Waardenburg syndrome type 2

Summary

Waardenburg syndrome type 2 (MONDO:0019517) is a disease (an umbrella term covering 5 Mondo subtypes) caused by MITF (GenCC Definitive), with 6 cohort genes. The dominant Reactome pathway is Transcriptional and post-translational regulation of MITF-M expression and activity (5 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MITF (GenCC Definitive)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 6
• ClinVar variants: 7
• Phenotypes (HPO): 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0002216	Premature graying of hair	Very frequent (80-99%)
HP:0005599	Hypopigmentation of hair	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0001053	Hypopigmented skin patches	Frequent (30-79%)
HP:0001100	Heterochromia iridis	Frequent (30-79%)
HP:0002211	White forelock	Frequent (30-79%)
HP:0000077	Abnormality of the kidney	Occasional (5-29%)
HP:0000506	Telecanthus	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0002251	Aganglionic megacolon	Occasional (5-29%)
HP:0004414	Abnormality of the pulmonary artery	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Waardenburg syndrome type 2
Mondo ID	MONDO:0019517
MeSH	C536463
Orphanet	895
ICD-11	746815303
NCIT	C75009
UMLS	C2700265
MedGen	398443
GARD	0005520
Is cancer (heuristic)	no

Also known as: Waardenburg syndrome type 2 · Waardenburg syndrome type II · WS 2 · WS type 2 · WS2

Data availability: 7 ClinVar variants · 9 GenCC gene-disease records · 1 cell line.

Disease family

An umbrella term covering 5 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 syndrome type 2

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

Subtypes (5): Waardenburg syndrome type 2A, Waardenburg syndrome type 2B, Waardenburg syndrome type 2C, Waardenburg syndrome type 2D, Waardenburg syndrome type 2E

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

7 retrieved; paginated sample, class counts are floors:

5 pathogenic/likely pathogenic, 1 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
228363	NM_001354604.2(MITF):c.1129C>T (p.Arg377Ter)	MITF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
381604	NM_001354604.2(MITF):c.1230G>A (p.Thr410=)	MITF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545016	NM_001354604.2(MITF):c.997G>T (p.Glu333Ter)	MITF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545639	NM_001354604.2(MITF):c.355-1062G>C	MITF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620508	NM_001354604.2(MITF):c.931C>T (p.Gln311Ter)	MITF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
517197	NM_001354604.2(MITF):c.1179+4C>T	MITF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
226729	NM_001354604.2(MITF):c.880+9C>G	MITF	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 73 · Orphanet: 26 · 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
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
KITLG	Strong	Autosomal dominant	Waardenburg syndrome	11
SNAI2	Strong	Autosomal recessive	Waardenburg syndrome type 2D	7
TYR	Supportive	Autosomal dominant	Waardenburg syndrome type 2	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
SNAI2	Orphanet:2884	Piebaldism
SNAI2	Orphanet:895	Waardenburg syndrome type 2
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
TYR	Orphanet:352734	Minimal pigment oculocutaneous albinism type 1
TYR	Orphanet:352737	Temperature-sensitive oculocutaneous albinism type 1
TYR	Orphanet:79431	Oculocutaneous albinism type 1A
TYR	Orphanet:79434	Oculocutaneous albinism type 1B
TYR	Orphanet:895	Waardenburg syndrome type 2
EDNRB	Orphanet:388	Hirschsprung disease
EDNRB	Orphanet:895	Waardenburg syndrome type 2
EDNRB	Orphanet:897	Waardenburg-Shah syndrome
KITLG	Orphanet:280628	Familial progressive hyper- and hypopigmentation
KITLG	Orphanet:363494	Non-seminomatous germ cell tumor of testis
KITLG	Orphanet:79146	Familial progressive hyperpigmentation
KITLG	Orphanet:895	Waardenburg syndrome type 2
KITLG	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MITF	HGNC:7105	ENSG00000187098	O75030	Microphthalmia-associated transcription factor	gencc,clinvar
SNAI2	HGNC:11094	ENSG00000019549	O43623	Zinc finger protein SNAI2	gencc
SOX10	HGNC:11190	ENSG00000100146	P56693	Transcription factor SOX-10	gencc
TYR	HGNC:12442	ENSG00000077498	P14679	Tyrosinase	gencc
EDNRB	HGNC:3180	ENSG00000136160	P24530	Endothelin receptor type B	gencc
KITLG	HGNC:6343	ENSG00000049130	P21583	Kit ligand	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MITF	Microphthalmia-associated transcription factor	Transcription factor that acts as a master regulator of melanocyte survival and differentiation as well as melanosome biogenesis.
SNAI2	Zinc finger protein SNAI2	Transcriptional repressor that modulates both activator-dependent and basal transcription.
SOX10	Transcription factor SOX-10	Transcription factor that plays a central role in developing and mature glia.
TYR	Tyrosinase	This is a copper-containing oxidase that functions in the formation of pigments such as melanins and other polyphenolic compounds.
EDNRB	Endothelin receptor type B	Non-specific receptor for endothelin 1, 2, and 3.
KITLG	Kit ligand	Ligand for the receptor-type protein-tyrosine kinase KIT.

Protein-family classification

Druggable: 2 · Difficult: 3 · Unknown: 1 · Druggable fraction: 0.33

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	3	4.1×	0.107
GPCR	1	4.0×	0.452
Enzyme (other)	1	2.0×	0.543
Other/Unknown	1	0.3×	0.993

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MITF	Transcription factor	no		bHLH_dom, MiT/TFE_C, MiT/TFE_N
SNAI2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf,
SOX10	Transcription factor	no		HMG_box_dom, Sox_N, HMG_box_dom_sf
TYR	Enzyme (other)	yes	1.14.18.1	Tyrosinase_Cu-bd, Di-copper_centre_dom_sf, Tyrosinase/Hemocyanin
EDNRB	GPCR	yes		GPCR_Rhodpsn, Endthln_rcpt, ETB_rcpt
KITLG	Other/Unknown	no		SCF, 4_helix_cytokine-like_core

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pigmented layer of retina	2
lower lobe of lung	2
retina	1
skeletal muscle tissue of biceps brachii	1
cartilage tissue	1
stromal cell of endometrium	1
tibia	1
dorsal motor nucleus of vagus nerve	1
inferior olivary complex	1
sural nerve	1
male germ line stem cell (sensu Vertebrata) in testis	1
upper leg skin	1
lateral globus pallidus	1
parotid gland	1
cardia of stomach	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MITF	293	ubiquitous	marker	pigmented layer of retina, retina, skeletal muscle tissue of biceps brachii
SNAI2	254	ubiquitous	marker	tibia, cartilage tissue, stromal cell of endometrium
SOX10	218	broad	marker	inferior olivary complex, sural nerve, dorsal motor nucleus of vagus nerve
TYR	59	tissue_specific	marker	pigmented layer of retina, male germ line stem cell (sensu Vertebrata) in testis, upper leg skin
EDNRB	274	broad	marker	parotid gland, lateral globus pallidus, lower lobe of lung
KITLG	262	ubiquitous	marker	visceral pleura, cardia of stomach, lower lobe of lung

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SOX10	3,696
TYR	3,663
SNAI2	3,657
KITLG	3,075
MITF	2,908
EDNRB	2,415

Intra-cohort edges

A	B	Sources
EDNRB	KITLG	string_interaction
EDNRB	SOX10	string_interaction
MITF	SOX10	string_interaction
MITF	TYR	string_interaction
SNAI2	SOX10	string_interaction
SOX10	TYR	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EDNRB	P24530	18
MITF	O75030	12
KITLG	P21583	6
TYR	P14679	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SNAI2	O43623	64.87
SOX10	P56693	57.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 40. Enrichment computed across 6 evidence-associated genes (6 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 6 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	5	148.7×	1e-09	MITF, SNAI2, SOX10, EDNRB, KITLG
Regulation of MITF-M-dependent genes involved in pigmentation	3	132.8×	2e-05	MITF, SOX10, TYR
MITF-M-regulated melanocyte development	3	57.1×	2e-04	MITF, SNAI2, SOX10
Regulation of MITF-M dependent genes involved in metabolism	1	634.4×	0.016	MITF
Regulation of MITF-M dependent genes involved in invasion	1	475.8×	0.017	MITF
Melanin biosynthesis	1	380.7×	0.017	TYR
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	271.9×	0.018	MITF
PIP3 activates AKT signaling	2	22.3×	0.018	SNAI2, KITLG
Regulation of CDH19 Expression and Function	1	237.9×	0.019	SOX10
Developmental Biology	3	7.2×	0.023	MITF, SNAI2, SOX10
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	146.4×	0.023	MITF
Regulation of Homotypic Cell-Cell Adhesion	1	112.0×	0.023	SOX10
Regulation of Expression and Function of Type II Classical Cadherins	1	112.0×	0.023	SOX10
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	112.0×	0.023	MITF
Regulation of MITF-M-dependent genes involved in apoptosis	1	105.7×	0.023	MITF
Regulation of KIT signaling	1	100.2×	0.023	KITLG
SUMOylation of transcription factors	1	95.2×	0.023	MITF
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	1	95.2×	0.023	MITF
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	61.4×	0.034	SOX10
Signaling by SCF-KIT	1	41.4×	0.044	KITLG
Adherens junctions interactions	1	41.4×	0.044	SOX10
Cell-cell junction organization	1	41.4×	0.044	SOX10
PTEN Regulation	1	38.1×	0.045	SNAI2
Cell junction organization	1	31.2×	0.049	SOX10
MITF-M-dependent gene expression	1	30.2×	0.049	SOX10
SUMO E3 ligases SUMOylate target proteins	1	29.7×	0.049	MITF
Regulation of PTEN gene transcription	1	29.7×	0.049	SNAI2
SUMOylation	1	27.2×	0.052	MITF
Cell-Cell communication	1	22.9×	0.059	SOX10
Constitutive Signaling by Aberrant PI3K in Cancer	1	21.1×	0.062	KITLG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 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	3	401.2×	5e-06	MITF, SOX10, EDNRB
neural crest cell migration	3	168.5×	4e-05	SOX10, EDNRB, KITLG
enteric nervous system development	2	330.4×	8e-04	SOX10, EDNRB
pigmentation	2	234.1×	0.001	SNAI2, TYR
peripheral nervous system development	2	193.7×	0.001	SOX10, EDNRB
negative regulation of transcription by RNA polymerase II	4	11.8×	0.004	MITF, SNAI2, SOX10, EDNRB
enteric smooth muscle cell differentiation	1	2808.7×	0.005	EDNRB
desmosome disassembly	1	2808.7×	0.005	SNAI2
response to endothelin	1	2808.7×	0.005	EDNRB
positive regulation of myeloid leukocyte differentiation	1	1404.3×	0.005	KITLG
eye pigment biosynthetic process	1	1404.3×	0.005	TYR
posterior midgut development	1	1404.3×	0.005	EDNRB
positive regulation of gliogenesis	1	1404.3×	0.005	SOX10
negative regulation of neuron maturation	1	1404.3×	0.005	EDNRB
regulation of fever generation	1	1404.3×	0.005	EDNRB
aldosterone metabolic process	1	1404.3×	0.005	EDNRB
negative regulation of vitamin D receptor signaling pathway	1	1404.3×	0.005	SNAI2
melanocyte apoptotic process	1	1404.3×	0.005	MITF
regulation of RNA biosynthetic process	1	1404.3×	0.005	MITF
myeloid leukocyte differentiation	1	936.2×	0.005	KITLG
regulation of chemokine production	1	936.2×	0.005	SNAI2
negative regulation of mast cell apoptotic process	1	936.2×	0.005	KITLG
positive regulation of penile erection	1	936.2×	0.005	EDNRB
regulation of branching involved in salivary gland morphogenesis	1	936.2×	0.005	SNAI2
melanocyte migration	1	936.2×	0.005	KITLG
mast cell migration	1	936.2×	0.005	KITLG
chordate pharynx development	1	936.2×	0.005	EDNRB
positive regulation of hematopoietic progenitor cell differentiation	1	936.2×	0.005	KITLG
negative regulation of hematopoietic stem cell proliferation	1	936.2×	0.005	SNAI2
negative regulation of canonical Wnt signaling pathway	2	39.3×	0.005	SNAI2, SOX10

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 6 evidence-associated genes (67%) 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
MITF	PERHEXILINE MALEATE
TYR	ASCORBIC ACID
EDNRB	AMBRISENTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EDNRB	16	4
TYR	10	4
MITF	3	4
SNAI2	0	0
SOX10	0	0
KITLG	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PERHEXILINE MALEATE	4	MITF
ASCORBIC ACID	4	TYR
HEXYLRESORCINOL	4	TYR
HYDROQUINONE	4	TYR
AMBRISENTAN	4	EDNRB
MODAFINIL	4	EDNRB
MACITENTAN	4	EDNRB
APROCITENTAN	4	EDNRB
SITAXENTAN	4	EDNRB
SULFISOXAZOLE	4	EDNRB
MAZINDOL	4	EDNRB
BOSENTAN	4	EDNRB
NIFUROXAZIDE	3	MITF
CURCUMIN	3	TYR
RESVERATROL	3	TYR
QUERCETIN	3	TYR
CLAZOSENTAN	3	EDNRB
DARUSENTAN	3	EDNRB
AVOSENTAN	3	EDNRB
TEZOSENTAN	3	EDNRB
ATRASENTAN	3	EDNRB
HOMIDIUM BROMIDE	2	MITF
BUTYLATED HYDROXYTOLUENE	2	TYR
LUTEOLIN	2	TYR
ARBUTIN	2	TYR
FELOPRENTAN	2	EDNRB
ENRASENTAN	2	EDNRB
ENDOTHELIN	2	EDNRB
KAEMPFEROL	1	TYR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
EDNRB	270	Binding:229, Functional:41
TYR	211	Binding:209, ADMET:2
MITF	10	Functional:10
KITLG	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TYR	1.14.18.1	tyrosinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TYR	211
EDNRB	270

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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)
PERHEXILINE MALEATE	4	MITF
ASCORBIC ACID	4	TYR
HEXYLRESORCINOL	4	TYR
HYDROQUINONE	4	TYR
AMBRISENTAN	4	EDNRB
MODAFINIL	4	EDNRB
MACITENTAN	4	EDNRB
APROCITENTAN	4	EDNRB
SITAXENTAN	4	EDNRB
SULFISOXAZOLE	4	EDNRB
MAZINDOL	4	EDNRB
BOSENTAN	4	EDNRB
NIFUROXAZIDE	3	MITF
CURCUMIN	3	TYR
RESVERATROL	3	TYR
QUERCETIN	3	TYR
CLAZOSENTAN	3	EDNRB
DARUSENTAN	3	EDNRB
AVOSENTAN	3	EDNRB
TEZOSENTAN	3	EDNRB
ATRASENTAN	3	EDNRB
HOMIDIUM BROMIDE	2	MITF
BUTYLATED HYDROXYTOLUENE	2	TYR
LUTEOLIN	2	TYR
ARBUTIN	2	TYR
FELOPRENTAN	2	EDNRB
ENRASENTAN	2	EDNRB
ENDOTHELIN	2	EDNRB
KAEMPFEROL	1	TYR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	MITF, TYR, EDNRB
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	3	SNAI2, SOX10, KITLG

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)
SOX10	0	MITF, EDNRB
SNAI2	0	—
KITLG	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.