PCWH syndrome

Summary

PCWH syndrome (MONDO:0012198) is a disease caused by SOX10 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SOX10 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 68
• Phenotypes (HPO): 36

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0000506	Telecanthus	Very frequent (80-99%)
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0001053	Hypopigmented skin patches	Very frequent (80-99%)
HP:0001100	Heterochromia iridis	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0002019	Constipation	Very frequent (80-99%)
HP:0002027	Abdominal pain	Very frequent (80-99%)
HP:0002251	Aganglionic megacolon	Very frequent (80-99%)
HP:0002595	Ileus	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)
HP:0009830	Peripheral neuropathy	Very frequent (80-99%)
HP:0000135	Hypogonadism	Frequent (30-79%)
HP:0000426	Prominent nasal bridge	Frequent (30-79%)
HP:0000430	Underdeveloped nasal alae	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000534	Abnormal eyebrow morphology	Frequent (30-79%)
HP:0000633	Decreased lacrimation	Frequent (30-79%)
HP:0000635	Blue irides	Frequent (30-79%)
HP:0000664	Synophrys	Frequent (30-79%)
HP:0002211	White forelock	Frequent (30-79%)
HP:0002216	Premature graying of hair	Frequent (30-79%)
HP:0004388	Microcolon	Frequent (30-79%)
HP:0005599	Hypopigmentation of hair	Frequent (30-79%)
HP:0006978	Dysmyelinating leukodystrophy	Frequent (30-79%)
HP:0000966	Hypohidrosis	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002804	Arthrogryposis multiplex congenita	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0012332	Abnormal autonomic nervous system physiology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	PCWH syndrome
Mondo ID	MONDO:0012198
MeSH	C563789
OMIM	609136
Orphanet	163746
DOID	DOID:0090111
UMLS	C1836727
MedGen	373160
GARD	0017004
Is cancer (heuristic)	no

Also known as: neurologic Waardenburg-Shah syndrome · PCWH · peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease · WS4 plus

Data availability: 68 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 › PCWH syndrome

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

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

68 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 14 pathogenic, 11 conflicting classifications of pathogenicity, 7 benign, 6 likely pathogenic, 6 benign/likely benign, 3 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065839	NM_006941.4(SOX10):c.267del (p.Met90fs)	POLR2F	Pathogenic	no assertion criteria provided
1329463	NM_006941.4(SOX10):c.395C>G (p.Ala132Gly)	POLR2F	Pathogenic	criteria provided, single submitter
1329464	NM_006941.4(SOX10):c.966dup (p.Ala323fs)	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
2441943	NM_006941.4(SOX10):c.671C>A (p.Ser224Ter)	POLR2F	Pathogenic	criteria provided, single submitter
4074718	NM_006941.4(SOX10):c.1114C>T (p.Gln372Ter)	POLR2F	Pathogenic	criteria provided, single submitter
523884	NM_006941.4(SOX10):c.232C>T (p.Gln78Ter)	POLR2F	Pathogenic	criteria provided, multiple submitters, no conflicts
7398	NM_006941.4(SOX10):c.939C>G (p.Tyr313Ter)	POLR2F	Pathogenic	criteria provided, single submitter
7399	NM_006941.4(SOX10):c.752C>A (p.Ser251Ter)	POLR2F	Pathogenic	criteria provided, single submitter
7403	NM_006941.4(SOX10):c.748C>T (p.Gln250Ter)	POLR2F	Pathogenic	no assertion criteria provided
7412	NM_006941.4(SOX10):c.915del (p.His306fs)	POLR2F	Pathogenic	no assertion criteria provided
805532	NM_006941.4(SOX10):c.1352_1359dup (p.His454fs)	POLR2F	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
816906	NM_006941.4(SOX10):c.404G>A (p.Ser135Asn)	POLR2F	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
872923	NM_006941.4(SOX10):c.207_208del (p.Cys71fs)	POLR2F	Pathogenic	no assertion criteria provided
915453	NM_006941.4(SOX10):c.1155_1174dup (p.Phe392fs)	POLR2F	Pathogenic	no assertion criteria provided
915461	NM_006941.4(SOX10):c.425G>C (p.Trp142Ser)	POLR2F	Pathogenic	no assertion criteria provided
976284	NM_006941.4(SOX10):c.941C>A (p.Ser314Ter)	POLR2F	Pathogenic	criteria provided, single submitter
1065613	NM_006941.4(SOX10):c.1400A>T (p.Ter467Leu)	POLR2F	Likely pathogenic	criteria provided, single submitter
1329465	NM_006941.4(SOX10):c.850G>T (p.Glu284Ter)	POLR2F	Likely pathogenic	criteria provided, single submitter
133302	NM_006941.4(SOX10):c.1127C>G (p.Ser376Ter)	POLR2F	Likely pathogenic	criteria provided, single submitter
4071010	NM_006941.4(SOX10):c.698-4_698-2delinsATG	POLR2F	Likely pathogenic	criteria provided, single submitter
4294480	NM_006941.4(SOX10):c.580G>T (p.Glu194Ter)	POLR2F	Likely pathogenic	criteria provided, single submitter
7400	NM_006941.4(SOX10):c.1400_*10del (p.Ter467Xaa)	POLR2F	Likely pathogenic	criteria provided, single submitter
1205874	NM_006941.4(SOX10):c.1093G>C (p.Gly365Arg)	POLR2F	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341616	NM_006941.4(SOX10):c.906G>A (p.Pro302=)	POLR2F	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341617	NM_006941.4(SOX10):c.753G>A (p.Ser251=)	POLR2F	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
452278	NM_006941.4(SOX10):c.131C>G (p.Ala44Gly)	POLR2F	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
547778	NM_006941.4(SOX10):c.334A>G (p.Met112Val)	POLR2F	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
702405	NM_006941.4(SOX10):c.274G>C (p.Val92Leu)	POLR2F	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
733585	NM_006941.4(SOX10):c.918C>T (p.His306=)	POLR2F	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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	PCWH syndrome	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.