN3	GFRA1	P56159	708
EDN3	PAX3	P23760	701
EDN3	KITLG	P21583	698
EDN3	PHOX2A	O14813	634

IntAct

5 interactions, top by confidence:

A	B	Type	Score
EDN3	MGRN1	psi-mi:“MI:0914”(association)	0.530
EDN3	ZNF195	psi-mi:“MI:0914”(association)	0.350
EDN3	POTEF	psi-mi:“MI:0914”(association)	0.350
NAA10	SUPT5H	psi-mi:“MI:0914”(association)	0.350

BioGRID (103): FBXO11 (Affinity Capture-MS), ZNF146 (Affinity Capture-MS), ABHD17B (Affinity Capture-MS), LOXL2 (Affinity Capture-MS), TUBA1C (Affinity Capture-MS), TUBB3 (Affinity Capture-MS), LEPREL2 (Affinity Capture-MS), DSTYK (Affinity Capture-MS), TRIM11 (Affinity Capture-MS), TUBB1 (Affinity Capture-MS), TUBB7P (Affinity Capture-MS), TUBA4A (Affinity Capture-MS), TRMT44 (Affinity Capture-MS), GDF11 (Affinity Capture-MS), RSPRY1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0J9YXV3, A0A172M4N0, A2VE23, A5PL33, C7EMF5, E7EW31, F1NSM7, I3L273, O15027, O48582, O55189, O55196, O97939, P0C671, P0DV77, P14138, Q14D33, Q1XI13, Q28989, Q3B7M4, Q4R729, Q5R7U0, Q5SWP3, Q62840, Q63003, Q6E0U4, Q6H236, Q6NUN9, Q6UXA7, Q7Z2K8, Q86UU5, Q8BM15, Q8K4E0, Q8K4L6, Q8N1P7, Q8N3D4, Q96D09, Q96JG9, Q9BGL9, Q9D7G9

Diamond homologs: A5A752, P05305, P09558, P12064, P13206, P13207, P13211, P14138, P17322, P19998, P20800, P22387, P22388, P22389, P23943, P29560, P48299, P80163, P97740, Q5NRP8, Q5NRP9, Q5NRQ0, Q5NRQ1, Q765Z4, Q765Z5, Q867A9, Q867D0, Q8MJW9, Q9BG76, P0DJK0, Q28469, P0DJK1, P13208, Q28470, Q6RY98

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CMA1	“up-regulates activity”	EDN3	cleavage
EDN3	up-regulates	EDNRB	binding
KEL	“up-regulates activity”	EDN3	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

199 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	2
Uncertain significance	117
Likely benign	47
Benign	15

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
16643	NM_207034.3(EDN3):c.262_263delinsT (p.Ala88fs)	Pathogenic
16644	NM_207034.3(EDN3):c.476G>T (p.Cys159Phe)	Pathogenic
16649	NM_207034.3(EDN3):c.507C>A (p.Cys169Ter)	Pathogenic
16650	NM_207034.3(EDN3):c.335A>G (p.His112Arg)	Pathogenic
16651	NM_207034.3(EDN3):c.277C>G (p.Arg93Gly)	Pathogenic
547292	NM_207034.3(EDN3):c.334C>A (p.His112Asn)	Likely pathogenic
984392	NM_207034.3(EDN3):c.293C>T (p.Thr98Met)	Likely pathogenic

SpliceAI

1036 predictions. Top by Δscore:

Variant	Effect	Δscore
20:59321015:A:AG	acceptor_gain	1.0000
20:59321016:G:GG	acceptor_gain	1.0000
20:59321016:GACA:G	acceptor_gain	1.0000
20:59322450:G:GT	donor_gain	1.0000
20:59300865:G:T	donor_loss	0.9900
20:59300866:T:A	donor_loss	0.9900
20:59301721:GA:G	donor_gain	0.9900
20:59301723:G:GG	donor_gain	0.9900
20:59321011:TTGCA:T	acceptor_loss	0.9900
20:59321012:TGCAG:T	acceptor_loss	0.9900
20:59321013:GCAG:G	acceptor_loss	0.9900
20:59321014:CA:C	acceptor_loss	0.9900
20:59321015:AGACA:A	acceptor_loss	0.9900
20:59321016:G:T	acceptor_loss	0.9900
20:59321016:GAC:G	acceptor_gain	0.9900
20:59321189:AGCAG:A	donor_loss	0.9900
20:59321190:GCAG:G	donor_gain	0.9900
20:59321191:CAGG:C	donor_loss	0.9900
20:59321192:AGG:A	donor_loss	0.9900
20:59321193:GG:G	donor_loss	0.9900
20:59321194:G:C	donor_loss	0.9900
20:59321195:T:G	donor_loss	0.9900
20:59322370:A:AG	acceptor_gain	0.9900
20:59322371:G:GG	acceptor_gain	0.9900
20:59324310:T:TA	acceptor_gain	0.9900
20:59321016:GA:G	acceptor_gain	0.9800
20:59322371:GTA:G	acceptor_gain	0.9800
20:59324325:A:G	acceptor_gain	0.9800
20:59324330:GGTT:G	acceptor_gain	0.9800
20:59300865:G:GG	donor_gain	0.9700

AlphaMissense

1532 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:59301708:G:C	W117C	0.999
20:59301708:G:T	W117C	0.999
20:59301676:T:A	C107S	0.997
20:59301677:G:C	C107S	0.997
20:59301688:T:A	C111S	0.997
20:59301689:G:A	C111Y	0.997
20:59301689:G:C	C111S	0.997
20:59301690:C:G	C111W	0.997
20:59301646:T:A	C97S	0.996
20:59301647:G:C	C97S	0.996
20:59301652:T:A	C99S	0.996
20:59301653:G:C	C99S	0.996
20:59301668:A:C	D104A	0.996
20:59301689:G:T	C111F	0.996
20:59301691:C:G	H112D	0.996
20:59301653:G:A	C99Y	0.995
20:59301654:C:G	C99W	0.995
20:59301667:G:C	D104H	0.995
20:59301668:A:T	D104V	0.995
20:59301693:C:A	H112Q	0.995
20:59301693:C:G	H112Q	0.995
20:59301698:A:T	D114V	0.995
20:59301706:T:A	W117R	0.995
20:59301706:T:C	W117R	0.995
20:59301652:T:C	C99R	0.994
20:59301676:T:C	C107R	0.994
20:59301678:T:G	C107W	0.994
20:59301677:G:A	C107Y	0.993
20:59301688:T:C	C111R	0.993
20:59301704:T:A	I116N	0.993

dbSNP variants (sampled 300 via entrez): RS1000043767 (20:59300923 C>G,T), RS1000083831 (20:59309151 C>T), RS1000457552 (20:59309526 G>A), RS1000480710 (20:59313949 A>T), RS1000499175 (20:59325789 G>A,T), RS1000664372 (20:59319771 A>G), RS1000764014 (20:59325110 A>G), RS1000882264 (20:59302088 C>G), RS1000919823 (20:59319201 G>C), RS1000926248 (20:59301776 G>A), RS1001357854 (20:59321820 A>G), RS1001450052 (20:59324240 C>T), RS1001588565 (20:59316141 G>A), RS1001597527 (20:59308779 T>A,C), RS1001633124 (20:59316348 G>A)

Disease associations

OMIM: gene MIM:131242 | disease phenotypes: MIM:613265, MIM:613712, MIM:142623, MIM:209880, MIM:193500

GenCC curated gene-disease

Disease	Classification	Inheritance
Waardenburg syndrome type 4B	Definitive	Autosomal dominant
Waardenburg-Shah syndrome	Strong	Autosomal recessive
Hirschsprung disease, susceptibility to, 4	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Waardenburg syndrome type 4B	Limited	AD
Waardenburg syndrome type 4B	Moderate	AR

Mondo (8): Waardenburg syndrome type 4B (MONDO:0013201), Hirschsprung disease, susceptibility to, 4 (MONDO:0013384), Hirschsprung disease (MONDO:0018309), central hypoventilation syndrome, congenital (MONDO:0800031), Waardenburg syndrome (MONDO:0018094), megacolon (MONDO:0001273), sensorineural hearing loss disorder (MONDO:0020678), Waardenburg-Shah syndrome (MONDO:0019518)

Orphanet (5): Waardenburg-Shah syndrome (Orphanet:897), Hirschsprung disease (Orphanet:388), Congenital central hypoventilation syndrome (Orphanet:661), Haddad syndrome (Orphanet:99803), Waardenburg syndrome (Orphanet:3440)

HPO phenotypes

54 total (30 of 54 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000366	Abnormality of the nose
HP:0000407	Sensorineural hearing impairment
HP:0000426	Prominent nasal bridge
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000478	Abnormality of the eye
HP:0000504	Abnormality of vision
HP:0000506	Telecanthus
HP:0000534	Abnormal eyebrow morphology
HP:0000635	Blue irides
HP:0000664	Synophrys
HP:0001053	Hypopigmented skin patches
HP:0001100	Heterochromia iridis
HP:0001103	Abnormal macular morphology
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001341	Olfactory lobe agenesis
HP:0001510	Growth delay
HP:0001531	Failure to thrive in infancy
HP:0001561	Polyhydramnios
HP:0001824	Weight loss
HP:0002014	Diarrhea
HP:0002017	Nausea and vomiting
HP:0002019	Constipation
HP:0002027	Abdominal pain
HP:0002093	Respiratory insufficiency
HP:0002211	White forelock

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000398_3	Hypertension	2.000000e-07
GCST001227_14	Systolic blood pressure	4.000000e-23
GCST001228_16	Diastolic blood pressure	6.000000e-23
GCST001235_12	Blood pressure	2.000000e-06
GCST001236_15	Blood pressure	2.000000e-12
GCST001238_10	Hypertension	4.000000e-14
GCST002067_1	Response to diuretic therapy in hypertension	6.000000e-08
GCST004776_27	Systolic blood pressure	4.000000e-13
GCST004777_58	Diastolic blood pressure	2.000000e-15
GCST006021_32	Systolic blood pressure	4.000000e-18
GCST006187_45	Diastolic blood pressure (cigarette smoking interaction)	7.000000e-37
GCST006188_15	Systolic blood pressure (cigarette smoking interaction)	3.000000e-22
GCST006258_57	Diastolic blood pressure	5.000000e-24
GCST006259_17	Systolic blood pressure	3.000000e-22
GCST009391_325	Metabolite levels	8.000000e-06
GCST009391_42	Metabolite levels	2.000000e-07

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0006340	mean arterial pressure
EFO:0006527	smoking status measurement
EFO:0010431	triacylglycerol 56:4 measurement
EFO:0010114	citrate measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
D008531	Megacolon	C06.405.469.158.701
D014849	Waardenburg Syndrome	C16.131.077.938
C567680	Waardenburg Syndrome, Type 4b (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects cotreatment, increases expression	3
propionaldehyde	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
acyline	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
(+)-JQ1 compound	decreases expression	1
Arsenic	increases expression	1
Ascorbic Acid	affects cotreatment, decreases expression	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Carbamazepine	affects expression	1
Diazinon	increases methylation	1
Estradiol	affects cotreatment, decreases expression	1
Hydroxyurea	decreases expression	1
Progesterone	affects cotreatment, decreases expression	1
Quartz	decreases expression	1
Silicon Dioxide	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Dronabinol	decreases expression	1
Tretinoin	affects cotreatment, decreases expression	1
Okadaic Acid	increases expression	1
Raloxifene Hydrochloride	affects expression, affects reaction, decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A1E2	SEES3-1V human EDN3, clone1	Embryonic stem cell	Male
CVCL_A1E3	SEES3-1V human EDN3, clone2	Embryonic stem cell	Male
CVCL_A1E4	SEES3-1V human EDN3, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

145 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT03660176	PHASE3	UNKNOWN	Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung’s Disease
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT00671684	PHASE1/PHASE2	UNKNOWN	Endoscopic Mucosal Resection (EMR) for Diagnosis of Hirschsprung’s Disease
NCT01985646	EARLY_PHASE1	COMPLETED	A Trial on Conservative Treatment for Infants’ Hirschsprung Disease
NCT00478712	Not specified	RECRUITING	Hirschsprung Disease Genetic Study
NCT01515501	Not specified	COMPLETED	Endoscopic Mucosal Resection for the Diagnosis of a-Ganglionosis, a Controlled Prospective Trial (EDGE Trial)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01927809	Not specified	UNKNOWN	Genetic Mosaicism in Hirschsprung’s Disease
NCT02193685	Not specified	UNKNOWN	Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease
NCT02216994	Not specified	UNKNOWN	A New Scoring System Improves Diagnostic Accuracy of Intestinal Dysganglionosis –a Prospective Study
NCT02296008	Not specified	COMPLETED	3D High Resolution Anorectal Manometry in Children After Surgery for Anorectal Disorders
NCT02776176	Not specified	UNKNOWN	Enhanced Recovery After Surgery In Hirschsprung Disease
NCT02857205	Not specified	COMPLETED	MICROPRUNG : Intestinal Microbiota Analysis in Patients With or Without Hirschsprung’s Associated EnteroColitis
NCT03269812	Not specified	UNKNOWN	Laparoscopic Assisted Pull-through Versus Other Surgical Procedures for Treatment of Hirschsprung Disease
NCT03406741	Not specified	COMPLETED	Neuropsychological Development and Functional Outcome Sin Children With Hirschsprung Disease at School Age
NCT03626350	Not specified	ACTIVE_NOT_RECRUITING	Prospective Evaluation of the Efficacy and Safety of Submucosal Endoscopy
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT04020939	Not specified	COMPLETED	The Role of Indocyanine Green Angiography Fluorescence on Intestinal Resections in Pediatric Surgery.
NCT04106947	Not specified	UNKNOWN	Transition of Care for Patients With Hirschsprung Disease and Anorectal Malformations
NCT04149093	Not specified	UNKNOWN	The Association Between Calretinin and the Function of Ganglion Cells in Hirschsprung Disease
NCT04150120	Not specified	COMPLETED	eHealth as an Aid for Facilitating and Supporting Self-management in Families With Long-term Childhood Illness
NCT04213976	Not specified	UNKNOWN	Ostomy in Continuity or Conventional Ileostomy: a Retrospective Multicentric Analysis
NCT04476225	Not specified	COMPLETED	Induced Pluripotent Stem Cells for Disease Research
NCT04598841	Not specified	COMPLETED	Nutrition Support for Hirschsprung Disease
NCT04622410	Not specified	RECRUITING	Registry for Hirschsprung Disease of the BELAPS
NCT04624334	Not specified	TERMINATED	Non-invasive Assessment of Colonic Motility
NCT04713085	Not specified	COMPLETED	Sacral Neuromodulation in Children and Adolescents
NCT04730128	Not specified	COMPLETED	Translation and Validation of a Disease-specific Questionnaire for Hirschsprung’s Disease in Danish Patients