Waardenburg syndrome type 4A

Summary

Waardenburg syndrome type 4A (MONDO:0010192) is a disease caused by EDNRB (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: EDNRB (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 39

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Waardenburg syndrome type 4A
Mondo ID	MONDO:0010192
OMIM	277580
DOID	DOID:0110953
UMLS	C1848519
MedGen	341244
GARD	0015245
Is cancer (heuristic)	no

Also known as: EDNRB Waardenburg syndrome · Waardenburg syndrome caused by mutation in EDNRB · Waardenburg syndrome type 4A · Waardenburg syndrome, type 4A · Waardenburg-Shah syndrome · WS4A

Data availability: 39 ClinVar variants · 8 GenCC gene-disease records · 1 cell line.

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-Shah syndrome › Waardenburg syndrome type 4A

Related subtypes (2): 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

ClinVar germline variants

39 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 8 pathogenic, 7 likely pathogenic, 5 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 1 benign, 1 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
16639	NM_001122659.3(EDNRB):c.757C>T (p.Arg253Ter)	EDNRB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16640	NM_001122659.3(EDNRB):c.601C>T (p.Arg201Ter)	EDNRB	Pathogenic	criteria provided, multiple submitters, no conflicts
3064541	NM_001122659.3(EDNRB):c.292G>T (p.Glu98Ter)	EDNRB	Pathogenic	criteria provided, single submitter
545012	NM_001122659.3(EDNRB):c.57C>A (p.Cys19Ter)	EDNRB	Pathogenic/Likely pathogenic	no assertion criteria provided
16634	NM_001122659.3(EDNRB):c.548C>G (p.Ala183Gly)	EDNRB-AS1	Pathogenic	no assertion criteria provided
2633374	NM_001122659.3(EDNRB):c.1143dup (p.Asn382Ter)	EDNRB-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3233625	NM_001122659.3(EDNRB):c.902del (p.Met300_Leu301insTer)	EDNRB-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3376674	NM_001122659.3(EDNRB):c.677G>A (p.Trp226Ter)	EDNRB-AS1	Pathogenic	criteria provided, single submitter
547293	NM_001122659.3(EDNRB):c.521del (p.Cys174fs)	EDNRB-AS1	Pathogenic	criteria provided, single submitter
3775100	Single allele	LINC00347	Pathogenic	criteria provided, single submitter
590850	NM_006941.4(SOX10):c.429-1G>A	POLR2F	Pathogenic	criteria provided, single submitter
620636	NM_006941.4(SOX10):c.1315_1329del (p.Ile439_Ser443del)	POLR2F	Pathogenic	no assertion criteria provided
1064869	NM_001122659.3(EDNRB):c.777del (p.Val260fs)	EDNRB	Likely pathogenic	criteria provided, single submitter
1333432	NM_001122659.3(EDNRB):c.801+1G>T	EDNRB	Likely pathogenic	criteria provided, single submitter
1334125	NM_001122659.3(EDNRB):c.801+2T>C	EDNRB	Likely pathogenic	criteria provided, single submitter
3601071	NM_001122659.3(EDNRB):c.430G>T (p.Ala144Ser)	EDNRB	Likely pathogenic	criteria provided, single submitter
3601072	NM_001122659.3(EDNRB):c.431C>T (p.Ala144Val)	EDNRB	Likely pathogenic	criteria provided, single submitter
3236824	NM_001122659.3(EDNRB):c.1085+1G>A	EDNRB-AS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
547294	NM_001122659.3(EDNRB):c.550T>C (p.Ser184Pro)	EDNRB-AS1	Likely pathogenic	criteria provided, single submitter
1064933	NM_001201397.2(EDNRB):c.18T>A (p.Cys6Ter)	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
16638	NM_001122659.3(EDNRB):c.914G>A (p.Ser305Asn)	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225346	NM_001122659.3(EDNRB):c.-26G>A	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
619136	NM_001122659.3(EDNRB):c.553G>A (p.Val185Met)	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
16633	NM_001122659.3(EDNRB):c.828G>T (p.Trp276Cys)	EDNRB-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1064870	NM_001122659.3(EDNRB):c.1103A>T (p.Asp368Val)	EDNRB	Uncertain significance	criteria provided, single submitter
1218338	NM_001122659.3(EDNRB):c.1212G>A (p.Trp404Ter)	EDNRB	Uncertain significance	criteria provided, multiple submitters, no conflicts
228662	NM_001122659.3(EDNRB):c.1285G>A (p.Gly429Arg)	EDNRB	Uncertain significance	criteria provided, multiple submitters, no conflicts
2584680	NM_001122659.3(EDNRB):c.886A>G (p.Met296Val)	EDNRB	Uncertain significance	criteria provided, single submitter
3377465	NM_001122659.3(EDNRB):c.41C>T (p.Ala14Val)	EDNRB	Uncertain significance	criteria provided, single submitter
3893125	NM_001122659.3(EDNRB):c.1059T>G (p.Asn353Lys)	EDNRB	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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

Orphanet rare-disease linkage (cohort genes)

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

Cohort genes → proteins

4 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EDNRB	HGNC:3180	ENSG00000136160	P24530	Endothelin receptor type B	gencc,clinvar
LINC00347	HGNC:27890	ENSG00000236678		long intergenic non-protein coding RNA 347	clinvar
EDNRB-AS1	HGNC:49045	ENSG00000225579		EDNRB antisense RNA 1	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)
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: 0 · Unknown: 3 · 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
GPCR	1	6.0×	0.314
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EDNRB	GPCR	yes		GPCR_Rhodpsn, Endthln_rcpt, ETB_rcpt
LINC00347	Other/Unknown	no
EDNRB-AS1	Other/Unknown	no
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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lateral globus pallidus	1
lower lobe of lung	1
parotid gland	1
left testis	1
right testis	1
testis	1
ganglionic eminence	1
male germ line stem cell (sensu Vertebrata) in testis	1
ventricular zone	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
EDNRB	274	broad	marker	parotid gland, lateral globus pallidus, lower lobe of lung
LINC00347	114	tissue_specific	marker	left testis, testis, right testis
EDNRB-AS1	101		yes	male germ line stem cell (sensu Vertebrata) in testis, ventricular zone, ganglionic eminence
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
EDNRB	2,415
POLR2F	369
LINC00347	0
EDNRB-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR2F	P61218	60
EDNRB	P24530	18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 100. Enrichment computed across 4 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
FGFR2 mutant receptor activation	1	380.7×	0.017	POLR2F
RNA Polymerase III Chain Elongation	1	317.2×	0.017	POLR2F
Signaling by FGFR2 IIIa TM	1	300.5×	0.017	POLR2F
Abortive elongation of HIV-1 transcript in the absence of Tat	1	248.3×	0.017	POLR2F
RNA Polymerase III Transcription Termination	1	248.3×	0.017	POLR2F
MicroRNA (miRNA) biogenesis	1	228.4×	0.017	POLR2F
Activation of HOX genes during differentiation	1	219.6×	0.017	POLR2F
Signaling by FGFR in disease	1	211.5×	0.017	POLR2F
FGFR2 alternative splicing	1	211.5×	0.017	POLR2F
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	211.5×	0.017	POLR2F
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	1	203.9×	0.017	POLR2F
Signaling by FGFR2	1	203.9×	0.017	POLR2F
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	203.9×	0.017	POLR2F
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	203.9×	0.017	POLR2F
RNA Pol II CTD phosphorylation and interaction with CE	1	203.9×	0.017	POLR2F
PIWI-interacting RNA (piRNA) biogenesis	1	196.9×	0.017	POLR2F
mRNA Capping	1	190.3×	0.017	POLR2F
Telomere Maintenance	1	184.2×	0.017	POLR2F
Pausing and recovery of Tat-mediated HIV elongation	1	184.2×	0.017	POLR2F
Tat-mediated HIV elongation arrest and recovery	1	184.2×	0.017	POLR2F
Gene Silencing by RNA	1	178.4×	0.017	POLR2F
HIV elongation arrest and recovery	1	173.0×	0.017	POLR2F
Pausing and recovery of HIV elongation	1	173.0×	0.017	POLR2F
Signaling by FGFR	1	173.0×	0.017	POLR2F
Positive epigenetic regulation of rRNA expression	1	173.0×	0.017	POLR2F
Formation of the Early Elongation Complex	1	167.9×	0.017	POLR2F
Formation of the HIV-1 Early Elongation Complex	1	167.9×	0.017	POLR2F
HIV Transcription Elongation	1	167.9×	0.017	POLR2F
RNA Polymerase III Transcription Initiation	1	167.9×	0.017	POLR2F
RNA Polymerase I Transcription Termination	1	163.1×	0.017	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
enteric smooth muscle cell differentiation	1	8426.0×	0.002	EDNRB
response to endothelin	1	8426.0×	0.002	EDNRB
posterior midgut development	1	4213.0×	0.002	EDNRB
negative regulation of neuron maturation	1	4213.0×	0.002	EDNRB
regulation of fever generation	1	4213.0×	0.002	EDNRB
aldosterone metabolic process	1	4213.0×	0.002	EDNRB
positive regulation of penile erection	1	2808.7×	0.002	EDNRB
chordate pharynx development	1	2808.7×	0.002	EDNRB
renin secretion into blood stream	1	2106.5×	0.002	EDNRB
vein smooth muscle contraction	1	2106.5×	0.002	EDNRB
renal sodium excretion	1	2106.5×	0.002	EDNRB
renal albumin absorption	1	1685.2×	0.002	EDNRB
neuroblast migration	1	1685.2×	0.002	EDNRB
heparin proteoglycan metabolic process	1	1404.3×	0.003	EDNRB
epithelial fluid transport	1	1053.2×	0.003	EDNRB
developmental pigmentation	1	1053.2×	0.003	EDNRB
negative regulation of protein metabolic process	1	1053.2×	0.003	EDNRB
endothelin receptor signaling pathway	1	842.6×	0.003	EDNRB
response to sodium phosphate	1	842.6×	0.003	EDNRB
tRNA transcription by RNA polymerase III	1	766.0×	0.003	POLR2F
transcription by RNA polymerase I	1	702.2×	0.003	POLR2F
regulation of pH	1	702.2×	0.003	EDNRB
negative regulation of adenylate cyclase activity	1	702.2×	0.003	EDNRB
podocyte differentiation	1	702.2×	0.003	EDNRB
positive regulation of urine volume	1	648.1×	0.003	EDNRB
protein transmembrane transport	1	648.1×	0.003	EDNRB
enteric nervous system development	1	495.6×	0.004	EDNRB
renal sodium ion absorption	1	495.6×	0.004	EDNRB
macrophage chemotaxis	1	468.1×	0.004	EDNRB
regulation of epithelial cell proliferation	1	468.1×	0.004	EDNRB

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EDNRB	16	4
LINC00347	0	0
EDNRB-AS1	0	0
POLR2F	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
CLAZOSENTAN	3	EDNRB
DARUSENTAN	3	EDNRB
AVOSENTAN	3	EDNRB
TEZOSENTAN	3	EDNRB
ATRASENTAN	3	EDNRB
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

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: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

16 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
CLAZOSENTAN	3	EDNRB
DARUSENTAN	3	EDNRB
AVOSENTAN	3	EDNRB
TEZOSENTAN	3	EDNRB
ATRASENTAN	3	EDNRB
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)	1	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	LINC00347, EDNRB-AS1, POLR2F

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)
LINC00347	0	—
EDNRB-AS1	0	—
POLR2F	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.