Schizencephaly

Summary

Schizencephaly (MONDO:0010011) is a disease with 5 cohort genes.

At a glance

• Prevalence: 1-9 / 100 000 (United Kingdom) [Orphanet-validated]
• Cohort genes: 5
• ClinVar variants: 29
• Phenotypes (HPO): 10

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	1.48	United Kingdom	Validated
Prevalence at birth	1-9 / 100 000	1.54	United States	Validated
Prevalence at birth	1-9 / 100 000	1	Japan	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000486	Strabismus	Very frequent (80-99%)
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0002132	Porencephaly	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0007370	Aplasia/Hypoplasia of the corpus callosum	Very frequent (80-99%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001269	Hemiparesis	Frequent (30-79%)
HP:0002510	Spastic tetraplegia	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	schizencephaly
Mondo ID	MONDO:0010011
MeSH	D065707
OMIM	269160
Orphanet	799
ICD-11	1693546163
NCIT	C99056
SNOMED CT	253159001
UMLS	C0266484
MedGen	78606
GARD	0000166
Is cancer (heuristic)	no

Also known as: schizencephaly

Data availability: 29 ClinVar variants · 5 GenCC gene-disease records · 6 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › schizencephaly

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

Subtypes (2): familial schizencephaly, acquired schizencephaly

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

29 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 7 pathogenic, 4 benign/likely benign, 3 conflicting classifications of pathogenicity, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
9519	NM_004098.4(EMX2):c.575_576insA (p.Ser192fs)	EMX2	Pathogenic	no assertion criteria provided
9520	NM_004098.4(EMX2):c.407-1G>A	EMX2	Pathogenic	no assertion criteria provided
9521	NM_004098.4(EMX2):c.407-4G>T	EMX2	Pathogenic	no assertion criteria provided
9522	NM_004098.4(EMX2):c.407G>T (p.Gly136Val)	EMX2	Pathogenic	no assertion criteria provided
2671957	NM_000193.4(SHH):c.44C>A (p.Ser15Ter)	SHH	Pathogenic	criteria provided, single submitter
931342	NM_000193.4(SHH):c.593G>A (p.Cys198Tyr)	SHH	Pathogenic	criteria provided, single submitter
30380	NM_005413.4(SIX3):c.385G>T (p.Glu129Ter)	SIX3	Pathogenic	no assertion criteria provided
195868	NM_001845.6(COL4A1):c.1588C>T (p.Pro530Ser)	COL4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289628	NM_001845.6(COL4A1):c.7C>A (p.Pro3Thr)	COL4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193312	NM_005413.4(SIX3):c.187GGC[8] (p.Gly69dup)	SIX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1342532	NM_004098.4(EMX2):c.260C>T (p.Pro87Leu)	EMX2	Uncertain significance	criteria provided, single submitter
499434	NM_004098.4(EMX2):c.161CCG[8] (p.Ala58_Ala59dup)	EMX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1696669	NM_004098.4(EMX2):c.231C>G (p.His77Gln)	EMX2OS	Uncertain significance	criteria provided, single submitter
992740	NM_004098.4(EMX2):c.112T>C (p.Tyr38His)	EMX2OS	Uncertain significance	criteria provided, single submitter
1362086	NM_000193.4(SHH):c.1178C>G (p.Ala393Gly)	SHH	Uncertain significance	criteria provided, multiple submitters, no conflicts
3237470	NM_000193.4(SHH):c.736G>T (p.Asp246Tyr)	SHH	Uncertain significance	criteria provided, single submitter
3594442	NM_000193.4(SHH):c.887G>C (p.Gly296Ala)	SHH	Uncertain significance	criteria provided, single submitter
8886	NM_000193.4(SHH):c.1147G>A (p.Ala383Thr)	SHH	Uncertain significance	criteria provided, multiple submitters, no conflicts
30382	NM_005413.4(SIX3):c.499G>T (p.Ala167Ser)	SIX3	Uncertain significance	criteria provided, single submitter
3892439	NM_005413.4(SIX3):c.106A>G (p.Asn36Asp)	SIX3	Uncertain significance	criteria provided, single submitter
3892440	NM_005413.4(SIX3):c.778C>T (p.Arg260Cys)	SIX3	Uncertain significance	criteria provided, single submitter
487087	NM_005413.4(SIX3):c.206G>A (p.Gly69Asp)	SIX3	Uncertain significance	criteria provided, multiple submitters, no conflicts
498633	NM_005413.4(SIX3):c.127G>T (p.Gly43Cys)	SIX3	Uncertain significance	criteria provided, multiple submitters, no conflicts
931003	NM_005413.4(SIX3):c.208T>C (p.Ser70Pro)	SIX3	Uncertain significance	criteria provided, single submitter
193270	NM_004098.4(EMX2):c.161CCG[4] (p.Ala58_Ala59del)	EMX2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
378580	NM_000193.4(SHH):c.300+17G>A	SHH	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
8887	NM_000193.4(SHH):c.869G>A (p.Gly290Asp)	SHH	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
30381	NM_005413.4(SIX3):c.109G>T (p.Gly37Cys)	SIX3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
65500	NM_005413.4(SIX3):c.576C>T (p.Arg192=)	SIX3	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 28 · 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
EMX2	Moderate	Autosomal dominant	schizencephaly	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EMX2	Orphanet:485275	Acquired schizencephaly
SHH	Orphanet:220386	Semilobar holoprosencephaly
SHH	Orphanet:280195	Septopreoptic holoprosencephaly
SHH	Orphanet:280200	Microform holoprosencephaly
SHH	Orphanet:476119	Autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome
SHH	Orphanet:485275	Acquired schizencephaly
SHH	Orphanet:93321	Isolated radial hemimelia
SHH	Orphanet:93336	Polydactyly of a triphalangeal thumb
SHH	Orphanet:93405	Syndactyly type 4
SHH	Orphanet:93924	Lobar holoprosencephaly
SHH	Orphanet:93925	Alobar holoprosencephaly
SHH	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
SHH	Orphanet:988	Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome
SHH	Orphanet:98938	Colobomatous microphthalmia
SIX3	Orphanet:220386	Semilobar holoprosencephaly
SIX3	Orphanet:280195	Septopreoptic holoprosencephaly
SIX3	Orphanet:280200	Microform holoprosencephaly
SIX3	Orphanet:485275	Acquired schizencephaly
SIX3	Orphanet:93924	Lobar holoprosencephaly
SIX3	Orphanet:93925	Alobar holoprosencephaly
SIX3	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
COL4A1	Orphanet:36383	COL4A1/2-related familial vascular leukoencephalopathy
COL4A1	Orphanet:477749	Pontine autosomal dominant microangiopathy with leukoencephalopathy
COL4A1	Orphanet:481986	Familial schizencephaly
COL4A1	Orphanet:73229	HANAC syndrome
COL4A1	Orphanet:75326	Familial isolated retinal arteriolar tortuosity
COL4A1	Orphanet:899	Walker-Warburg syndrome
COL4A1	Orphanet:99810	Familial porencephaly

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EMX2	HGNC:3341	ENSG00000170370	Q04743	Homeobox protein EMX2	gencc,clinvar
SHH	HGNC:10848	ENSG00000164690	Q15465	Sonic hedgehog protein	clinvar
SIX3	HGNC:10889	ENSG00000138083	O95343	Homeobox protein SIX3	clinvar
EMX2OS	HGNC:18511	ENSG00000229847		EMX2 opposite strand/antisense RNA	clinvar
COL4A1	HGNC:2202	ENSG00000187498	P02462	Collagen alpha-1(IV) chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EMX2	Homeobox protein EMX2	Transcription factor, which in cooperation with EMX1, acts to generate the boundary between the roof and archipallium in the developing brain.
SHH	Sonic hedgehog protein	The C-terminal part of the sonic hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity.
SIX3	Homeobox protein SIX3	Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a ATTA homeodomain core recognition sequence on these target genes.
COL4A1	Collagen alpha-1(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 3 · 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	2	3.3×	0.229
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EMX2	Transcription factor	no		HTH_motif, HD, Homeodomain-like_sf
SHH	Other/Unknown	no		Hedgehog_signalling_dom, Hedgehog, Hedgehog_Hint
SIX3	Transcription factor	no		HD, Homeodomain-like_sf, SIX1_SD
EMX2OS	Other/Unknown	no
COL4A1	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
caput epididymis	2
corpus epididymis	2
cauda epididymis	1
buccal mucosa cell	1
epithelial cell of pancreas	1
right lobe of liver	1
nasal cavity epithelium	1
pigmented layer of retina	1
retina	1
kidney epithelium	1
placenta	1
right coronary artery	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EMX2	203	broad	marker	corpus epididymis, caput epididymis, cauda epididymis
SHH	131	broad	marker	buccal mucosa cell, right lobe of liver, epithelial cell of pancreas
SIX3	92	broad	marker	pigmented layer of retina, retina, nasal cavity epithelium
EMX2OS	205	broad	marker	corpus epididymis, kidney epithelium, caput epididymis
COL4A1	283	ubiquitous	marker	visceral pleura, placenta, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SHH	4,953
COL4A1	2,909
SIX3	1,536
EMX2	1,515
EMX2OS	0

Intra-cohort edges

A	B	Sources
EMX2	SHH	string_interaction
SHH	SIX3	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SHH	Q15465	20
COL4A1	P02462	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SIX3	O95343	70.38
EMX2	Q04743	67.26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 38. Enrichment computed across 5 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
HHAT G278V doesn’t palmitoylate Hh-Np	1	761.3×	0.015	SHH
Formation of lateral plate mesoderm	1	761.3×	0.015	SHH
Release of Hh-Np from the secreting cell	1	475.8×	0.015	SHH
Hh mutants abrogate ligand secretion	1	475.8×	0.015	SHH
Ligand-receptor interactions	1	475.8×	0.015	SHH
Formation of axial mesoderm	1	271.9×	0.015	SHH
Anchoring fibril formation	1	253.8×	0.015	COL4A1
Activation of SMO	1	211.5×	0.015	SHH
Formation of the nephric duct	1	211.5×	0.015	EMX2
Scavenging by Class A Receptors	1	200.3×	0.015	COL4A1
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	200.3×	0.015	SHH
Fibronectin matrix formation	1	190.3×	0.015	COL4A1
Crosslinking of collagen fibrils	1	190.3×	0.015	COL4A1
Attachment of bacteria to epithelial cells	1	165.5×	0.016	COL4A1
Laminin interactions	1	126.9×	0.020	COL4A1
Developmental Lineage of Pancreatic Acinar Cells	1	100.2×	0.022	SHH
Collagen chain trimerization	1	86.5×	0.022	COL4A1
Gastrulation	1	86.5×	0.022	SHH
Signaling by PDGF	1	84.6×	0.022	COL4A1
NCAM1 interactions	1	82.8×	0.022	COL4A1
Hh mutants are degraded by ERAD	1	81.0×	0.022	SHH
Developmental Cell Lineages	1	74.6×	0.023	SHH
Hedgehog ligand biogenesis	1	70.5×	0.023	SHH
Assembly of collagen fibrils and other multimeric structures	1	66.8×	0.024	COL4A1
Class B/2 (Secretin family receptors)	1	63.4×	0.024	SHH
Signaling by Hedgehog	1	61.4×	0.024	SHH
Collagen degradation	1	58.6×	0.024	COL4A1
Collagen biosynthesis and modifying enzymes	1	56.8×	0.024	COL4A1
Hedgehog ‘on’ state	1	52.9×	0.024	SHH
Non-integrin membrane-ECM interactions	1	51.4×	0.024	COL4A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
telencephalon regionalization	2	1404.3×	1e-04	SHH, SIX3
cell proliferation in forebrain	2	648.1×	3e-04	EMX2, SIX3
brain development	3	59.6×	5e-04	EMX2, SIX3, COL4A1
thyroid gland development	2	271.8×	9e-04	SHH, SIX3
branching involved in blood vessel morphogenesis	2	263.3×	9e-04	SHH, COL4A1
proximal/distal axis specification	1	4213.0×	0.002	SIX3
polarity specification of anterior/posterior axis	1	4213.0×	0.002	SHH
trachea morphogenesis	1	4213.0×	0.002	SHH
right lung development	1	4213.0×	0.002	SHH
left lung development	1	4213.0×	0.002	SHH
primary prostatic bud elongation	1	4213.0×	0.002	SHH
regulation of prostatic bud formation	1	4213.0×	0.002	SHH
obsolete regulation of mesenchymal cell proliferation involved in prostate gland development	1	4213.0×	0.002	SHH
mesenchymal smoothened signaling pathway involved in prostate gland development	1	4213.0×	0.002	SHH
positive regulation of sclerotome development	1	4213.0×	0.002	SHH
tracheoesophageal septum formation	1	4213.0×	0.002	SHH
negative regulation of ureter smooth muscle cell differentiation	1	4213.0×	0.002	SHH
positive regulation of ureter smooth muscle cell differentiation	1	4213.0×	0.002	SHH
negative regulation of kidney smooth muscle cell differentiation	1	4213.0×	0.002	SHH
positive regulation of kidney smooth muscle cell differentiation	1	4213.0×	0.002	SHH
protein import into nucleus	2	72.0×	0.003	SHH, SIX3
optic vesicle morphogenesis	1	2106.5×	0.003	SIX3
positive regulation of skeletal muscle cell proliferation	1	2106.5×	0.003	SHH
intein-mediated protein splicing	1	2106.5×	0.003	SHH
trunk neural crest cell migration	1	2106.5×	0.003	SHH
stereocilium bundle organization	1	2106.5×	0.003	EMX2
regulation of nodal signaling pathway	1	2106.5×	0.003	SHH
positive regulation of mesenchymal cell proliferation involved in ureter development	1	2106.5×	0.003	SHH
central nervous system development	2	57.7×	0.003	EMX2, SHH
regulation of cell population proliferation	2	57.7×	0.003	SHH, SIX3

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
SHH	VISMODEGIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SHH	1	4
EMX2	0	0
SIX3	0	0
EMX2OS	0	0
COL4A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VISMODEGIB	4	SHH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SHH	27	Binding:23, Functional:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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)
VISMODEGIB	4	SHH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SHH
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	4	EMX2, SIX3, EMX2OS, COL4A1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SIX3	0	SHH
EMX2	0	—
EMX2OS	0	—
COL4A1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.