Waardenburg syndrome type 3

Summary

Waardenburg syndrome type 3 (MONDO:0007862) is a disease caused by PAX3 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: PAX3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 23
• Phenotypes (HPO): 22

Clinical features

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000271	Abnormality of the face	Very frequent (80-99%)
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000446	Narrow nasal bridge	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0000574	Thick eyebrow	Very frequent (80-99%)
HP:0000581	Blepharophimosis	Very frequent (80-99%)
HP:0001167	Abnormality of finger	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0002817	Abnormality of the upper limb	Very frequent (80-99%)
HP:0005048	Synostosis of carpal bones	Very frequent (80-99%)
HP:0010554	Cutaneous finger syndactyly	Very frequent (80-99%)
HP:0010804	Tented upper lip vermilion	Very frequent (80-99%)
HP:0000506	Telecanthus	Frequent (30-79%)
HP:0011364	White hair	Frequent (30-79%)
HP:0100750	Atelectasis	Frequent (30-79%)
HP:0001063	Acrocyanosis	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001258	Spastic paraplegia	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0002779	Tracheomalacia	Occasional (5-29%)
HP:0100490	Camptodactyly of finger	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Waardenburg syndrome type 3
Mondo ID	MONDO:0007862
OMIM	148820
Orphanet	896
DOID	DOID:0110949
ICD-11	847608197
UMLS	C0079661
MedGen	86948
GARD	0005523
Is cancer (heuristic)	no

Also known as: Klein-Waardenburg syndrome · Waardenburg syndrome type III · Waardenburg syndrome with limb anomalies · Waardenburg syndrome with upper limb anomalies · Waardenburg syndrome, type 3 · White forelock (poliosis) syndrome with multiple congenital malformations · WS3

Data availability: 23 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 3

Related subtypes (4): 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

23 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 7 pathogenic, 5 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064867	NM_181458.4(PAX3):c.829C>T (p.Gln277Ter)	PAX3	Pathogenic	criteria provided, single submitter
279964	NM_181458.4(PAX3):c.812G>A (p.Arg271His)	PAX3	Pathogenic	criteria provided, multiple submitters, no conflicts
3382706	NM_181458.4(PAX3):c.452-1G>A	PAX3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4212	NM_181458.4(PAX3):c.251C>T (p.Ser84Phe)	PAX3	Pathogenic	criteria provided, multiple submitters, no conflicts
4214	NM_181458.4(PAX3):c.139A>C (p.Asn47His)	PAX3	Pathogenic	no assertion criteria provided
4215	NM_181458.4(PAX3):c.386_398del (p.Phe129fs)	PAX3	Pathogenic	no assertion criteria provided
4216	NM_181458.4(PAX3):c.268T>C (p.Tyr90His)	PAX3	Pathogenic	no assertion criteria provided
503680	NM_181458.4(PAX3):c.667C>T (p.Arg223Ter)	PAX3	Pathogenic	criteria provided, multiple submitters, no conflicts
3336795	NM_181458.4(PAX3):c.265A>G (p.Arg89Gly)	PAX3	Likely pathogenic	criteria provided, single submitter
3764710	NM_181458.4(PAX3):c.178G>T (p.Val60Leu)	PAX3	Likely pathogenic	criteria provided, single submitter
4526662	NM_181458.4(PAX3):c.587-10416A>G	PAX3	Likely pathogenic	criteria provided, single submitter
488032	NM_181458.4(PAX3):c.142G>T (p.Gly48Cys)	PAX3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
547736	NM_181458.4(PAX3):c.246C>G (p.Cys82Trp)	PAX3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
504786	NM_181458.4(PAX3):c.580G>A (p.Glu194Lys)	PAX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
504788	NM_181458.4(PAX3):c.540C>G (p.Ser180Arg)	PAX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1306788	NM_181458.4(PAX3):c.1036T>C (p.Ser346Pro)	LOC126806529	Uncertain significance	criteria provided, multiple submitters, no conflicts
1387929	NM_181458.4(PAX3):c.998C>T (p.Pro333Leu)	LOC126806529	Uncertain significance	criteria provided, multiple submitters, no conflicts
1027898	NM_181458.4(PAX3):c.467G>C (p.Arg156Pro)	PAX3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1696489	NM_181458.4(PAX3):c.683C>T (p.Ala228Val)	PAX3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3382692	NM_181458.4(PAX3):c.709G>C (p.Ala237Pro)	PAX3	Uncertain significance	criteria provided, single submitter
3775243	NM_181458.4(PAX3):c.193C>A (p.His65Asn)	PAX3	Uncertain significance	criteria provided, single submitter
4082071	NM_181458.4(PAX3):c.109C>G (p.Arg37Gly)	PAX3	Uncertain significance	no assertion criteria provided
195432	NM_181458.4(PAX3):c.129T>C (p.Gly43=)	PAX3	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 4 · 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
PAX3	Definitive	Autosomal dominant	Waardenburg syndrome	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PAX3	HGNC:8617	ENSG00000135903	P23760	Paired box protein Pax-3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PAX3	Paired box protein Pax-3	Transcription factor that may regulate cell proliferation, migration and apoptosis.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PAX3	Transcription factor	no		HD, Paired_dom, Homeodomain-like_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
nasal cavity mucosa	1
olfactory segment of nasal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PAX3	116	broad	marker	olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis, nasal cavity mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAX3	2,960

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PAX3	P23760	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Specification of the neural plate border	1	634.4×	0.005	PAX3
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.008	PAX3
HATs acetylate histones	1	79.3×	0.013	PAX3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
animal organ morphogenesis	1	191.5×	0.024	PAX3
muscle organ development	1	166.8×	0.024	PAX3
sensory perception of sound	1	100.9×	0.026	PAX3
nervous system development	1	45.9×	0.044	PAX3
apoptotic process	1	28.7×	0.048	PAX3
positive regulation of DNA-templated transcription	1	27.9×	0.048	PAX3
positive regulation of transcription by RNA polymerase II	1	14.9×	0.077	PAX3
regulation of transcription by RNA polymerase II	1	11.7×	0.086	PAX3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PAX3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PAX3	17	Binding:17

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	PAX3

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)
PAX3	17	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.