Waardenburg syndrome type 2A

Summary

Waardenburg syndrome type 2A (MONDO:0008671) is a disease caused by MITF (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: MITF (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 988
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Waardenburg syndrome type 2A
Mondo ID	MONDO:0008671
MeSH	C536464
OMIM	193510
DOID	DOID:0110950
NCIT	C75011
UMLS	C1860339
MedGen	349786
GARD	0005521
Is cancer (heuristic)	no

Also known as: MITF Waardenburg syndrome type 2 · Waardenburg syndrome type 2 caused by mutation in MITF · Waardenburg syndrome type 2A · Waardenburg syndrome type IIA · Waardenburg syndrome, type 2A · WS2A

Data availability: 988 ClinVar variants · 3 GenCC gene-disease records.

Disease family

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 › Waardenburg syndrome type 2A

Related subtypes (4): 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

600 retrieved; paginated sample, class counts are floors:

287 uncertain significance, 173 likely benign, 46 pathogenic, 33 conflicting classifications of pathogenicity, 25 likely pathogenic, 23 benign, 9 benign/likely benign, 3 pathogenic/likely pathogenic, 1 pathogenic/likely pathogenic; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048557	NM_001354604.2(MITF):c.1291dup (p.Cys431fs)	MITF	Pathogenic	criteria provided, single submitter
1202631	NM_001354604.2(MITF):c.644dup (p.His215fs)	MITF	Pathogenic	criteria provided, single submitter
1202636	Single allele	MITF	Pathogenic	criteria provided, single submitter
1297077	NM_001354604.2(MITF):c.955+1G>C	MITF	Pathogenic	no assertion criteria provided
1324720	NM_001354604.2(MITF):c.1061T>G (p.Leu354Ter)	MITF	Pathogenic	criteria provided, single submitter
14270	NM_000248.4(MITF):c.33+1G>A	MITF	Pathogenic	no assertion criteria provided
14271	NM_001354604.2(MITF):c.763-2A>C	MITF	Pathogenic	no assertion criteria provided
14272	NM_001354604.2(MITF):c.964AGA[2] (p.Arg324del)	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
14273	NM_001354604.2(MITF):c.1069T>C (p.Ser357Pro)	MITF	Pathogenic	no assertion criteria provided
14274	NM_001354604.2(MITF):c.1145del (p.Glu382fs)	MITF	Pathogenic	no assertion criteria provided
14276	NM_001354604.2(MITF):c.961C>T (p.Arg321Ter)	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
2020473	NM_001354604.2(MITF):c.764T>A (p.Leu255Ter)	MITF	Pathogenic	criteria provided, single submitter
2024980	NM_001354604.2(MITF):c.643_644dup (p.Ser216fs)	MITF	Pathogenic	criteria provided, single submitter
2203401	NM_001354604.2(MITF):c.815del (p.Pro272fs)	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
228363	NM_001354604.2(MITF):c.1129C>T (p.Arg377Ter)	MITF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236050	NM_001354604.2(MITF):c.1208del (p.Gly403fs)	MITF	Pathogenic	no assertion criteria provided
2422628	NC_000003.11:g.(?69985874)(70014399_?)del	MITF	Pathogenic	criteria provided, single submitter
2422629	NC_000003.11:g.(?70013978)(70014399_?)del	MITF	Pathogenic	criteria provided, single submitter
2422630	NC_000003.11:g.(?69985874)(69990502_?)del	MITF	Pathogenic	criteria provided, single submitter
2922420	NM_001354604.2(MITF):c.367del (p.Leu123fs)	MITF	Pathogenic	criteria provided, single submitter
2947585	NM_001354604.2(MITF):c.440T>G (p.Leu147Ter)	MITF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29792	NM_001354604.2(MITF):c.1273G>A (p.Glu425Lys)	MITF	Pathogenic/Likely pathogenic; risk factor	criteria provided, multiple submitters, no conflicts
3382232	NM_001354604.2(MITF):c.959A>G (p.Glu320Gly)	MITF	Pathogenic	criteria provided, single submitter
3601241	NM_001354604.2(MITF):c.1574del (p.Thr525fs)	MITF	Pathogenic	criteria provided, single submitter
3601242	NM_001354604.2(MITF):c.673del (p.Asp225fs)	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
3601243	NM_001354604.2(MITF):c.689del (p.Ile230fs)	MITF	Pathogenic	criteria provided, single submitter
3601244	NM_001354604.2(MITF):c.723del (p.Leu242fs)	MITF	Pathogenic	criteria provided, single submitter
3601246	NM_001354604.2(MITF):c.759_760del (p.Thr254fs)	MITF	Pathogenic	criteria provided, single submitter
3601247	NM_001354604.2(MITF):c.763-1G>A	MITF	Pathogenic	criteria provided, single submitter
3601248	NM_001354604.2(MITF):c.772_773del (p.Ser258fs)	MITF	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 10 · 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

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
EDNRB	Orphanet:388	Hirschsprung disease
EDNRB	Orphanet:895	Waardenburg syndrome type 2
EDNRB	Orphanet:897	Waardenburg-Shah syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MITF	HGNC:7105	ENSG00000187098	O75030	Microphthalmia-associated transcription factor	gencc,clinvar
EDNRB	HGNC:3180	ENSG00000136160	P24530	Endothelin receptor type B	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.
EDNRB	Endothelin receptor type B	Non-specific receptor for endothelin 1, 2, and 3.
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: 1 · Difficult: 1 · 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
GPCR	1	8.0×	0.360
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MITF	Transcription factor	no		bHLH_dom, MiT/TFE_C, MiT/TFE_N
EDNRB	GPCR	yes		GPCR_Rhodpsn, Endthln_rcpt, ETB_rcpt
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.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pigmented layer of retina	1
retina	1
skeletal muscle tissue of biceps brachii	1
lateral globus pallidus	1
lower lobe of lung	1
parotid gland	1
C1 segment of cervical spinal cord	1
spinal cord	1
tibial nerve	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
EDNRB	274	broad	marker	parotid gland, lateral globus pallidus, lower lobe of lung
POLR2F	293	ubiquitous	marker	C1 segment of cervical spinal cord, spinal cord, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MITF	2,908
EDNRB	2,415
POLR2F	369

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR2F	P61218	60
EDNRB	P24530	18
MITF	O75030	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 114. Enrichment computed across 3 evidence-associated genes (3 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 3 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	2	119.0×	0.011	MITF, EDNRB
Regulation of MITF-M dependent genes involved in metabolism	1	1268.9×	0.025	MITF
Regulation of MITF-M dependent genes involved in invasion	1	951.7×	0.025	MITF
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	543.8×	0.025	MITF
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	292.8×	0.025	MITF
FGFR2 mutant receptor activation	1	253.8×	0.025	POLR2F
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	223.9×	0.025	MITF
RNA Polymerase III Chain Elongation	1	211.5×	0.025	POLR2F
Regulation of MITF-M-dependent genes involved in apoptosis	1	211.5×	0.025	MITF
Signaling by FGFR2 IIIa TM	1	200.3×	0.025	POLR2F
SUMOylation of transcription factors	1	190.3×	0.025	MITF
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	1	190.3×	0.025	MITF
Abortive elongation of HIV-1 transcript in the absence of Tat	1	165.5×	0.025	POLR2F
RNA Polymerase III Transcription Termination	1	165.5×	0.025	POLR2F
MicroRNA (miRNA) biogenesis	1	152.3×	0.025	POLR2F
Activation of HOX genes during differentiation	1	146.4×	0.025	POLR2F
Signaling by FGFR in disease	1	141.0×	0.025	POLR2F
FGFR2 alternative splicing	1	141.0×	0.025	POLR2F
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	141.0×	0.025	POLR2F
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	1	135.9×	0.025	POLR2F
Signaling by FGFR2	1	135.9×	0.025	POLR2F
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	135.9×	0.025	POLR2F
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	135.9×	0.025	POLR2F
RNA Pol II CTD phosphorylation and interaction with CE	1	135.9×	0.025	POLR2F
PIWI-interacting RNA (piRNA) biogenesis	1	131.3×	0.025	POLR2F
mRNA Capping	1	126.9×	0.025	POLR2F
Telomere Maintenance	1	122.8×	0.025	POLR2F
Pausing and recovery of Tat-mediated HIV elongation	1	122.8×	0.025	POLR2F
Tat-mediated HIV elongation arrest and recovery	1	122.8×	0.025	POLR2F
Gene Silencing by RNA	1	119.0×	0.025	POLR2F

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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	2	535.0×	3e-04	MITF, EDNRB
enteric smooth muscle cell differentiation	1	5617.3×	0.003	EDNRB
response to endothelin	1	5617.3×	0.003	EDNRB
posterior midgut development	1	2808.7×	0.003	EDNRB
negative regulation of neuron maturation	1	2808.7×	0.003	EDNRB
regulation of fever generation	1	2808.7×	0.003	EDNRB
aldosterone metabolic process	1	2808.7×	0.003	EDNRB
melanocyte apoptotic process	1	2808.7×	0.003	MITF
regulation of RNA biosynthetic process	1	2808.7×	0.003	MITF
positive regulation of penile erection	1	1872.4×	0.003	EDNRB
chordate pharynx development	1	1872.4×	0.003	EDNRB
renin secretion into blood stream	1	1404.3×	0.004	EDNRB
vein smooth muscle contraction	1	1404.3×	0.004	EDNRB
renal sodium excretion	1	1404.3×	0.004	EDNRB
renal albumin absorption	1	1123.5×	0.004	EDNRB
neuroblast migration	1	1123.5×	0.004	EDNRB
heparin proteoglycan metabolic process	1	936.2×	0.004	EDNRB
epithelial fluid transport	1	702.2×	0.005	EDNRB
developmental pigmentation	1	702.2×	0.005	EDNRB
negative regulation of protein metabolic process	1	702.2×	0.005	EDNRB
positive regulation of DNA-templated transcription initiation	1	624.1×	0.005	MITF
endothelin receptor signaling pathway	1	561.7×	0.005	EDNRB
response to sodium phosphate	1	561.7×	0.005	EDNRB
tRNA transcription by RNA polymerase III	1	510.7×	0.005	POLR2F
regulation of osteoclast differentiation	1	510.7×	0.005	MITF
transcription by RNA polymerase I	1	468.1×	0.005	POLR2F
regulation of pH	1	468.1×	0.005	EDNRB
negative regulation of adenylate cyclase activity	1	468.1×	0.005	EDNRB
podocyte differentiation	1	468.1×	0.005	EDNRB
positive regulation of urine volume	1	432.1×	0.005	EDNRB

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 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
EDNRB	AMBRISENTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EDNRB	16	4
MITF	3	4
POLR2F	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
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: 3; 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	0
E	Difficult family or no structure, no drug	1	POLR2F

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
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
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns