Waardenburg-Shah syndrome

Summary

Waardenburg-Shah syndrome (MONDO:0019518) is a disease caused by EDN3 (GenCC Strong), with 4 cohort genes. The dominant Reactome pathway is Transcriptional and post-translational regulation of MITF-M expression and activity (4 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: EDN3 (GenCC Strong)
• Cohort genes: 4
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000478	Abnormality of the eye	Very frequent (80-99%)
HP:0000504	Abnormality of vision	Very frequent (80-99%)
HP:0000534	Abnormal eyebrow morphology	Very frequent (80-99%)
HP:0001103	Abnormal macular morphology	Very frequent (80-99%)
HP:0002019	Constipation	Very frequent (80-99%)
HP:0002211	White forelock	Very frequent (80-99%)
HP:0002216	Premature graying of hair	Very frequent (80-99%)
HP:0002226	White eyebrow	Very frequent (80-99%)
HP:0002227	White eyelashes	Very frequent (80-99%)
HP:0002242	Abnormal intestine morphology	Very frequent (80-99%)
HP:0002251	Aganglionic megacolon	Very frequent (80-99%)
HP:0005214	Intestinal obstruction	Very frequent (80-99%)
HP:0005599	Hypopigmentation of hair	Very frequent (80-99%)
HP:0000366	Abnormality of the nose	Frequent (30-79%)
HP:0000426	Prominent nasal bridge	Frequent (30-79%)
HP:0000430	Underdeveloped nasal alae	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000664	Synophrys	Frequent (30-79%)
HP:0001341	Olfactory lobe agenesis	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0000506	Telecanthus	Occasional (5-29%)
HP:0007703	Abnormality of retinal pigmentation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Waardenburg-Shah syndrome
Mondo ID	MONDO:0019518
Orphanet	897
ICD-11	1420151003
NCIT	C124842
GARD	0005524
Is cancer (heuristic)	no

Also known as: Hirschsprung disease with pigmentary anomaly · Shah-Waardenburg syndrome · Waardenburg syndrome type 4 · Waardenburg syndrome type IV · Waardenburg-Hirschsprung disease · Waardenburg-Hirschsprung syndrome · Waardenburg-Shah syndrome · WS4

Data availability: 6 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Waardenburg syndrome › Waardenburg-Shah syndrome

Related subtypes (4): Waardenburg syndrome type 3, Waardenburg syndrome type 1, Waardenburg syndrome type 2, Waardenburg syndrome 2F

Subtypes (3): Waardenburg syndrome type 4A, Waardenburg syndrome type 4B, Waardenburg syndrome type 4C

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: 57 · Orphanet: 17 · 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	Definitive	Autosomal dominant	Waardenburg syndrome type 4B	12
EDNRB	Definitive	Autosomal dominant	Waardenburg syndrome type 4A	11
MITF	Definitive	Autosomal dominant	Waardenburg syndrome type 2A	19
SOX10	Definitive	Autosomal dominant	Waardenburg syndrome type 4C	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOX10	Orphanet:163746	Peripheral demyelinating neuropathy-central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung disease
SOX10	Orphanet:478	Kallmann syndrome
SOX10	Orphanet:895	Waardenburg syndrome type 2
SOX10	Orphanet:897	Waardenburg-Shah syndrome
EDN3	Orphanet:388	Hirschsprung disease
EDN3	Orphanet:661	Congenital central hypoventilation syndrome
EDN3	Orphanet:897	Waardenburg-Shah syndrome
EDNRB	Orphanet:388	Hirschsprung disease
EDNRB	Orphanet:895	Waardenburg syndrome type 2
EDNRB	Orphanet:897	Waardenburg-Shah syndrome
MITF	Orphanet:293822	MITF-related melanoma and renal cell carcinoma predisposition syndrome
MITF	Orphanet:319298	Papillary renal cell carcinoma
MITF	Orphanet:404511	Clear cell papillary renal cell carcinoma
MITF	Orphanet:42665	Tietz syndrome
MITF	Orphanet:618	Familial melanoma
MITF	Orphanet:895	Waardenburg syndrome type 2
MITF	Orphanet:897	Waardenburg-Shah syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SOX10	HGNC:11190	ENSG00000100146	P56693	Transcription factor SOX-10	gencc
EDN3	HGNC:3178	ENSG00000124205	P14138	Endothelin-3	gencc
EDNRB	HGNC:3180	ENSG00000136160	P24530	Endothelin receptor type B	gencc
MITF	HGNC:7105	ENSG00000187098	O75030	Microphthalmia-associated transcription factor	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOX10	Transcription factor SOX-10	Transcription factor that plays a central role in developing and mature glia.
EDN3	Endothelin-3	Endothelins are endothelium-derived vasoconstrictor peptides.
EDNRB	Endothelin receptor type B	Non-specific receptor for endothelin 1, 2, and 3.
MITF	Microphthalmia-associated transcription factor	Transcription factor that acts as a master regulator of melanocyte survival and differentiation as well as melanosome biogenesis.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.25

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	2	4.1×	0.223
GPCR	1	6.0×	0.235
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOX10	Transcription factor	no		HMG_box_dom, Sox_N, HMG_box_dom_sf
EDN3	Other/Unknown	no		Endothln-like_toxin, Endothelin_toxin_CS, Endothelin
EDNRB	GPCR	yes		GPCR_Rhodpsn, Endthln_rcpt, ETB_rcpt
MITF	Transcription factor	no		bHLH_dom, MiT/TFE_C, MiT/TFE_N

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
dorsal motor nucleus of vagus nerve	1
inferior olivary complex	1
sural nerve	1
jejunal mucosa	1
penis	1
primordial germ cell in gonad	1
lateral globus pallidus	1
lower lobe of lung	1
parotid gland	1
pigmented layer of retina	1
retina	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOX10	218	broad	marker	inferior olivary complex, sural nerve, dorsal motor nucleus of vagus nerve
EDN3	175	broad	marker	penis, jejunal mucosa, primordial germ cell in gonad
EDNRB	274	broad	marker	parotid gland, lateral globus pallidus, lower lobe of lung
MITF	293	ubiquitous	marker	pigmented layer of retina, retina, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SOX10	3,696
MITF	2,908
EDNRB	2,415
EDN3	1,376

Intra-cohort edges

A	B	Sources
EDN3	EDNRB	string_interaction
EDN3	SOX10	string_interaction
EDNRB	SOX10	string_interaction
MITF	SOX10	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EDNRB	P24530	18
MITF	O75030	12
EDN3	P14138	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SOX10	P56693	57.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. Enrichment computed across 4 evidence-associated genes (4 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 4 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	4	178.4×	3e-08	SOX10, EDN3, EDNRB, MITF
Regulation of MITF-M-dependent genes involved in pigmentation	2	132.8×	0.001	SOX10, MITF
MITF-M-regulated melanocyte development	2	57.1×	0.004	SOX10, MITF
Regulation of MITF-M dependent genes involved in metabolism	1	951.7×	0.006	MITF
Peptide ligand-binding receptors	2	37.1×	0.006	EDN3, EDNRB
Regulation of MITF-M dependent genes involved in invasion	1	713.8×	0.007	MITF
G alpha (q) signalling events	2	28.7×	0.007	EDN3, EDNRB
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	407.9×	0.009	MITF
Regulation of CDH19 Expression and Function	1	356.9×	0.009	SOX10
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	219.6×	0.012	MITF
Regulation of Homotypic Cell-Cell Adhesion	1	167.9×	0.012	SOX10
Regulation of Expression and Function of Type II Classical Cadherins	1	167.9×	0.012	SOX10
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	167.9×	0.012	MITF
Regulation of MITF-M-dependent genes involved in apoptosis	1	158.6×	0.012	MITF
SUMOylation of transcription factors	1	142.8×	0.012	MITF
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	1	142.8×	0.012	MITF
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	92.1×	0.018	SOX10
Adherens junctions interactions	1	62.1×	0.024	SOX10
Cell-cell junction organization	1	62.1×	0.024	SOX10
Cell junction organization	1	46.8×	0.028	SOX10
MITF-M-dependent gene expression	1	45.3×	0.028	SOX10
SUMO E3 ligases SUMOylate target proteins	1	44.6×	0.028	MITF
SUMOylation	1	40.8×	0.030	MITF
Developmental Biology	2	7.2×	0.030	SOX10, MITF
Cell-Cell communication	1	34.4×	0.032	SOX10
Nervous system development	1	10.7×	0.097	SOX10
Post-translational protein modification	1	4.8×	0.200	MITF
Metabolism of proteins	1	3.1×	0.286	MITF

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
melanocyte differentiation	4	802.5×	2e-10	SOX10, EDN3, EDNRB, MITF
neural crest cell migration	3	252.8×	5e-06	SOX10, EDN3, EDNRB
vein smooth muscle contraction	2	2106.5×	9e-06	EDN3, EDNRB
enteric nervous system development	2	495.6×	2e-04	SOX10, EDNRB
vasoconstriction	2	443.5×	2e-04	EDN3, EDNRB
peripheral nervous system development	2	290.6×	3e-04	SOX10, EDNRB
negative regulation of apoptotic process	3	26.1×	0.001	SOX10, EDNRB, MITF
enteric smooth muscle cell differentiation	1	4213.0×	0.003	EDNRB
response to endothelin	1	4213.0×	0.003	EDNRB
posterior midgut development	1	2106.5×	0.003	EDNRB
positive regulation of gliogenesis	1	2106.5×	0.003	SOX10
negative regulation of neuron maturation	1	2106.5×	0.003	EDNRB
regulation of fever generation	1	2106.5×	0.003	EDNRB
aldosterone metabolic process	1	2106.5×	0.003	EDNRB
melanocyte apoptotic process	1	2106.5×	0.003	MITF
regulation of RNA biosynthetic process	1	2106.5×	0.003	MITF
regulation of developmental pigmentation	1	1404.3×	0.004	EDN3
positive regulation of penile erection	1	1404.3×	0.004	EDNRB
chordate pharynx development	1	1404.3×	0.004	EDNRB
negative regulation of transcription by RNA polymerase II	3	13.3×	0.004	SOX10, EDNRB, MITF
renin secretion into blood stream	1	1053.2×	0.005	EDNRB
renal sodium excretion	1	1053.2×	0.005	EDNRB
morphogenesis of a branching epithelium	1	842.6×	0.005	SOX10
renal albumin absorption	1	842.6×	0.005	EDNRB
neuroblast migration	1	842.6×	0.005	EDNRB
regulation of systemic arterial blood pressure by endothelin	1	702.2×	0.005	EDN3
intracellular magnesium ion homeostasis	1	702.2×	0.005	EDN3
peptide hormone secretion	1	702.2×	0.005	EDN3
heparin proteoglycan metabolic process	1	702.2×	0.005	EDNRB
cellular response to progesterone stimulus	1	702.2×	0.005	SOX10

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
EDNRB	AMBRISENTAN
MITF	PERHEXILINE MALEATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EDNRB	16	4
MITF	3	4
SOX10	0	0
EDN3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMBRISENTAN	4	EDNRB
MODAFINIL	4	EDNRB
MACITENTAN	4	EDNRB
APROCITENTAN	4	EDNRB
SITAXENTAN	4	EDNRB
SULFISOXAZOLE	4	EDNRB
MAZINDOL	4	EDNRB
BOSENTAN	4	EDNRB
PERHEXILINE MALEATE	4	MITF
CLAZOSENTAN	3	EDNRB
DARUSENTAN	3	EDNRB
AVOSENTAN	3	EDNRB
TEZOSENTAN	3	EDNRB
ATRASENTAN	3	EDNRB
NIFUROXAZIDE	3	MITF
FELOPRENTAN	2	EDNRB
ENRASENTAN	2	EDNRB
ENDOTHELIN	2	EDNRB
HOMIDIUM BROMIDE	2	MITF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
EDNRB	270	Binding:229, Functional:41
MITF	10	Functional:10

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
EDNRB	270

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

19 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)
AMBRISENTAN	4	EDNRB
MODAFINIL	4	EDNRB
MACITENTAN	4	EDNRB
APROCITENTAN	4	EDNRB
SITAXENTAN	4	EDNRB
SULFISOXAZOLE	4	EDNRB
MAZINDOL	4	EDNRB
BOSENTAN	4	EDNRB
PERHEXILINE MALEATE	4	MITF
CLAZOSENTAN	3	EDNRB
DARUSENTAN	3	EDNRB
AVOSENTAN	3	EDNRB
TEZOSENTAN	3	EDNRB
ATRASENTAN	3	EDNRB
NIFUROXAZIDE	3	MITF
FELOPRENTAN	2	EDNRB
ENRASENTAN	2	EDNRB
ENDOTHELIN	2	EDNRB
HOMIDIUM BROMIDE	2	MITF

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	EDNRB, MITF
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	2	SOX10, EDN3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SOX10	0	MITF, EDNRB
EDN3	0	EDNRB

Clinical trials & evidence

Clinical trials

Clinical trials: 0.