Waardenburg syndrome type 4C

Summary

Waardenburg syndrome type 4C (MONDO:0013202) is a disease caused by SOX10 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: SOX10 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 119

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Waardenburg syndrome type 4C
Mondo ID	MONDO:0013202
MeSH	C567679
OMIM	613266
DOID	DOID:0110955
UMLS	C2750452
MedGen	413310
GARD	0015642
Is cancer (heuristic)	no

Also known as: Waardenburg syndrome type 4C · Waardenburg syndrome, type 4C · WS4C

Data availability: 119 ClinVar variants · 4 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-Shah syndrome › Waardenburg syndrome type 4C

Related subtypes (2): Waardenburg syndrome type 4A, Waardenburg syndrome type 4B

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

119 retrieved; paginated sample, class counts are floors:

60 pathogenic, 38 likely pathogenic, 7 pathogenic/likely pathogenic, 6 conflicting classifications of pathogenicity, 6 uncertain significance, 1 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
545010	GRCh38/hg38 22q13.1(chr22:37805546-37983784)x1	LOC130067392	Pathogenic	no assertion criteria provided
1065048	NM_006941.4(SOX10):c.570C>A (p.Cys190Ter)	POLR2F	Pathogenic	criteria provided, single submitter
1185066	NM_006941.4(SOX10):c.378C>A (p.Tyr126Ter)	POLR2F	Pathogenic	criteria provided, single submitter
1185090	NM_006941.4(SOX10):c.520C>T (p.Gln174Ter)	POLR2F	Pathogenic	criteria provided, single submitter
1202633	NM_006941.4(SOX10):c.448A>G (p.Lys150Glu)	POLR2F	Pathogenic	criteria provided, single submitter
1407649	NM_006941.4(SOX10):c.481C>T (p.Arg161Cys)	POLR2F	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3601802	NM_006941.4(SOX10):c.1155_1174del (p.His387fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601805	NM_006941.4(SOX10):c.1206C>A (p.Tyr402Ter)	POLR2F	Pathogenic	criteria provided, single submitter
3601806	NM_006941.4(SOX10):c.1207del (p.Ser403fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601808	NM_006941.4(SOX10):c.1214del (p.His405fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601809	NM_006941.4(SOX10):c.1309del (p.Thr437fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601810	NM_006941.4(SOX10):c.1338del (p.Gln448fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601811	NM_006941.4(SOX10):c.1369_1375del (p.Gln457fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601812	NM_006941.4(SOX10):c.207dup (p.Val70fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601814	NM_006941.4(SOX10):c.220G>T (p.Glu74Ter)	POLR2F	Pathogenic	criteria provided, multiple submitters, no conflicts
3601815	NM_006941.4(SOX10):c.272_275dup (p.Val94fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601816	NM_006941.4(SOX10):c.284_285del (p.Asn95fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601817	NM_006941.4(SOX10):c.318del (p.Pro107_Met108insTer)	POLR2F	Pathogenic	criteria provided, single submitter
3601819	NM_006941.4(SOX10):c.321del (p.Pro107_Met108insTer)	POLR2F	Pathogenic	criteria provided, single submitter
3601820	NM_006941.4(SOX10):c.332dup (p.Met112fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601825	NM_006941.4(SOX10):c.393C>A (p.Asn131Lys)	POLR2F	Pathogenic	criteria provided, single submitter
3601826	NM_006941.4(SOX10):c.397G>T (p.Glu133Ter)	POLR2F	Pathogenic	criteria provided, single submitter
3601828	NM_006941.4(SOX10):c.405_406insTGGGCAC (p.Lys136fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601829	NM_006941.4(SOX10):c.407_408insCGCT (p.Lys136fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601830	NM_006941.4(SOX10):c.408_409insCTCA (p.Thr137fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601831	NM_006941.4(SOX10):c.409del (p.Thr137fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601833	NM_006941.4(SOX10):c.413_414del (p.Leu138fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601836	NM_006941.4(SOX10):c.424dup (p.Trp142fs)	POLR2F	Pathogenic	criteria provided, single submitter
3601837	NM_006941.4(SOX10):c.429-2A>C	POLR2F	Pathogenic	criteria provided, single submitter
3601840	NM_006941.4(SOX10):c.476G>A (p.Arg159Gln)	POLR2F	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · 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
SOX10	Definitive	Autosomal dominant	Waardenburg syndrome type 4C	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SOX10	HGNC:11190	ENSG00000100146	P56693	Transcription factor SOX-10	gencc
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)
SOX10	Transcription factor SOX-10	Transcription factor that plays a central role in developing and mature glia.
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: 0 · Difficult: 1 · Unknown: 1 · 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	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOX10	Transcription factor	no		HMG_box_dom, Sox_N, HMG_box_dom_sf
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.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
dorsal motor nucleus of vagus nerve	1
inferior olivary complex	1
sural nerve	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
SOX10	218	broad	marker	inferior olivary complex, sural nerve, dorsal motor nucleus of vagus nerve
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
SOX10	3,696
POLR2F	369

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR2F	P61218	60

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SOX10	P56693	57.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 110. Enrichment computed across 2 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
Regulation of CDH19 Expression and Function	1	713.8×	0.017	SOX10
FGFR2 mutant receptor activation	1	380.7×	0.017	POLR2F
Regulation of Homotypic Cell-Cell Adhesion	1	335.9×	0.017	SOX10
Regulation of Expression and Function of Type II Classical Cadherins	1	335.9×	0.017	SOX10
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
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	184.2×	0.017	SOX10
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

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
positive regulation of gliogenesis	1	4213.0×	0.006	SOX10
morphogenesis of a branching epithelium	1	1685.2×	0.006	SOX10
cellular response to progesterone stimulus	1	1404.3×	0.006	SOX10
negative regulation of Schwann cell proliferation	1	1203.7×	0.006	SOX10
lacrimal gland development	1	1053.2×	0.006	SOX10
tRNA transcription by RNA polymerase III	1	766.0×	0.006	POLR2F
transcription by RNA polymerase I	1	702.2×	0.006	POLR2F
central nervous system myelination	1	495.6×	0.006	SOX10
enteric nervous system development	1	495.6×	0.006	SOX10
digestive tract morphogenesis	1	495.6×	0.006	SOX10
melanocyte differentiation	1	401.2×	0.007	SOX10
positive regulation of myelination	1	383.0×	0.007	SOX10
developmental growth	1	366.4×	0.007	SOX10
oligodendrocyte development	1	300.9×	0.007	SOX10
positive regulation of neuroblast proliferation	1	290.6×	0.007	SOX10
peripheral nervous system development	1	290.6×	0.007	SOX10
transcription elongation by RNA polymerase II	1	221.7×	0.008	SOX10
cell maturation	1	221.7×	0.008	SOX10
oligodendrocyte differentiation	1	210.7×	0.008	SOX10
neuroblast proliferation	1	183.2×	0.009	SOX10
morphogenesis of an epithelium	1	172.0×	0.009	SOX10
neural crest cell migration	1	168.5×	0.009	SOX10
cellular response to xenobiotic stimulus	1	120.4×	0.012	SOX10
anatomical structure morphogenesis	1	69.6×	0.019	SOX10
negative regulation of canonical Wnt signaling pathway	1	58.9×	0.022	SOX10
in utero embryonic development	1	36.0×	0.033	SOX10
transcription by RNA polymerase II	1	35.3×	0.033	POLR2F
positive regulation of gene expression	1	19.4×	0.058	SOX10
negative regulation of apoptotic process	1	17.4×	0.063	SOX10
positive regulation of DNA-templated transcription	1	14.0×	0.075	SOX10

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SOX10	0	0
POLR2F	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	2	SOX10, POLR2F

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SOX10	0	—
POLR2F	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.