Combined pituitary hormone deficiencies, genetic form

Summary

Combined pituitary hormone deficiencies, genetic form (MONDO:0013099) is a disease (an umbrella term covering 9 Mondo subtypes) caused by HESX1 (GenCC Strong), with 10 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: HESX1 (GenCC Strong)
• Umbrella term: 9 Mondo subtypes
• Cohort genes: 10
• ClinVar variants: 39
• Phenotypes (HPO): 39
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0040075	Hypopituitarism	Obligate (100%)
HP:0000044	Hypogonadotropic hypogonadism	Frequent (30-79%)
HP:0000141	Amenorrhea	Frequent (30-79%)
HP:0000457	Depressed nasal ridge	Frequent (30-79%)
HP:0000789	Infertility	Frequent (30-79%)
HP:0000824	Decreased response to growth hormone stimulation test	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001943	Hypoglycemia	Frequent (30-79%)
HP:0002615	Hypotension	Frequent (30-79%)
HP:0002920	Decreased circulating ACTH level	Frequent (30-79%)
HP:0008245	Pituitary hypothyroidism	Frequent (30-79%)
HP:0008734	Decreased testicular size	Frequent (30-79%)
HP:0009888	Abnormality of secondary sexual hair	Frequent (30-79%)
HP:0010311	Aplasia/Hypoplasia of the breasts	Frequent (30-79%)
HP:0010626	Anterior pituitary agenesis	Frequent (30-79%)
HP:0010627	Anterior pituitary hypoplasia	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0040086	Abnormal prolactin level	Frequent (30-79%)
HP:0000823	Delayed puberty	Occasional (5-29%)
HP:0000839	Pituitary dwarfism	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)
HP:0005625	Osteoporosis of vertebrae	Occasional (5-29%)
HP:0008187	Absence of secondary sex characteristics	Occasional (5-29%)
HP:0009099	Median cleft palate	Very rare (<1-4%)
HP:0000478	Abnormality of the eye	Very rare (<1-4%)
HP:0000609	Optic nerve hypoplasia	Very rare (<1-4%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0001274	Agenesis of corpus callosum	Very rare (<1-4%)
HP:0001331	Absent septum pellucidum	Very rare (<1-4%)
HP:0001360	Holoprosencephaly	Very rare (<1-4%)
HP:0004637	Decreased cervical spine mobility	Very rare (<1-4%)
HP:0010442	Polydactyly	Very rare (<1-4%)
HP:0011297	Abnormal digit morphology	Very rare (<1-4%)
HP:0011344	Severe global developmental delay	Very rare (<1-4%)
HP:0011755	Ectopic posterior pituitary	Very rare (<1-4%)
HP:0012731	Ectopic anterior pituitary gland	Very rare (<1-4%)
HP:0100842	Septo-optic dysplasia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	combined pituitary hormone deficiencies, genetic form
Mondo ID	MONDO:0013099
OMIM	613038
Orphanet	95494
SNOMED CT	718182008
UMLS	C4273747
MedGen	906592
GARD	0010602
Is cancer (heuristic)	no

Also known as: familial congenital hypopituitarism · familial hypopituitarism · genetic hypopituitarism · multiple pituitary hormone deficiencies, genetic forms · pituitary hormone deficiency, combined

Data availability: 39 ClinVar variants · 9 GenCC gene-disease records.

Disease family

An umbrella term covering 9 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › combined pituitary hormone deficiencies, genetic form

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, 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 (9): isolated congenital growth hormone deficiency, septooptic dysplasia, congenital isolated adrenocorticotropic hormone deficiency, non-acquired combined pituitary hormone deficiency with spine abnormalities, short stature-pituitary and cerebellar defects-small sella turcica syndrome, pituitary hormone deficiency, combined, 6, panhypopituitarism, pituitary hormone deficiency, combined, 1, pituitary hormone deficiency, combined or isolated, 8

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

39 retrieved; paginated sample, class counts are floors:

8 conflicting classifications of pathogenicity, 8 likely benign, 6 pathogenic/likely pathogenic, 5 pathogenic, 4 benign/likely benign, 4 likely pathogenic, 2 benign, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
3630033	NM_178138.6(LHX3):c.528C>G (p.Tyr176Ter)	LHX3	Pathogenic	criteria provided, single submitter
13604	NM_000306.4(POU1F1):c.472G>C (p.Ala158Pro)	POU1F1	Pathogenic	criteria provided, multiple submitters, no conflicts
13606	NM_000306.4(POU1F1):c.428G>A (p.Arg143Gln)	POU1F1	Pathogenic	criteria provided, single submitter
13613	NM_000306.4(POU1F1):c.688G>A (p.Glu230Lys)	POU1F1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13614	NM_000306.4(POU1F1):c.515G>A (p.Arg172Gln)	POU1F1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2258706	NM_000306.4(POU1F1):c.427C>T (p.Arg143Ter)	POU1F1	Pathogenic	criteria provided, multiple submitters, no conflicts
2734543	NM_000306.4(POU1F1):c.793C>T (p.Arg265Trp)	POU1F1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36702	NM_006261.5(PROP1):c.46C>T (p.Arg16Ter)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8098	NM_006261.5(PROP1):c.301_302del (p.Leu102fs)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8102	NM_006261.5(PROP1):c.150del (p.Arg53fs)	PROP1	Pathogenic	criteria provided, multiple submitters, no conflicts
8106	NM_006261.5(PROP1):c.296G>A (p.Arg99Gln)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3899943	NM_001374353.1(GLI2):c.2515del (p.Asp839fs)	GLI2	Likely pathogenic	criteria provided, single submitter
1067231	NM_178138.6(LHX3):c.607-3_630del	LHX3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
9024	NM_178138.6(LHX3):c.629C>T (p.Ala210Val)	LHX3	Likely pathogenic	criteria provided, single submitter
4526068	NM_006261.5(PROP1):c.374G>A (p.Arg125Gln)	PROP1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1417884	NM_003865.3(HESX1):c.350A>C (p.Gln117Pro)	HESX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
279836	NM_178138.6(LHX3):c.79+1902C>T	LHX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
279837	NM_178138.6(LHX3):c.920G>C (p.Arg307Pro)	LHX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365821	NM_178138.6(LHX3):c.441C>T (p.Thr147=)	LHX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
709265	NM_178138.6(LHX3):c.79+1935C>G	LHX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
753609	NM_178138.6(LHX3):c.251+9C>T	LHX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
765894	NM_178138.6(LHX3):c.915G>A (p.Gln305=)	LHX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
36701	NM_006261.5(PROP1):c.359G>A (p.Arg120His)	PROP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4845424	NM_021784.5(FOXA2):c.497C>T (p.Pro166Leu)	FOXA2	Uncertain significance	criteria provided, single submitter
913183	NM_178138.6(LHX3):c.79+1904C>T	LHX3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1050485	NM_033343.4(LHX4):c.724_726del (p.Lys242del)	ACBD6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
193372	NM_178138.6(LHX3):c.79+1975G>A	LHX3	Benign	criteria provided, multiple submitters, no conflicts
365820	NM_178138.6(LHX3):c.454+3C>T	LHX3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
669245	NM_178138.6(LHX3):c.79+1933G>C	LHX3	Likely benign	criteria provided, multiple submitters, no conflicts
734416	NM_178138.6(LHX3):c.804G>A (p.Pro268=)	LHX3	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 68 · Orphanet: 33 · 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
GLI2	Definitive	Autosomal dominant	postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome	11
LHX4	Definitive	Autosomal dominant	short stature-pituitary and cerebellar defects-small sella turcica syndrome	8
POU1F1	Definitive	Semidominant	pituitary hormone deficiency, combined, 1	10
PROP1	Definitive	Autosomal recessive	pituitary hormone deficiency, combined, 2	8
HESX1	Strong	Autosomal dominant	combined pituitary hormone deficiencies, genetic form	12
OTX2	Strong	Autosomal dominant	pituitary hormone deficiency, combined, 6	11
FOXA2	Supportive	Autosomal dominant	combined pituitary hormone deficiencies, genetic form	2
TCF7L1	Limited	Autosomal dominant	combined pituitary hormone deficiencies, genetic form	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
HESX1	Orphanet:226307	Hypothyroidism due to deficient transcription factors involved in pituitary development or function
HESX1	Orphanet:3157	Septo-optic dysplasia spectrum
HESX1	Orphanet:478	Kallmann syndrome
HESX1	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
HESX1	Orphanet:95496	Pituitary stalk interruption syndrome
FOXA2	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
POU1F1	Orphanet:226307	Hypothyroidism due to deficient transcription factors involved in pituitary development or function
POU1F1	Orphanet:231679	Isolated growth hormone deficiency type II
POU1F1	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
PROP1	Orphanet:226307	Hypothyroidism due to deficient transcription factors involved in pituitary development or function
PROP1	Orphanet:90695	Non-acquired panhypopituitarism
PROP1	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
LHX4	Orphanet:226307	Hypothyroidism due to deficient transcription factors involved in pituitary development or function
LHX4	Orphanet:85442	Short stature-pituitary and cerebellar defects-small sella turcica syndrome
LHX4	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
LHX4	Orphanet:95496	Pituitary stalk interruption syndrome
OTX2	Orphanet:178364	Syndromic microphthalmia type 5
OTX2	Orphanet:3157	Septo-optic dysplasia spectrum
OTX2	Orphanet:35612	Nanophthalmos
OTX2	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
OTX2	Orphanet:98938	Colobomatous microphthalmia
OTX2	Orphanet:990	Agnathia-holoprosencephaly-situs inversus syndrome
OTX2	Orphanet:99001	Butterfly-shaped pigment dystrophy
LHX3	Orphanet:226307	Hypothyroidism due to deficient transcription factors involved in pituitary development or function
LHX3	Orphanet:231720	Non-acquired combined pituitary hormone deficiency-sensorineural hearing loss-spine abnormalities syndrome

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GLI2	HGNC:4318	ENSG00000074047	P10070	Zinc finger protein GLI2	gencc,clinvar
HESX1	HGNC:4877	ENSG00000163666	Q9UBX0	Homeobox expressed in ES cells 1	gencc,clinvar
FOXA2	HGNC:5022	ENSG00000125798	Q9Y261	Hepatocyte nuclear factor 3-beta	gencc,clinvar
POU1F1	HGNC:9210	ENSG00000064835	P28069	Pituitary-specific positive transcription factor 1	gencc,clinvar
PROP1	HGNC:9455	ENSG00000175325	O75360	Homeobox protein prophet of Pit-1	gencc,clinvar
TCF7L1	HGNC:11640	ENSG00000152284	Q9HCS4	Transcription factor 7-like 1	gencc
LHX4	HGNC:21734	ENSG00000121454	Q969G2	LIM/homeobox protein Lhx4	gencc
OTX2	HGNC:8522	ENSG00000165588	P32243	Homeobox protein OTX2	gencc
ACBD6	HGNC:23339	ENSG00000230124	Q9BR61	Acyl-CoA-binding domain-containing protein 6	clinvar
LHX3	HGNC:6595	ENSG00000107187	Q9UBR4	LIM/homeobox protein Lhx3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLI2	Zinc finger protein GLI2	Functions as a transcription regulator in the hedgehog (Hh) pathway.
HESX1	Homeobox expressed in ES cells 1	Required for the normal development of the forebrain, eyes and other anterior structures such as the olfactory placodes and pituitary gland.
FOXA2	Hepatocyte nuclear factor 3-beta	Transcription factor that is involved in embryonic development, establishment of tissue-specific gene expression and regulation of gene expression in differentiated tissues.
POU1F1	Pituitary-specific positive transcription factor 1	Transcription factor involved in the specification of the lactotrope, somatotrope, and thyrotrope phenotypes in the developing anterior pituitary.
PROP1	Homeobox protein prophet of Pit-1	Possibly involved in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes.
TCF7L1	Transcription factor 7-like 1	Participates in the Wnt signaling pathway.
LHX4	LIM/homeobox protein Lhx4	May play a critical role in the development of respiratory control mechanisms and in the normal growth and maturation of the lung.
OTX2	Homeobox protein OTX2	Transcription factor probably involved in the development of the brain and the sense organs.
ACBD6	Acyl-CoA-binding domain-containing protein 6	Binds long-chain acyl-coenzyme A molecules with a strong preference for unsaturated C18:1-CoA, lower affinity for unsaturated C20:4-CoA, and very weak affinity for saturated C16:0-CoA.
LHX3	LIM/homeobox protein Lhx3	Transcription factor.

Protein-family classification

Druggable: 0 · Difficult: 9 · 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	8	6.6×	5e-06
Scaffold/PPI	1	1.7×	0.673
Other/Unknown	1	0.2×	1.000

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLI2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
HESX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
FOXA2	Transcription factor	no		Fork_head_dom, Fork-head_N, TF_fork_head_CS_1
POU1F1	Transcription factor	no		POU_dom, HD, Homeodomain-like_sf
PROP1	Transcription factor	no		HTH_motif, HD, Homeodomain-like_sf
TCF7L1	Other/Unknown	no		HMG_box_dom, CTNNB1-bd_N, TCF/LEF
LHX4	Transcription factor	no		HD, Znf_LIM, Homeodomain-like_sf
OTX2	Transcription factor	no		HD, Otx2_TF, Otx_TF
ACBD6	Scaffold/PPI	no		Acyl-CoA-binding_protein, Ankyrin_rpt, FERM/acyl-CoA-bd_prot_sf
LHX3	Transcription factor	no		HD, Znf_LIM, Homeodomain-like_sf

Expression context

Cohort genes with no expression data: 0.

6 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
moderate (6-20)	0
broad (>20)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	3
adenohypophysis	3
pituitary gland	3
pancreatic ductal cell	2
germinal epithelium of ovary	1
tibia	1
ventricular zone	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
pylorus	1
decidua	1
bone marrow cell	1
aorta	1
popliteal artery	1
tibial artery	1
sperm	1
oocyte	1
pigmented layer of retina	1
secondary oocyte	1
cortical plate	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLI2	211	ubiquitous	marker	tibia, germinal epithelium of ovary, ventricular zone
HESX1	167	broad	marker	buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
FOXA2	105	broad	marker	pancreatic ductal cell, pylorus, buccal mucosa cell
POU1F1	73	tissue_specific	yes	pituitary gland, adenohypophysis, decidua
PROP1	4		yes	pituitary gland, adenohypophysis, bone marrow cell
TCF7L1	230	ubiquitous	marker	popliteal artery, tibial artery, aorta
LHX4	166	tissue_specific	yes	buccal mucosa cell, sperm, pancreatic ductal cell
OTX2	62	broad	marker	secondary oocyte, oocyte, pigmented layer of retina
ACBD6	231	ubiquitous	marker	cortical plate, ganglionic eminence, left testis
LHX3	22	tissue_specific	yes	pituitary gland, diaphragm, adenohypophysis

Protein interactions among cohort

Intra-cohort edges: 7.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLI2	3,112
FOXA2	2,789
OTX2	2,368
LHX3	1,661
TCF7L1	1,635
LHX4	1,566
ACBD6	1,486
POU1F1	1,170
PROP1	1,160
HESX1	888

Intra-cohort edges

A	B	Sources
FOXA2	OTX2	biogrid_interaction, string_interaction
HESX1	POU1F1	string_interaction
LHX3	LHX4	intact
LHX3	POU1F1	string_interaction
LHX4	OTX2	string_interaction
LHX4	POU1F1	biogrid_interaction, intact, string_interaction
POU1F1	PROP1	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FOXA2	Q9Y261	3
HESX1	Q9UBX0	1
POU1F1	P28069	1
LHX4	Q969G2	1
ACBD6	Q9BR61	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PROP1	O75360	70.74
LHX3	Q9UBR4	68.68
OTX2	P32243	60.99
TCF7L1	Q9HCS4	52.59
GLI2	P10070	42.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 44. Enrichment computed across 10 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RUNX2 regulates chondrocyte maturation	1	326.3×	0.030	GLI2
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	233.1×	0.030	GLI2
Binding of TCF/LEF:CTNNB1 to target gene promoters	1	163.1×	0.030	TCF7L1
RUNX3 regulates WNT signaling	1	163.1×	0.030	TCF7L1
Formation of the posterior neural plate	1	163.1×	0.030	OTX2
Formation of the anterior neural plate	1	148.3×	0.030	OTX2
Positive Regulation of CDH1 Gene Transcription	1	135.9×	0.030	FOXA2
Formation of axial mesoderm	1	116.5×	0.030	FOXA2
Repression of WNT target genes	1	102.0×	0.030	TCF7L1
Formation of definitive endoderm	1	102.0×	0.030	FOXA2
Specification of the neural plate border	1	90.6×	0.030	TCF7L1
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	85.9×	0.030	FOXA2
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	1	81.6×	0.030	TCF7L1
Signaling by ROBO receptors	2	35.5×	0.030	LHX4, LHX3
Regulation of expression of SLITs and ROBOs	2	19.8×	0.030	LHX4, LHX3
Axon guidance	2	12.9×	0.030	LHX4, LHX3
Nervous system development	2	12.3×	0.030	LHX4, LHX3
Developmental Biology	3	6.2×	0.030	TCF7L1, LHX4, LHX3
Regulation of gene expression in beta cells	1	74.2×	0.031	FOXA2
Mitochondrial Fatty Acid Beta-Oxidation	1	54.4×	0.040	ACBD6
Developmental Lineage of Pancreatic Acinar Cells	1	42.9×	0.047	FOXA2
Beta-catenin independent WNT signaling	1	41.8×	0.047	TCF7L1
Transcriptional regulation by RUNX3	1	38.8×	0.049	TCF7L1
Gastrulation	1	37.1×	0.049	TCF7L1
Deactivation of the beta-catenin transactivating complex	1	33.3×	0.050	TCF7L1
Developmental Lineage of Pancreatic Ductal Cells	1	32.6×	0.050	FOXA2
Degradation of GLI2 by the proteasome	1	32.0×	0.050	GLI2
MITF-M-dependent gene expression	1	25.9×	0.056	TCF7L1
Ca2+ pathway	1	25.5×	0.056	TCF7L1
Hedgehog ‘off’ state	1	25.5×	0.056	GLI2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of transcription by RNA polymerase II	9	11.7×	2e-08	GLI2, HESX1, FOXA2, POU1F1, PROP1, TCF7L1, LHX4, LHX3 (+1 more)
medial motor column neuron differentiation	2	1872.4×	1e-05	LHX4, LHX3
somatotropin secreting cell differentiation	2	936.2×	5e-05	PROP1, LHX3
positive regulation of gastrulation	2	535.0×	1e-04	FOXA2, OTX2
positive regulation of transcription by RNA polymerase II	6	9.9×	1e-04	GLI2, FOXA2, POU1F1, LHX4, LHX3, OTX2
primitive streak formation	2	312.1×	3e-04	FOXA2, OTX2
positive regulation of embryonic development	2	249.7×	4e-04	FOXA2, OTX2
motor neuron axon guidance	2	156.0×	8e-04	LHX4, LHX3
pituitary gland development	2	144.0×	8e-04	GLI2, HESX1
dopaminergic neuron differentiation	2	138.7×	8e-04	FOXA2, OTX2
placenta development	2	98.5×	0.001	LHX4, LHX3
positive regulation of DNA-templated transcription	4	12.4×	0.001	GLI2, FOXA2, LHX3, OTX2
hypophysis morphogenesis	1	936.2×	0.006	PROP1
prolactin secreting cell differentiation	1	936.2×	0.006	LHX3
lung development	2	44.1×	0.006	GLI2, LHX3
animal organ morphogenesis	2	42.6×	0.006	LHX4, LHX3
negative regulation of transcription by RNA polymerase II	4	7.9×	0.006	GLI2, HESX1, FOXA2, POU1F1
ventral midline development	1	624.1×	0.007	GLI2
floor plate formation	1	624.1×	0.007	GLI2
spinal cord ventral commissure morphogenesis	1	624.1×	0.007	GLI2
canonical Wnt signaling pathway	2	34.0×	0.007	HESX1, TCF7L1
negative regulation of apoptotic process	3	11.6×	0.008	PROP1, LHX4, LHX3
hindgut morphogenesis	1	468.1×	0.008	GLI2
tube development	1	468.1×	0.008	GLI2
leukemia inhibitory factor signaling pathway	1	468.1×	0.008	HESX1
response to interleukin-6	1	468.1×	0.008	FOXA2
regulation of DNA-templated transcription	3	10.5×	0.008	GLI2, POU1F1, TCF7L1
hypothalamus cell differentiation	1	374.5×	0.009	PROP1
ventral spinal cord interneuron specification	1	312.1×	0.010	LHX3
cerebellar cortex morphogenesis	1	312.1×	0.010	GLI2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 10

Druggability breadth: 1 of 10 evidence-associated genes (10%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLI2	0	0
HESX1	0	0
FOXA2	0	0
POU1F1	0	0
PROP1	0	0
TCF7L1	0	0
LHX4	0	0
OTX2	0	0
ACBD6	0	0
LHX3	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: 10; 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	10	GLI2, HESX1, FOXA2, POU1F1, PROP1, TCF7L1, LHX4, OTX2, ACBD6, LHX3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GLI2	6	—
HESX1	0	—
FOXA2	0	—
POU1F1	0	—
PROP1	0	—
TCF7L1	0	—
LHX4	0	—
OTX2	0	—
ACBD6	0	—
LHX3	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
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening