Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome

Summary

Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome (MONDO:0014606) is a disease caused by POGZ (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: POGZ (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 249
• Phenotypes (HPO): 72

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

72 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000540	Hypermetropia	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000752	Hyperactivity	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001513	Obesity	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0006863	Severe expressive language delay	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0011024	Abnormality of the gastrointestinal tract	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0000160	Narrow mouth	Occasional (5-29%)
HP:0000194	Open mouth	Occasional (5-29%)
HP:0000219	Thin upper lip vermilion	Occasional (5-29%)
HP:0000248	Brachycephaly	Occasional (5-29%)
HP:0000307	Pointed chin	Occasional (5-29%)
HP:0000356	Abnormality of the outer ear	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000483	Astigmatism	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000510	Rod-cone dystrophy	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0000733	Abnormal repetitive mannerisms	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002353	EEG abnormality	Occasional (5-29%)
HP:0010864	Intellectual disability, severe	Occasional (5-29%)
HP:0011800	Midface retrusion	Occasional (5-29%)
HP:0012450	Chronic constipation	Occasional (5-29%)
HP:0002714	Downturned corners of mouth	Very rare (<1-4%)
HP:0002870	Obstructive sleep apnea	Very rare (<1-4%)
HP:0002933	Ventral hernia	Very rare (<1-4%)
HP:0005280	Depressed nasal bridge	Very rare (<1-4%)
HP:0012110	Hypoplasia of the pons	Very rare (<1-4%)
HP:0012157	Subcortical cerebral atrophy	Very rare (<1-4%)
HP:0012448	Delayed myelination	Very rare (<1-4%)
HP:0100716	Self-injurious behavior	Very rare (<1-4%)
HP:0000023	Inguinal hernia	Very rare (<1-4%)
HP:0000081	Duplicated collecting system	Very rare (<1-4%)
HP:0000218	High palate	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome
Mondo ID	MONDO:0014606
OMIM	616364
Orphanet	468678
DOID	DOID:0070067
UMLS	C4225351
MedGen	897984
GARD	0013774
Is cancer (heuristic)	no

Also known as: autosomal dominant intellectual disability 37 · intellectual disability, autosomal dominant 37 · intellectual disability, autosomal dominant type 37 · intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome · mental retardation, autosomal dominant 37 · mental retardation, autosomal dominant type 37 · MRD37 · WHSUS

Data availability: 249 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome

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, schizencephaly, 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, 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

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

249 retrieved; paginated sample, class counts are floors:

71 uncertain significance, 62 pathogenic, 44 likely pathogenic, 28 benign/likely benign, 14 benign, 12 conflicting classifications of pathogenicity, 11 pathogenic/likely pathogenic, 6 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
816868	NM_001374353.1(GLI2):c.3387G>A (p.Trp1129Ter)	GLI2	Pathogenic	criteria provided, single submitter
1032656	NM_015100.4(POGZ):c.2768dup (p.His923fs)	POGZ	Pathogenic	criteria provided, multiple submitters, no conflicts
1164015	NM_015100.4(POGZ):c.3040C>T (p.Gln1014Ter)	POGZ	Pathogenic	criteria provided, single submitter
1172624	NM_015100.4(POGZ):c.3121C>T (p.Gln1041Ter)	POGZ	Pathogenic	criteria provided, single submitter
1184815	NM_015100.4(POGZ):c.1679-3C>G	POGZ	Pathogenic	criteria provided, single submitter
1299665	NM_015100.4(POGZ):c.3351dup (p.Pro1118fs)	POGZ	Pathogenic	no assertion criteria provided
1323483	NM_015100.4(POGZ):c.2570+1G>T	POGZ	Pathogenic	criteria provided, single submitter
1343160	NM_015100.4(POGZ):c.460-2A>C	POGZ	Pathogenic	criteria provided, single submitter
1343243	NM_015100.4(POGZ):c.1135C>T (p.Arg379Ter)	POGZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1684515	NM_015100.4(POGZ):c.2700_2710del (p.Leu901fs)	POGZ	Pathogenic	criteria provided, single submitter
1691144	NM_015100.4(POGZ):c.3118G>A (p.Glu1040Lys)	POGZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705564	NM_015100.4(POGZ):c.2709del (p.Pro903_Leu904insTer)	POGZ	Pathogenic	criteria provided, multiple submitters, no conflicts
1710349	NM_015100.4(POGZ):c.1053del (p.Ser352fs)	POGZ	Pathogenic	criteria provided, single submitter
1710479	NM_015100.4(POGZ):c.2022dup (p.Lys675Ter)	POGZ	Pathogenic	criteria provided, single submitter
1789395	NM_015100.4(POGZ):c.2309dup (p.Tyr770Ter)	POGZ	Pathogenic	criteria provided, multiple submitters, no conflicts
1803698	NM_015100.4(POGZ):c.1679-1G>A	POGZ	Pathogenic	criteria provided, single submitter
1804028	NM_015100.4(POGZ):c.2819_2826del (p.Leu940fs)	POGZ	Pathogenic	criteria provided, single submitter
190307	NM_015100.4(POGZ):c.3354del (p.Leu1119fs)	POGZ	Pathogenic	no assertion criteria provided
190308	NM_015100.4(POGZ):c.2711T>A (p.Leu904Ter)	POGZ	Pathogenic	no assertion criteria provided
207798	NM_015100.4(POGZ):c.3041del (p.Gln1014fs)	POGZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218146	NM_015100.4(POGZ):c.2321_2324del (p.Ser774fs)	POGZ	Pathogenic	criteria provided, multiple submitters, no conflicts
218147	NM_015100.4(POGZ):c.2763dup (p.Thr922fs)	POGZ	Pathogenic	criteria provided, single submitter
218148	NM_015100.4(POGZ):c.833C>G (p.Ser278Ter)	POGZ	Pathogenic	criteria provided, single submitter
218149	NM_015100.4(POGZ):c.2935C>T (p.Arg979Ter)	POGZ	Pathogenic	criteria provided, multiple submitters, no conflicts
218150	NM_015100.4(POGZ):c.2780dup (p.Leu927fs)	POGZ	Pathogenic	criteria provided, single submitter
224722	NM_015100.4(POGZ):c.1277dup (p.Pro426_Glu427insTer)	POGZ	Pathogenic	no assertion criteria provided
224723	NM_015100.4(POGZ):c.2590C>T (p.Arg864Ter)	POGZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224724	NM_015100.4(POGZ):c.3001C>T (p.Arg1001Ter)	POGZ	Pathogenic	criteria provided, multiple submitters, no conflicts
224725	NM_015100.4(POGZ):c.3847C>T (p.Gln1283Ter)	POGZ	Pathogenic	no assertion criteria provided
224726	NM_015100.4(POGZ):c.3456_3457del (p.Glu1154fs)	POGZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 16 · 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
POGZ	Definitive	Autosomal dominant	intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POGZ	Orphanet:468678	White-Sutton syndrome
GLI2	Orphanet:220386	Semilobar holoprosencephaly
GLI2	Orphanet:280195	Septopreoptic holoprosencephaly
GLI2	Orphanet:280200	Microform holoprosencephaly
GLI2	Orphanet:420584	Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome
GLI2	Orphanet:93924	Lobar holoprosencephaly
GLI2	Orphanet:93925	Alobar holoprosencephaly
GLI2	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
GLI2	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
GLI3	Orphanet:36	Acrocallosal syndrome
GLI3	Orphanet:380	Greig cephalopolysyndactyly syndrome
GLI3	Orphanet:672	Pallister-Hall syndrome
GLI3	Orphanet:93322	Isolated tibial hemimelia
GLI3	Orphanet:93334	Postaxial polydactyly type A
GLI3	Orphanet:93335	Postaxial polydactyly type B
GLI3	Orphanet:93338	Polysyndactyly

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
POGZ	HGNC:18801	ENSG00000143442	Q7Z3K3	Pogo transposable element with ZNF domain	gencc,clinvar
GLI2	HGNC:4318	ENSG00000074047	P10070	Zinc finger protein GLI2	clinvar
GLI3	HGNC:4319	ENSG00000106571	P10071	Transcriptional activator GLI3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POGZ	Pogo transposable element with ZNF domain	Plays a role in mitotic cell cycle progression and is involved in kinetochore assembly and mitotic sister chromatid cohesion.
GLI2	Zinc finger protein GLI2	Functions as a transcription regulator in the hedgehog (Hh) pathway.
GLI3	Transcriptional activator GLI3	Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development.

Protein-family classification

Druggable: 0 · Difficult: 3 · 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	3	8.3×	0.002

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POGZ	Transcription factor	no		DDE_SF_endonuclease_dom, HTH_CenpB_DNA-bd_dom, Homeodomain-like_sf
GLI2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
GLI3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like

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
ventricular zone	2
cerebellar hemisphere	1
right hemisphere of cerebellum	1
right uterine tube	1
germinal epithelium of ovary	1
tibia	1
olfactory bulb	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POGZ	298	ubiquitous	marker	right uterine tube, right hemisphere of cerebellum, cerebellar hemisphere
GLI2	211	ubiquitous	marker	tibia, germinal epithelium of ovary, ventricular zone
GLI3	263	ubiquitous	marker	ventricular zone, olfactory bulb, tendon of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLI2	3,112
GLI3	2,825
POGZ	2,586

Intra-cohort edges

A	B	Sources
GLI2	GLI3	intact

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POGZ	Q7Z3K3	3
GLI3	P10071	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GLI2	P10070	42.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 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
GLI proteins bind promoters of Hh responsive genes to promote transcription	2	1631.4×	2e-06	GLI2, GLI3
Hedgehog ‘off’ state	2	178.4×	9e-05	GLI2, GLI3
Hedgehog ‘on’ state	2	158.6×	9e-05	GLI2, GLI3
RUNX2 regulates chondrocyte maturation	1	1142.0×	0.002	GLI2
RUNX2 regulates osteoblast differentiation	1	228.4×	0.006	GLI3
Degradation of GLI2 by the proteasome	1	112.0×	0.009	GLI2
GLI3 is processed to GLI3R by the proteasome	1	112.0×	0.009	GLI3

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
hindgut morphogenesis	2	2808.7×	1e-05	GLI2, GLI3
embryonic digestive tract development	2	660.9×	1e-04	GLI2, GLI3
developmental growth	2	488.5×	2e-04	GLI2, GLI3
proximal/distal pattern formation	2	432.1×	2e-04	GLI2, GLI3
odontogenesis of dentin-containing tooth	2	200.6×	6e-04	GLI2, GLI3
lung development	2	132.2×	0.001	GLI2, GLI3
smoothened signaling pathway	2	120.8×	0.001	GLI2, GLI3
lateral ganglionic eminence cell proliferation	1	5617.3×	0.001	GLI3
lambdoid suture morphogenesis	1	5617.3×	0.001	GLI3
sagittal suture morphogenesis	1	5617.3×	0.001	GLI3
mammary gland specification	1	5617.3×	0.001	GLI3
anterior semicircular canal development	1	5617.3×	0.001	GLI3
lateral semicircular canal development	1	5617.3×	0.001	GLI3
osteoblast differentiation	2	80.8×	0.001	GLI2, GLI3
smoothened signaling pathway involved in ventral spinal cord interneuron specification	1	2808.7×	0.002	GLI3
smoothened signaling pathway involved in spinal cord motor neuron cell fate specification	1	2808.7×	0.002	GLI3
larynx morphogenesis	1	2808.7×	0.002	GLI3
axon guidance	2	60.4×	0.002	GLI2, GLI3
positive regulation of transcription by RNA polymerase II	3	14.9×	0.002	POGZ, GLI2, GLI3
ventral midline development	1	1872.4×	0.002	GLI2
floor plate formation	1	1872.4×	0.002	GLI2
spinal cord ventral commissure morphogenesis	1	1872.4×	0.002	GLI2
nose morphogenesis	1	1872.4×	0.002	GLI3
negative regulation of alpha-beta T cell differentiation	1	1872.4×	0.002	GLI3
frontal suture morphogenesis	1	1872.4×	0.002	GLI3
cell differentiation involved in kidney development	1	1872.4×	0.002	GLI3
heart development	2	52.5×	0.002	GLI2, GLI3
tube development	1	1404.3×	0.002	GLI2
smoothened signaling pathway involved in dorsal/ventral neural tube patterning	1	1404.3×	0.002	GLI3
optic nerve morphogenesis	1	1123.5×	0.003	GLI3

Therapeutics

Drug target analysis

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

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
POGZ	0	0
GLI2	0	0
GLI3	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
GLI2	6	Binding:6

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

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	3	POGZ, GLI2, GLI3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
POGZ	0	—
GLI2	6	—
GLI3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.