Waardenburg syndrome type 2E

Summary

Waardenburg syndrome type 2E (MONDO:0012698) is a disease caused by SOX10 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: SOX10 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 59
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Waardenburg syndrome type 2E
Mondo ID	MONDO:0012698
OMIM	611584
DOID	DOID:0110956
UMLS	C2700405
MedGen	398476
GARD	0015521
Is cancer (heuristic)	no

Also known as: SOX10 Waardenburg syndrome type 2 · Waardenburg syndrome type 2 caused by mutation in SOX10 · Waardenburg syndrome, type 2E · WS2E

Data availability: 59 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 2E

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

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

59 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
995941	GRCh37/hg19 22q13.1(chr22:38155164-38541997)	PLA2G6	Pathogenic	criteria provided, single submitter
1048554	NM_006941.4(SOX10):c.198_262del (p.Lys67fs)	POLR2F	Pathogenic	criteria provided, single submitter
1048555	NM_006941.4(SOX10):c.529_556del (p.Arg177fs)	POLR2F	Pathogenic	criteria provided, single submitter
1185090	NM_006941.4(SOX10):c.520C>T (p.Gln174Ter)	POLR2F	Pathogenic	criteria provided, single submitter
1220524	NM_006941.4(SOX10):c.12_13delinsAT (p.Gln5Ter)	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
1704560	NM_006941.4(SOX10):c.1086dup (p.Pro363fs)	POLR2F	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445675	NM_006941.4(SOX10):c.1195_1196del (p.Gln399fs)	POLR2F	Pathogenic	criteria provided, single submitter
3775367	NM_006941.4(SOX10):c.119C>A (p.Ser40Ter)	POLR2F	Pathogenic	criteria provided, single submitter
4538433	NM_006941.4(SOX10):c.405C>G (p.Ser135Arg)	POLR2F	Pathogenic	no assertion criteria provided
505653	NM_006941.4(SOX10):c.424T>C (p.Trp142Arg)	POLR2F	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
521356	NM_006941.4(SOX10):c.523C>T (p.Pro175Ser)	POLR2F	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523884	NM_006941.4(SOX10):c.232C>T (p.Gln78Ter)	POLR2F	Pathogenic	criteria provided, multiple submitters, no conflicts
545014	NM_006941.4(SOX10):c.1169C>G (p.Ser390Ter)	POLR2F	Pathogenic	no assertion criteria provided
547774	NM_006941.4(SOX10):c.127C>T (p.Arg43Ter)	POLR2F	Pathogenic	criteria provided, multiple submitters, no conflicts
599071	NM_006941.4(SOX10):c.487C>T (p.Gln163Ter)	POLR2F	Pathogenic	criteria provided, single submitter
801016	NM_006941.4(SOX10):c.426G>T (p.Trp142Cys)	POLR2F	Pathogenic	criteria provided, single submitter
805532	NM_006941.4(SOX10):c.1352_1359dup (p.His454fs)	POLR2F	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
915452	NM_006941.4(SOX10):c.479T>C (p.Leu160Pro)	POLR2F	Pathogenic	criteria provided, single submitter
915460	NM_006941.4(SOX10):c.1379del (p.Tyr460fs)	POLR2F	Pathogenic	no assertion criteria provided
995928	NM_006941.4(SOX10):c.7G>T (p.Glu3Ter)	POLR2F	Pathogenic	criteria provided, single submitter
995930	NM_006941.4(SOX10):c.326A>G (p.Asn109Ser)	POLR2F	Pathogenic	criteria provided, single submitter
995932	NM_006941.4(SOX10):c.341G>A (p.Trp114Ter)	POLR2F	Pathogenic	criteria provided, single submitter
995934	NM_006941.4(SOX10):c.428+1G>A	POLR2F	Pathogenic	criteria provided, single submitter
995935	NM_006941.4(SOX10):c.448A>T (p.Lys150Ter)	POLR2F	Pathogenic	criteria provided, single submitter
995936	NM_006941.4(SOX10):c.463G>T (p.Glu155Ter)	POLR2F	Pathogenic	criteria provided, single submitter
995937	NM_006941.4(SOX10):c.502del (p.His168fs)	POLR2F	Pathogenic	criteria provided, single submitter
995938	NM_006941.4(SOX10):c.776_780del (p.Asp259fs)	POLR2F	Pathogenic	criteria provided, single submitter
995939	NM_006941.4(SOX10):c.1063C>T (p.Gln355Ter)	POLR2F	Pathogenic	criteria provided, single submitter
995940	NM_006941.4(SOX10):c.1195C>T (p.Gln399Ter)	POLR2F	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 6 · 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
PLA2G6	Orphanet:199351	Adult-onset dystonia-parkinsonism
PLA2G6	Orphanet:35069	Infantile neuroaxonal dystrophy

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
SOX10	HGNC:11190	ENSG00000100146	P56693	Transcription factor SOX-10	gencc
PLA2G6	HGNC:9039	ENSG00000184381	O60733	85/88 kDa calcium-independent phospholipase A2	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)
SOX10	Transcription factor SOX-10	Transcription factor that plays a central role in developing and mature glia.
PLA2G6	85/88 kDa calcium-independent phospholipase A2	Calcium-independent phospholipase involved in phospholipid remodeling with implications in cellular membrane homeostasis, mitochondrial integrity and signal transduction.
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: 2 · 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
Scaffold/PPI	1	5.8×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOX10	Transcription factor	no		HMG_box_dom, Sox_N, HMG_box_dom_sf
PLA2G6	Scaffold/PPI	no	3.1.1.4	Ankyrin_rpt, PNPLA_dom, Acyl_Trfase/lysoPLipase
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
dorsal motor nucleus of vagus nerve	1
inferior olivary complex	1
sural nerve	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
right uterine tube	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
PLA2G6	232	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, left lobe of thyroid gland
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
PLA2G6	1,769
POLR2F	369

Structural data

PDB: 1 · AlphaFold-only: 2 · 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
PLA2G6	O60733	86.16
SOX10	P56693	57.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 115. 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
Acyl chain remodeling of CL	1	634.4×	0.025	PLA2G6
Regulation of CDH19 Expression and Function	1	475.8×	0.025	SOX10
FGFR2 mutant receptor activation	1	253.8×	0.025	POLR2F
Regulation of Homotypic Cell-Cell Adhesion	1	223.9×	0.025	SOX10
Regulation of Expression and Function of Type II Classical Cadherins	1	223.9×	0.025	SOX10
RNA Polymerase III Chain Elongation	1	211.5×	0.025	POLR2F
Signaling by FGFR2 IIIa TM	1	200.3×	0.025	POLR2F
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
Role of phospholipids in phagocytosis	1	152.3×	0.025	PLA2G6
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
Acyl chain remodelling of PC	1	141.0×	0.025	PLA2G6
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
Acyl chain remodelling of PE	1	131.3×	0.025	PLA2G6
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
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	122.8×	0.025	SOX10
Gene Silencing by RNA	1	119.0×	0.025	POLR2F
HIV elongation arrest and recovery	1	115.3×	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
positive regulation of gliogenesis	1	2808.7×	0.006	SOX10
platelet activating factor metabolic process	1	1872.4×	0.006	PLA2G6
cardiolipin acyl-chain remodeling	1	1404.3×	0.006	PLA2G6
phosphatidylethanolamine catabolic process	1	1404.3×	0.006	PLA2G6
morphogenesis of a branching epithelium	1	1123.5×	0.006	SOX10
phosphatidic acid metabolic process	1	936.2×	0.006	PLA2G6
cellular response to progesterone stimulus	1	936.2×	0.006	SOX10
negative regulation of Schwann cell proliferation	1	802.5×	0.006	SOX10
positive regulation of ceramide biosynthetic process	1	802.5×	0.006	PLA2G6
lacrimal gland development	1	702.2×	0.006	SOX10
tRNA transcription by RNA polymerase III	1	510.7×	0.007	POLR2F
transcription by RNA polymerase I	1	468.1×	0.007	POLR2F
phosphatidylcholine catabolic process	1	432.1×	0.007	PLA2G6
central nervous system myelination	1	330.4×	0.008	SOX10
enteric nervous system development	1	330.4×	0.008	SOX10
digestive tract morphogenesis	1	330.4×	0.008	SOX10
melanocyte differentiation	1	267.5×	0.009	SOX10
positive regulation of myelination	1	255.3×	0.009	SOX10
developmental growth	1	244.2×	0.009	SOX10
Fc-gamma receptor signaling pathway involved in phagocytosis	1	234.1×	0.009	PLA2G6
oligodendrocyte development	1	200.6×	0.009	SOX10
positive regulation of neuroblast proliferation	1	193.7×	0.009	SOX10
peripheral nervous system development	1	193.7×	0.009	SOX10
transcription elongation by RNA polymerase II	1	147.8×	0.011	SOX10
cell maturation	1	147.8×	0.011	SOX10
oligodendrocyte differentiation	1	140.4×	0.011	SOX10
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	124.8×	0.012	PLA2G6
neuroblast proliferation	1	122.1×	0.012	SOX10
morphogenesis of an epithelium	1	114.6×	0.012	SOX10
neural crest cell migration	1	112.3×	0.012	SOX10

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLA2G6	1	2
SOX10	0	0
POLR2F	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARESPLADIB	2	PLA2G6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PLA2G6	47	Binding:47

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLA2G6	3.1.1.4	phospholipase A2

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

1 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)
VARESPLADIB	2	PLA2G6

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	1	PLA2G6
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: 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