Waardenburg syndrome

Summary

Waardenburg syndrome (MONDO:0018094) is a disease (an umbrella term covering 5 Mondo subtypes) caused by variants in PAX3, KITLG, and SNAI2, with 11 cohort genes and 1 clinical trial. The dominant Reactome pathway is Transcriptional and post-translational regulation of MITF-M expression and activity (6 cohort genes).

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal genes: PAX3 (GenCC Definitive), KITLG (GenCC Strong), SNAI2 (GenCC Strong)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 11
• ClinVar variants: 99
• Phenotypes (HPO): 32
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.37	Europe	Validated
Prevalence at birth	1-9 / 100 000	2.4	Netherlands	Validated
Point prevalence	1-9 / 100 000		Europe	Not yet validated
Point prevalence	1-9 / 100 000	1.74	United States	Not yet validated
Point prevalence	1-9 / 100 000		Netherlands	Not yet validated

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000426	Prominent nasal bridge	Very frequent (80-99%)
HP:0000664	Synophrys	Very frequent (80-99%)
HP:0001000	Abnormality of skin pigmentation	Very frequent (80-99%)
HP:0001053	Hypopigmented skin patches	Very frequent (80-99%)
HP:0001100	Heterochromia iridis	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	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:0000430	Underdeveloped nasal alae	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000478	Abnormality of the eye	Frequent (30-79%)
HP:0000506	Telecanthus	Frequent (30-79%)
HP:0000534	Abnormal eyebrow morphology	Frequent (30-79%)
HP:0002211	White forelock	Frequent (30-79%)
HP:0008527	Congenital sensorineural hearing impairment	Frequent (30-79%)
HP:0000202	Orofacial cleft	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000635	Blue irides	Occasional (5-29%)
HP:0002227	White eyelashes	Occasional (5-29%)
HP:0002251	Aganglionic megacolon	Occasional (5-29%)
HP:0002321	Vertigo	Occasional (5-29%)
HP:0002414	Spina bifida	Occasional (5-29%)
HP:0002475	Myelomeningocele	Occasional (5-29%)
HP:0005214	Intestinal obstruction	Occasional (5-29%)
HP:0008568	Vestibular areflexia	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0011024	Abnormality of the gastrointestinal tract	Occasional (5-29%)
HP:0012385	Camptodactyly	Occasional (5-29%)
HP:0034391	Elbow contracture	Occasional (5-29%)
HP:0100811	Aplasia/Hypoplasia of the colon	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Waardenburg syndrome
Mondo ID	MONDO:0018094
MeSH	D014849
OMIM	193500
Orphanet	3440
DOID	DOID:9258
ICD-11	304883627
NCIT	C85222
SNOMED CT	715952000
UMLS	C3266898
MedGen	473809
GARD	0005525
MedDRA	10069203
NORD	1832
Is cancer (heuristic)	no

Also known as: Mende syndrome · Van der Hoeve Halbertsma Waardenburg Gualdi syndrome · Waardenburg syndrome · Waardenburg’s syndrome

Data availability: 99 ClinVar variants · 6 GenCC gene-disease records · 14 cell lines.

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

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (5): Waardenburg syndrome type 3, Waardenburg syndrome type 1, Waardenburg syndrome type 2, Waardenburg-Shah syndrome, Waardenburg syndrome 2F

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

99 retrieved; paginated sample, class counts are floors:

38 uncertain significance, 19 conflicting classifications of pathogenicity, 18 benign, 10 benign/likely benign, 7 pathogenic, 5 likely pathogenic, 1 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
228386	NC_000002.12:g.(?222293620)(222298692_?)del	LOC107980445	Pathogenic	criteria provided, single submitter
14272	NM_001354604.2(MITF):c.964AGA[2] (p.Arg324del)	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
1185059	NM_181458.4(PAX3):c.372_373del (p.Asn125fs)	PAX3	Pathogenic	criteria provided, single submitter
228387	NM_181458.4(PAX3):c.668G>A (p.Arg223Gln)	PAX3	Pathogenic	criteria provided, multiple submitters, no conflicts
4217	NM_181458.4(PAX3):c.167G>T (p.Arg56Leu)	PAX3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
505425	NM_181458.4(PAX3):c.879dup (p.Phe294fs)	PAX3	Pathogenic	criteria provided, multiple submitters, no conflicts
547733	NM_181458.4(PAX3):c.218C>T (p.Ser73Leu)	PAX3	Pathogenic	criteria provided, multiple submitters, no conflicts
547748	NM_181458.4(PAX3):c.811C>T (p.Arg271Cys)	PAX3	Pathogenic	criteria provided, multiple submitters, no conflicts
373914	NM_001354604.2(MITF):c.794A>G (p.Tyr265Cys)	MITF	Likely pathogenic	no assertion criteria provided
425300	NM_001354604.2(MITF):c.1180-2A>G	MITF	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3381829	NM_181458.4(PAX3):c.185T>C (p.Met62Thr)	PAX3	Likely pathogenic	criteria provided, single submitter
3381830	NM_181458.4(PAX3):c.797_798inv (p.Trp266Ser)	PAX3	Likely pathogenic	criteria provided, single submitter
2637901	NM_006941.4(SOX10):c.400C>T (p.Leu134Phe)	POLR2F	Likely pathogenic	criteria provided, single submitter
1317500	NM_018429.3(BDP1):c.6610G>T (p.Val2204Phe)	BDP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1064933	NM_001201397.2(EDNRB):c.18T>A (p.Cys6Ter)	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
226993	NM_181458.4(PAX3):c.1003C>T (p.Pro335Ser)	LOC126806529	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
504759	NM_181458.4(PAX3):c.958+9G>A	LOC126806529	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218940	NM_181458.4(PAX3):c.944C>A (p.Thr315Lys)	PAX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
334559	NM_181458.4(PAX3):c.1118C>T (p.Pro373Leu)	PAX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4526475	NM_181458.4(PAX3):c.124G>A (p.Gly42Ser)	PAX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
504786	NM_181458.4(PAX3):c.580G>A (p.Glu194Lys)	PAX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
739452	NM_181458.4(PAX3):c.1029G>A (p.Thr343=)	PAX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
743485	NM_181458.4(PAX3):c.1248C>T (p.Thr416=)	PAX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895017	NM_181458.4(PAX3):c.981C>T (p.Thr327=)	PAX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896459	NM_181458.4(PAX3):c.567C>T (p.Asp189=)	PAX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341616	NM_006941.4(SOX10):c.906G>A (p.Pro302=)	POLR2F	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341617	NM_006941.4(SOX10):c.753G>A (p.Ser251=)	POLR2F	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
452278	NM_006941.4(SOX10):c.131C>G (p.Ala44Gly)	POLR2F	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
702405	NM_006941.4(SOX10):c.274G>C (p.Val92Leu)	POLR2F	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
733585	NM_006941.4(SOX10):c.918C>T (p.His306=)	POLR2F	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 50 · Orphanet: 29 · 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
MITF	Definitive	Autosomal dominant	Waardenburg syndrome type 2A	19
PAX3	Definitive	Autosomal dominant	Waardenburg syndrome	13
KITLG	Strong	Autosomal dominant	Waardenburg syndrome	11
SNAI2	Strong	Autosomal recessive	Waardenburg syndrome type 2D	7

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
PAX3	Orphanet:1529	Craniofacial-deafness-hand syndrome
PAX3	Orphanet:894	Waardenburg syndrome type 1
PAX3	Orphanet:896	Waardenburg syndrome type 3
PAX3	Orphanet:99756	Alveolar rhabdomyosarcoma
SNAI2	Orphanet:2884	Piebaldism
SNAI2	Orphanet:895	Waardenburg syndrome type 2
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
TMPRSS3	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
BDP1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
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
MYO6	Orphanet:228012	Progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome
MYO6	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
MYO6	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

11 cohort genes, 11 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	11

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MITF	HGNC:7105	ENSG00000187098	O75030	Microphthalmia-associated transcription factor	gencc,clinvar
PAX3	HGNC:8617	ENSG00000135903	P23760	Paired box protein Pax-3	gencc,clinvar
SNAI2	HGNC:11094	ENSG00000019549	O43623	Zinc finger protein SNAI2	gencc
KITLG	HGNC:6343	ENSG00000049130	P21583	Kit ligand	gencc
TMPRSS3	HGNC:11877	ENSG00000160183	P57727	Transmembrane protease serine 3	clinvar
BDP1	HGNC:13652	ENSG00000145734	A6H8Y1	Transcription factor TFIIIB component B’’ homolog	clinvar
CCDC140	HGNC:26514	ENSG00000163081	Q96MF4	Coiled-coil domain-containing protein 140	clinvar
EDN3	HGNC:3178	ENSG00000124205	P14138	Endothelin-3	clinvar
EDNRB	HGNC:3180	ENSG00000136160	P24530	Endothelin receptor type B	clinvar
MYO6	HGNC:7605	ENSG00000196586	Q9UM54	Unconventional myosin-VI	clinvar
POLR2F	HGNC:9193	ENSG00000100142	P61218	DNA-directed RNA polymerases I, II, and III subunit RPABC2	clinvar

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.
PAX3	Paired box protein Pax-3	Transcription factor that may regulate cell proliferation, migration and apoptosis.
SNAI2	Zinc finger protein SNAI2	Transcriptional repressor that modulates both activator-dependent and basal transcription.
KITLG	Kit ligand	Ligand for the receptor-type protein-tyrosine kinase KIT.
TMPRSS3	Transmembrane protease serine 3	Probable serine protease that plays a role in hearing.
BDP1	Transcription factor TFIIIB component B’’ homolog	General activator of RNA polymerase III transcription.
EDN3	Endothelin-3	Endothelins are endothelium-derived vasoconstrictor peptides.
EDNRB	Endothelin receptor type B	Non-specific receptor for endothelin 1, 2, and 3.
MYO6	Unconventional myosin-VI	Myosins are actin-based motor molecules with ATPase activity.
POLR2F	DNA-directed RNA polymerases I, II, and III subunit RPABC2	DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.

Protein-family classification

Druggable: 2 · Difficult: 5 · Unknown: 4 · Druggable fraction: 0.18

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	4	3.0×	0.176
Protease	1	3.3×	0.601
GPCR	1	2.2×	0.601
Scaffold/PPI	1	1.6×	0.601
Other/Unknown	4	0.7×	0.946

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MITF	Transcription factor	no		bHLH_dom, MiT/TFE_C, MiT/TFE_N
PAX3	Transcription factor	no		HD, Paired_dom, Homeodomain-like_sf
SNAI2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf,
KITLG	Other/Unknown	no		SCF, 4_helix_cytokine-like_core
TMPRSS3	Protease	yes		SRCR, Trypsin_dom, Peptidase_S1A
BDP1	Transcription factor	no		SANT/Myb, Homeodomain-like_sf, TFIIIB_B’’_Myb
CCDC140	Other/Unknown	no
EDN3	Other/Unknown	no		Endothln-like_toxin, Endothelin_toxin_CS, Endothelin
EDNRB	GPCR	yes		GPCR_Rhodpsn, Endthln_rcpt, ETB_rcpt
MYO6	Scaffold/PPI	no		Myosin_head_motor_dom-like, SH3_Myosin, Myosin_S1_N
POLR2F	Other/Unknown	no		Pol_omega/Rpo6/RPB6, Rpo6/Rpb6, DNA-dir_RNA_polK_14-18kDa_CS

Expression context

Cohort genes with no expression data: 0.

10 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)	11
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower lobe of lung	2
pigmented layer of retina	1
retina	1
skeletal muscle tissue of biceps brachii	1
male germ line stem cell (sensu Vertebrata) in testis	1
nasal cavity mucosa	1
olfactory segment of nasal mucosa	1
cartilage tissue	1
stromal cell of endometrium	1
tibia	1
cardia of stomach	1
visceral pleura	1
bronchial epithelial cell	1
pancreatic ductal cell	1
right uterine tube	1
calcaneal tendon	1
colonic epithelium	1
sural nerve	1
epithelium of nasopharynx	1
mucosa of paranasal sinus	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
PAX3	116	broad	marker	olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis, nasal cavity mucosa
SNAI2	254	ubiquitous	marker	tibia, cartilage tissue, stromal cell of endometrium
KITLG	262	ubiquitous	marker	visceral pleura, cardia of stomach, lower lobe of lung
TMPRSS3	177	tissue_specific	marker	pancreatic ductal cell, right uterine tube, bronchial epithelial cell
BDP1	134	ubiquitous	marker	sural nerve, calcaneal tendon, colonic epithelium
CCDC140	42		yes	superficial temporal artery, epithelium of nasopharynx, mucosa of paranasal sinus
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
MYO6	278	ubiquitous	marker	amniotic fluid, medial globus pallidus, corpus callosum
POLR2F	293	ubiquitous	marker	C1 segment of cervical spinal cord, spinal cord, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 9.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SNAI2	3,657
KITLG	3,075
MYO6	2,972
PAX3	2,960
MITF	2,908
EDNRB	2,415
BDP1	1,581
EDN3	1,376
TMPRSS3	1,056
POLR2F	369

Intra-cohort edges

A	B	Sources
BDP1	POLR2F	intact
CCDC140	PAX3	string_interaction
EDN3	EDNRB	string_interaction
EDN3	KITLG	string_interaction
EDN3	PAX3	string_interaction
EDNRB	KITLG	string_interaction
MITF	PAX3	string_interaction
MYO6	TMPRSS3	string_interaction
PAX3	SNAI2	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR2F	P61218	60
EDNRB	P24530	18
BDP1	A6H8Y1	13
MITF	O75030	12
MYO6	Q9UM54	8
KITLG	P21583	6
PAX3	P23760	1
EDN3	P14138	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMPRSS3	P57727	87.09
SNAI2	O43623	64.87
CCDC140	Q96MF4	58.70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 143. Enrichment computed across 11 evidence-associated genes (9 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 9 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	6	119.0×	3e-10	MITF, PAX3, SNAI2, EDN3, EDNRB, KITLG
RNA Polymerase III Transcription Initiation From Type 2 Promoter	2	94.0×	0.007	BDP1, POLR2F
RNA Polymerase III Transcription Initiation From Type 1 Promoter	2	90.6×	0.007	BDP1, POLR2F
RNA Polymerase III Transcription Initiation From Type 3 Promoter	2	90.6×	0.007	BDP1, POLR2F
RNA Polymerase III Transcription Initiation	2	74.6×	0.008	BDP1, POLR2F
RNA Polymerase III Transcription	2	72.5×	0.008	BDP1, POLR2F
RNA Polymerase III Abortive And Retractive Initiation	2	61.9×	0.009	BDP1, POLR2F
Regulation of MITF-M dependent genes involved in metabolism	1	423.0×	0.042	MITF
MITF-M-regulated melanocyte development	2	25.4×	0.042	MITF, SNAI2
Regulation of MITF-M dependent genes involved in invasion	1	317.2×	0.045	MITF
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	181.3×	0.069	MITF
Gap junction degradation	1	105.7×	0.069	MYO6
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	97.6×	0.069	MITF
RHOBTB GTPase Cycle	1	90.6×	0.069	MYO6
FGFR2 mutant receptor activation	1	84.6×	0.069	POLR2F
Glutamate binding, activation of AMPA receptors and synaptic plasticity	1	84.6×	0.069	MYO6
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	74.6×	0.069	MITF
RNA Polymerase III Chain Elongation	1	70.5×	0.069	POLR2F
Regulation of MITF-M-dependent genes involved in apoptosis	1	70.5×	0.069	MITF
Specification of the neural plate border	1	70.5×	0.069	PAX3
Regulation of KIT signaling	1	66.8×	0.069	KITLG
Signaling by FGFR2 IIIa TM	1	66.8×	0.069	POLR2F
SUMOylation of transcription factors	1	63.4×	0.069	MITF
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	1	63.4×	0.069	MITF
Trafficking of AMPA receptors	1	60.4×	0.069	MYO6
Abortive elongation of HIV-1 transcript in the absence of Tat	1	55.2×	0.069	POLR2F
RNA Polymerase III Transcription Termination	1	55.2×	0.069	POLR2F
Gap junction trafficking and regulation	1	52.9×	0.069	MYO6
Gap junction trafficking	1	52.9×	0.069	MYO6
RHOBTB2 GTPase cycle	1	52.9×	0.069	MYO6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 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	240.7×	3e-05	MITF, EDN3, EDNRB
vein smooth muscle contraction	2	842.6×	1e-04	EDN3, EDNRB
sensory perception of sound	4	40.4×	1e-04	PAX3, SNAI2, TMPRSS3, MYO6
neural crest cell migration	3	101.1×	1e-04	EDN3, EDNRB, KITLG
vasoconstriction	2	177.4×	0.002	EDN3, EDNRB
enteric smooth muscle cell differentiation	1	1685.2×	0.011	EDNRB
desmosome disassembly	1	1685.2×	0.011	SNAI2
RNA polymerase III preinitiation complex assembly	1	1685.2×	0.011	BDP1
response to endothelin	1	1685.2×	0.011	EDNRB
positive regulation of myeloid leukocyte differentiation	1	842.6×	0.011	KITLG
posterior midgut development	1	842.6×	0.011	EDNRB
negative regulation of neuron maturation	1	842.6×	0.011	EDNRB
regulation of fever generation	1	842.6×	0.011	EDNRB
aldosterone metabolic process	1	842.6×	0.011	EDNRB
negative regulation of vitamin D receptor signaling pathway	1	842.6×	0.011	SNAI2
melanocyte apoptotic process	1	842.6×	0.011	MITF
regulation of RNA biosynthetic process	1	842.6×	0.011	MITF
myeloid leukocyte differentiation	1	561.7×	0.011	KITLG
regulation of chemokine production	1	561.7×	0.011	SNAI2
negative regulation of mast cell apoptotic process	1	561.7×	0.011	KITLG
regulation of developmental pigmentation	1	561.7×	0.011	EDN3
positive regulation of penile erection	1	561.7×	0.011	EDNRB
regulation of branching involved in salivary gland morphogenesis	1	561.7×	0.011	SNAI2
melanocyte migration	1	561.7×	0.011	KITLG
mast cell migration	1	561.7×	0.011	KITLG
chordate pharynx development	1	561.7×	0.011	EDNRB
positive regulation of hematopoietic progenitor cell differentiation	1	561.7×	0.011	KITLG
negative regulation of hematopoietic stem cell proliferation	1	561.7×	0.011	SNAI2
renin secretion into blood stream	1	421.3×	0.012	EDNRB
cell migration involved in endocardial cushion formation	1	421.3×	0.012	SNAI2

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 9

Druggability breadth: 4 of 11 evidence-associated genes (36%) 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
EDNRB	AMBRISENTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EDNRB	16	4
MITF	3	4
PAX3	0	0
SNAI2	0	0
KITLG	0	0
TMPRSS3	0	0
BDP1	0	0
CCDC140	0	0
EDN3	0	0
MYO6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PERHEXILINE MALEATE	4	MITF
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
CLAZOSENTAN	3	EDNRB
DARUSENTAN	3	EDNRB
AVOSENTAN	3	EDNRB
TEZOSENTAN	3	EDNRB
ATRASENTAN	3	EDNRB
HOMIDIUM BROMIDE	2	MITF
FELOPRENTAN	2	EDNRB
ENRASENTAN	2	EDNRB
ENDOTHELIN	2	EDNRB

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
PAX3	17	Binding:17
MITF	10	Functional:10
KITLG	1	Binding:1

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: 11; 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)
PERHEXILINE MALEATE	4	MITF
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
CLAZOSENTAN	3	EDNRB
DARUSENTAN	3	EDNRB
AVOSENTAN	3	EDNRB
TEZOSENTAN	3	EDNRB
ATRASENTAN	3	EDNRB
HOMIDIUM BROMIDE	2	MITF
FELOPRENTAN	2	EDNRB
ENRASENTAN	2	EDNRB
ENDOTHELIN	2	EDNRB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	MITF, EDNRB
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	TMPRSS3
E	Difficult family or no structure, no drug	8	PAX3, SNAI2, KITLG, BDP1, CCDC140, EDN3, MYO6, POLR2F

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EDN3	0	EDNRB
PAX3	17	—
SNAI2	0	—
KITLG	1	—
TMPRSS3	0	—
BDP1	0	—
CCDC140	0	—
MYO6	0	—
POLR2F	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02418936	Not specified	UNKNOWN	Development and Clinical Application of Two New Genetic Deafness Gene Diagnostic Kit