Septooptic dysplasia
diseaseOn this page
Also known as De Morsier syndromehypopituitarism and septooptic 'dysplasia'septo-optic dysplasiasepto-optic dysplasia sequencesepto-optic dysplasia with growth hormone deficiencySOD
Summary
Septooptic dysplasia (MONDO:0008428) is a disease caused by HESX1 (GenCC Strong), with 11 cohort genes and 4 clinical trials. Top therapeutic interventions include setmelanotide.
At a glance
- Prevalence: Unknown (Worldwide) [Orphanet-validated]
- Causal gene: HESX1 (GenCC Strong)
- Cohort genes: 11
- ClinVar variants: 99
- Phenotypes (HPO): 33
- Clinical trials: 4
Clinical features
Epidemiology
Prevalence records
1 prevalence record(s), Orphanet:
| Type | Class | Value | Geography | Validation |
|---|---|---|---|---|
| Prevalence at birth | 1-5 / 10 000 | 10 | Europe | Validated |
Signs & symptoms
Clinical features (HPO)
33 HPO clinical features (Orphanet curated; top 33 by frequency):
| HPO ID | Term | Frequency |
|---|---|---|
| HP:0000505 | Visual impairment | Very frequent (80-99%) |
| HP:0000609 | Optic nerve hypoplasia | Very frequent (80-99%) |
| HP:0100842 | Septo-optic dysplasia | Very frequent (80-99%) |
| HP:0000028 | Cryptorchidism | Frequent (30-79%) |
| HP:0000175 | Cleft palate | Frequent (30-79%) |
| HP:0000486 | Strabismus | Frequent (30-79%) |
| HP:0000639 | Nystagmus | Frequent (30-79%) |
| HP:0000864 | Abnormality of the hypothalamus-pituitary axis | Frequent (30-79%) |
| HP:0001250 | Seizure | Frequent (30-79%) |
| HP:0001274 | Agenesis of corpus callosum | Frequent (30-79%) |
| HP:0001331 | Absent septum pellucidum | Frequent (30-79%) |
| HP:0004322 | Short stature | Frequent (30-79%) |
| HP:0004374 | Hemiplegia/hemiparesis | Frequent (30-79%) |
| HP:0008736 | Hypoplasia of penis | Frequent (30-79%) |
| HP:0010627 | Anterior pituitary hypoplasia | Frequent (30-79%) |
| HP:0000407 | Sensorineural hearing impairment | Occasional (5-29%) |
| HP:0000458 | Anosmia | Occasional (5-29%) |
| HP:0000717 | Autism | Occasional (5-29%) |
| HP:0000873 | Diabetes insipidus | Occasional (5-29%) |
| HP:0000958 | Dry skin | Occasional (5-29%) |
| HP:0000966 | Hypohidrosis | Occasional (5-29%) |
| HP:0001249 | Intellectual disability | Occasional (5-29%) |
| HP:0001263 | Global developmental delay | Occasional (5-29%) |
| HP:0001513 | Obesity | Occasional (5-29%) |
| HP:0001959 | Polydipsia | Occasional (5-29%) |
| HP:0002019 | Constipation | Occasional (5-29%) |
| HP:0002032 | Esophageal atresia | Occasional (5-29%) |
| HP:0002360 | Sleep abnormality | Occasional (5-29%) |
| HP:0002575 | Tracheoesophageal fistula | Occasional (5-29%) |
| HP:0007360 | Aplasia/Hypoplasia of the cerebellum | Occasional (5-29%) |
| HP:0009800 | Maternal diabetes | Occasional (5-29%) |
| HP:0012378 | Fatigue | Occasional (5-29%) |
| HP:0030680 | Abnormal cardiovascular system morphology | Occasional (5-29%) |
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | septooptic dysplasia |
| Mondo ID | MONDO:0008428 |
| MeSH | D025962 |
| OMIM | 182230 |
| Orphanet | 3157 |
| DOID | DOID:0060857 |
| NCIT | C85063 |
| SNOMED CT | 7611002 |
| UMLS | C0338503 |
| MedGen | 90926 |
| GARD | 0007627 |
| MedDRA | 10067159 |
| Is cancer (heuristic) | no |
Also known as: De Morsier syndrome · hypopituitarism and septooptic ‘dysplasia’ · septo-optic dysplasia · septo-optic dysplasia sequence · septo-optic dysplasia with growth hormone deficiency · septooptic dysplasia · SOD
Data availability: 99 ClinVar variants · 13 GenCC gene-disease records.
Disease family
An umbrella term covering 2 Mondo subtypes.
Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › septooptic dysplasia
Related subtypes (7): autosomal dominant disease, autosomal recessive disease, congenital factor XII deficiency, camptodactyly-tall stature-scoliosis-hearing loss syndrome, brachydactyly-syndactyly syndrome, congenital factor XI deficiency, Weill-Marchesani syndrome
Subtypes (2): congenital absence of septum pellucidum, pagon stephan 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
99 retrieved; paginated sample, class counts are floors:
45 uncertain significance, 18 likely benign, 12 conflicting classifications of pathogenicity, 12 pathogenic, 7 likely pathogenic, 2 benign, 2 benign/likely benign, 1 pathogenic/likely pathogenic
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 1693158 | NM_006015.6(ARID1A):c.6625C>T (p.Gln2209Ter) | ARID1A | Pathogenic | criteria provided, single submitter |
| 1405989 | NM_003865.3(HESX1):c.173del (p.Leu58fs) | HESX1 | Pathogenic | criteria provided, single submitter |
| 1470869 | NM_003865.3(HESX1):c.135G>A (p.Trp45Ter) | HESX1 | Pathogenic | criteria provided, single submitter |
| 2061888 | NM_003865.3(HESX1):c.389del (p.Asn130fs) | HESX1 | Pathogenic | criteria provided, single submitter |
| 2094701 | NM_003865.3(HESX1):c.241G>T (p.Glu81Ter) | HESX1 | Pathogenic | criteria provided, single submitter |
| 2163319 | NM_003865.3(HESX1):c.305_306del (p.Glu102fs) | HESX1 | Pathogenic | criteria provided, single submitter |
| 2444374 | NM_003865.3(HESX1):c.349C>T (p.Gln117Ter) | HESX1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 492848 | NM_003865.3(HESX1):c.240del (p.Glu81fs) | HESX1 | Pathogenic | no assertion criteria provided |
| 7691 | NM_003865.3(HESX1):c.478C>T (p.Arg160Cys) | HESX1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 7694 | NM_003865.3(HESX1):c.305_306dup (p.Leu103fs) | HESX1 | Pathogenic | no assertion criteria provided |
| 7696 | NM_003865.3(HESX1):c.525del (p.Asn178fs) | HESX1 | Pathogenic | no assertion criteria provided |
| 94104 | NM_003106.4(SOX2):c.70_89del (p.Asn24fs) | LOC108281177 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1693157 | NM_000193.4(SHH):c.562+1G>A | SHH | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 427836 | NM_020336.3(RALGAPB):c.[1918A>G];[2324G>T] | Likely pathogenic | criteria provided, single submitter | |
| 1722764 | GRCh37/hg19 Xq28(chrX:153560562-153864851)x3 | G6PD | Likely pathogenic | no assertion criteria provided |
| 4294353 | NM_003865.3(HESX1):c.48del (p.Ser17fs) | HESX1 | Likely pathogenic | criteria provided, single submitter |
| 4845672 | NM_003865.3(HESX1):c.533del (p.Asn178fs) | HESX1 | Likely pathogenic | criteria provided, single submitter |
| 492849 | NM_003865.3(HESX1):c.308T>A (p.Leu103Ter) | HESX1 | Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 537760 | NM_003865.3(HESX1):c.158-1G>C | HESX1 | Likely pathogenic | criteria provided, single submitter |
| 370037 | NM_020336.4(RALGAPB):c.2324G>T (p.Arg775Leu) | RALGAPB | Likely pathogenic | criteria provided, single submitter |
| 1206790 | NM_003865.3(HESX1):c.475C>T (p.Arg159Trp) | HESX1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1324528 | NM_003865.3(HESX1):c.3G>A (p.Met1Ile) | HESX1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1417884 | NM_003865.3(HESX1):c.350A>C (p.Gln117Pro) | HESX1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 197222 | NM_003865.3(HESX1):c.525G>A (p.Ala175=) | HESX1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 197223 | NM_003865.3(HESX1):c.511_512del (p.Gln171fs) | HESX1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 2074752 | NM_003865.3(HESX1):c.219C>T (p.Ser73=) | HESX1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 267733 | NM_003865.3(HESX1):c.385G>A (p.Val129Ile) | HESX1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 346285 | NM_003865.3(HESX1):c.220G>A (p.Val74Met) | HESX1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 497545 | NM_003865.3(HESX1):c.326G>A (p.Arg109Gln) | HESX1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 7693 | NM_003865.3(HESX1):c.541A>G (p.Thr181Ala) | HESX1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 92 · Orphanet: 58 · 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 |
|---|---|---|---|---|
| FGFR1 | Definitive | Autosomal dominant | osteoglophonic dysplasia | 36 |
| HESX1 | Strong | Autosomal dominant | septooptic dysplasia | 12 |
| ARNT2 | Supportive | Autosomal dominant | septooptic dysplasia | 4 |
| OTX2 | Supportive | Autosomal dominant | septooptic dysplasia | 11 |
| PROKR2 | Supportive | Autosomal dominant | septooptic dysplasia | 8 |
| SOX2 | Supportive | Autosomal dominant | septooptic dysplasia | 8 |
| SOX3 | Supportive | Autosomal dominant | septooptic dysplasia | 13 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| 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 |
| SOX2 | Orphanet:3157 | Septo-optic dysplasia spectrum |
| SOX2 | Orphanet:35612 | Nanophthalmos |
| SOX2 | Orphanet:77298 | Anophthalmia/microphthalmia-esophageal atresia syndrome |
| SOX2 | Orphanet:98938 | Colobomatous microphthalmia |
| SOX3 | Orphanet:3157 | Septo-optic dysplasia spectrum |
| SOX3 | Orphanet:393 | 46,XX testicular difference of sex development |
| SOX3 | Orphanet:67045 | X-linked intellectual disability with isolated growth hormone deficiency |
| SOX3 | Orphanet:79495 | X-linked congenital generalized hypertrichosis |
| SOX3 | Orphanet:90695 | Non-acquired panhypopituitarism |
| PROKR2 | Orphanet:3157 | Septo-optic dysplasia spectrum |
| PROKR2 | Orphanet:432 | Normosmic congenital hypogonadotropic hypogonadism |
| PROKR2 | Orphanet:478 | Kallmann syndrome |
| PROKR2 | Orphanet:95496 | Pituitary stalk interruption syndrome |
| ARNT2 | Orphanet:3157 | Septo-optic dysplasia spectrum |
| FGFR1 | Orphanet:168953 | Myeloid/lymphoid neoplasm associated with FGFR1 rearrangement |
| FGFR1 | Orphanet:2117 | Hartsfield syndrome |
| FGFR1 | Orphanet:220386 | Semilobar holoprosencephaly |
| FGFR1 | Orphanet:2396 | Encephalocraniocutaneous lipomatosis |
| FGFR1 | Orphanet:251576 | Gliosarcoma |
| FGFR1 | Orphanet:251579 | Giant cell glioblastoma |
| FGFR1 | Orphanet:251615 | Pilomyxoid astrocytoma |
| FGFR1 | Orphanet:2645 | Osteoglosphonic dysplasia |
| FGFR1 | Orphanet:280200 | Microform holoprosencephaly |
| FGFR1 | Orphanet:314950 | Primary hypereosinophilic syndrome |
| FGFR1 | Orphanet:3157 | Septo-optic dysplasia spectrum |
| FGFR1 | Orphanet:3366 | Non-syndromic metopic craniosynostosis |
| FGFR1 | Orphanet:432 | Normosmic congenital hypogonadotropic hypogonadism |
| FGFR1 | Orphanet:478 | Kallmann syndrome |
| FGFR1 | Orphanet:93258 | Pfeiffer syndrome type 1 |
| FGFR1 | Orphanet:93924 | Lobar holoprosencephaly |
| FGFR1 | Orphanet:99798 | Oligodontia |
| 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 |
| 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 |
Cohort genes → proteins
11 cohort genes, 11 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 11 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| HESX1 | HGNC:4877 | ENSG00000163666 | Q9UBX0 | Homeobox expressed in ES cells 1 | gencc,clinvar |
| SOX2 | HGNC:11195 | ENSG00000181449 | P48431 | Transcription factor SOX-2 | gencc |
| SOX3 | HGNC:11199 | ENSG00000134595 | P41225 | Transcription factor SOX-3 | gencc |
| PROKR2 | HGNC:15836 | ENSG00000101292 | Q8NFJ6 | Prokineticin receptor 2 | gencc |
| ARNT2 | HGNC:16876 | ENSG00000172379 | Q9HBZ2 | Aryl hydrocarbon receptor nuclear translocator 2 | gencc |
| FGFR1 | HGNC:3688 | ENSG00000077782 | P11362 | Fibroblast growth factor receptor 1 | gencc |
| OTX2 | HGNC:8522 | ENSG00000165588 | P32243 | Homeobox protein OTX2 | gencc |
| SHH | HGNC:10848 | ENSG00000164690 | Q15465 | Sonic hedgehog protein | clinvar |
| ARID1A | HGNC:11110 | ENSG00000117713 | O14497 | AT-rich interactive domain-containing protein 1A | clinvar |
| RALGAPB | HGNC:29221 | ENSG00000170471 | Q86X10 | Ral GTPase-activating protein subunit beta | clinvar |
| G6PD | HGNC:4057 | ENSG00000160211 | P11413 | Glucose-6-phosphate 1-dehydrogenase | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| 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. |
| SOX2 | Transcription factor SOX-2 | Transcription factor that forms a trimeric complex with OCT4 on DNA and controls the expression of a number of genes involved in embryonic development such as YES1, FGF4, UTF1 and ZFP206. |
| SOX3 | Transcription factor SOX-3 | Transcription factor required during the formation of the hypothalamo-pituitary axis. |
| PROKR2 | Prokineticin receptor 2 | Receptor for prokineticin 2. |
| ARNT2 | Aryl hydrocarbon receptor nuclear translocator 2 | Transcription factor that plays a role in the development of the hypothalamo-pituitary axis, postnatal brain growth, and visual and renal function. |
| FGFR1 | Fibroblast growth factor receptor 1 | Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. |
| OTX2 | Homeobox protein OTX2 | Transcription factor probably involved in the development of the brain and the sense organs. |
| SHH | Sonic hedgehog protein | The C-terminal part of the sonic hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity. |
| ARID1A | AT-rich interactive domain-containing protein 1A | Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). |
| RALGAPB | Ral GTPase-activating protein subunit beta | Non-catalytic subunit of the heterodimeric RalGAP1 and RalGAP2 complexes which act as GTPase activators for the Ras-like small GTPases RALA and RALB. |
| G6PD | Glucose-6-phosphate 1-dehydrogenase | Catalyzes the rate-limiting step of the oxidative pentose-phosphate pathway, which represents a route for the dissimilation of carbohydrates besides glycolysis. |
Protein-family classification
Druggable: 3 · Difficult: 5 · Unknown: 3 · Druggable fraction: 0.27
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 | 5 | 3.8× | 0.032 |
| Kinase | 1 | 2.5× | 0.624 |
| GPCR | 1 | 2.2× | 0.624 |
| Enzyme (other) | 1 | 1.1× | 0.770 |
| Other/Unknown | 3 | 0.5× | 0.987 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| HESX1 | Transcription factor | no | HD, Homeodomain-like_sf, Homeobox_CS | |
| SOX2 | Transcription factor | no | HMG_box_dom, SOX_fam, HMG_box_dom_sf | |
| SOX3 | Transcription factor | no | HMG_box_dom, SOX_fam, HMG_box_dom_sf | |
| PROKR2 | GPCR | yes | GPCR_Rhodpsn, NPY_rcpt, GPCR_Rhodpsn_7TM | |
| ARNT2 | Transcription factor | no | PAS, Nuc_translocat, PAC | |
| FGFR1 | Kinase | yes | 2.7.10.1 | Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2 |
| OTX2 | Transcription factor | no | HD, Otx2_TF, Otx_TF | |
| SHH | Other/Unknown | no | Hedgehog_signalling_dom, Hedgehog, Hedgehog_Hint | |
| ARID1A | Other/Unknown | no | ARID_dom, ARM-like, ARM-type_fold | |
| RALGAPB | Other/Unknown | no | Rap/Ran_GAP_dom, Rap/Ran-GAP_sf, RALGAPB | |
| G6PD | Enzyme (other) | yes | 1.1.1.49 | G6P_DH, G6P_DH_AS, G6P_DH_NAD-bd |
Expression context
Cohort genes with no expression data: 0.
10 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) | 11 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| buccal mucosa cell | 4 |
| ventricular zone | 4 |
| ganglionic eminence | 3 |
| embryo | 2 |
| stromal cell of endometrium | 2 |
| male germ line stem cell (sensu Vertebrata) in testis | 1 |
| primordial germ cell in gonad | 1 |
| bronchial epithelial cell | 1 |
| cortical plate | 1 |
| frontal pole | 1 |
| lateral globus pallidus | 1 |
| middle temporal gyrus | 1 |
| calcaneal tendon | 1 |
| oocyte | 1 |
| pigmented layer of retina | 1 |
| secondary oocyte | 1 |
| epithelial cell of pancreas | 1 |
| right lobe of liver | 1 |
| bone marrow cell | 1 |
| male germ cell | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| HESX1 | 167 | broad | marker | buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad |
| SOX2 | 203 | broad | marker | ventricular zone, bronchial epithelial cell, ganglionic eminence |
| SOX3 | 72 | broad | marker | ventricular zone, ganglionic eminence, embryo |
| PROKR2 | 32 | tissue_specific | yes | cortical plate, ganglionic eminence, ventricular zone |
| ARNT2 | 246 | ubiquitous | marker | lateral globus pallidus, middle temporal gyrus, frontal pole |
| FGFR1 | 292 | ubiquitous | marker | buccal mucosa cell, stromal cell of endometrium, calcaneal tendon |
| OTX2 | 62 | broad | marker | secondary oocyte, oocyte, pigmented layer of retina |
| SHH | 131 | broad | marker | buccal mucosa cell, right lobe of liver, epithelial cell of pancreas |
| ARID1A | 286 | ubiquitous | marker | bone marrow cell, ventricular zone, embryo |
| RALGAPB | 292 | ubiquitous | marker | buccal mucosa cell, sperm, male germ cell |
| G6PD | 218 | ubiquitous | marker | stromal cell of endometrium, granulocyte, right testis |
Protein interactions among cohort
Intra-cohort edges: 5.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| SOX2 | 9,645 |
| FGFR1 | 5,693 |
| SHH | 4,953 |
| G6PD | 4,226 |
| ARID1A | 3,476 |
| OTX2 | 2,368 |
| RALGAPB | 1,605 |
| ARNT2 | 1,294 |
| HESX1 | 888 |
| PROKR2 | 844 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| FGFR1 | PROKR2 | string_interaction |
| HESX1 | PROKR2 | string_interaction |
| HESX1 | SOX2 | string_interaction |
| OTX2 | SHH | string_interaction |
| OTX2 | SOX2 | string_interaction |
Structural data
PDB: 7 · AlphaFold-only: 4 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| FGFR1 | P11362 | 83 |
| G6PD | P11413 | 25 |
| SHH | Q15465 | 20 |
| SOX2 | P48431 | 13 |
| ARID1A | O14497 | 7 |
| HESX1 | Q9UBX0 | 1 |
| RALGAPB | Q86X10 | 1 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| PROKR2 | Q8NFJ6 | 78.50 |
| OTX2 | P32243 | 60.99 |
| ARNT2 | Q9HBZ2 | 59.49 |
| SOX3 | P41225 | 58.40 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 97. Enrichment computed across 11 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Formation of the posterior neural plate | 2 | 228.4× | 0.002 | SOX2, OTX2 |
| Formation of the anterior neural plate | 2 | 207.6× | 0.002 | SOX2, OTX2 |
| Gastrulation | 2 | 51.9× | 0.019 | SHH, SOX2 |
| Deactivation of the beta-catenin transactivating complex | 2 | 46.6× | 0.019 | SOX2, SOX3 |
| MITF-M-dependent gene expression | 2 | 36.2× | 0.025 | ARID1A, SOX2 |
| Signaling by FGFR1 amplification mutants | 1 | 571.0× | 0.028 | FGFR1 |
| FGFR1c and Klotho ligand binding and activation | 1 | 285.5× | 0.031 | FGFR1 |
| Signaling by plasma membrane FGFR1 fusions | 1 | 285.5× | 0.031 | FGFR1 |
| TCF dependent signaling in response to WNT | 2 | 23.6× | 0.031 | SOX2, SOX3 |
| MITF-M-regulated melanocyte development | 2 | 22.8× | 0.031 | ARID1A, SOX2 |
| Signaling by WNT | 2 | 22.4× | 0.031 | SOX2, SOX3 |
| HHAT G278V doesn’t palmitoylate Hh-Np | 1 | 228.4× | 0.033 | SHH |
| Formation of lateral plate mesoderm | 1 | 228.4× | 0.033 | SHH |
| Aryl hydrocarbon receptor signalling | 1 | 190.3× | 0.036 | ARNT2 |
| Release of Hh-Np from the secreting cell | 1 | 142.8× | 0.036 | SHH |
| Hh mutants abrogate ligand secretion | 1 | 142.8× | 0.036 | SHH |
| Ligand-receptor interactions | 1 | 142.8× | 0.036 | SHH |
| Epithelial-Mesenchymal Transition (EMT) during gastrulation | 1 | 142.8× | 0.036 | FGFR1 |
| NFE2L2 regulates pentose phosphate pathway genes | 1 | 142.8× | 0.036 | G6PD |
| FGFR1b ligand binding and activation | 1 | 126.9× | 0.038 | FGFR1 |
| RNA Polymerase II Transcription | 3 | 6.8× | 0.038 | ARID1A, SOX2, ARNT2 |
| POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation | 1 | 114.2× | 0.038 | SOX2 |
| Signaling by activated point mutants of FGFR1 | 1 | 95.2× | 0.041 | FGFR1 |
| Pentose phosphate pathway | 1 | 95.2× | 0.041 | G6PD |
| Positive Regulation of CDH1 Gene Transcription | 1 | 95.2× | 0.041 | ARID1A |
| POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation | 1 | 87.8× | 0.041 | SOX2 |
| Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition | 1 | 87.8× | 0.041 | SOX2 |
| Formation of axial mesoderm | 1 | 81.6× | 0.042 | SHH |
| FGFR1c ligand binding and activation | 1 | 76.1× | 0.042 | FGFR1 |
| Cytochrome P450 - arranged by substrate type | 1 | 71.4× | 0.042 | ARNT2 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| pituitary gland development | 3 | 176.8× | 1e-04 | HESX1, SOX2, SOX3 |
| midbrain development | 3 | 164.1× | 1e-04 | SHH, FGFR1, OTX2 |
| forebrain development | 3 | 95.8× | 4e-04 | SHH, SOX2, OTX2 |
| positive regulation of cell differentiation | 3 | 73.0× | 5e-04 | ARID1A, SOX2, FGFR1 |
| brain development | 4 | 28.9× | 5e-04 | HESX1, SOX2, SOX3, ARNT2 |
| lung-associated mesenchyme development | 2 | 306.4× | 9e-04 | SHH, FGFR1 |
| positive regulation of DNA-templated transcription | 5 | 12.7× | 1e-03 | SHH, ARID1A, SOX2, ARNT2, OTX2 |
| branching involved in salivary gland morphogenesis | 2 | 255.3× | 1e-03 | SHH, FGFR1 |
| central nervous system development | 3 | 31.5× | 0.003 | SHH, SOX3, ARNT2 |
| dopaminergic neuron differentiation | 2 | 113.5× | 0.004 | SHH, OTX2 |
| thyroid gland development | 2 | 98.8× | 0.005 | HESX1, SHH |
| negative regulation of transcription by RNA polymerase II | 5 | 8.1× | 0.005 | HESX1, SHH, SOX2, SOX3, FGFR1 |
| polarity specification of anterior/posterior axis | 1 | 1532.0× | 0.006 | SHH |
| ribose phosphate biosynthetic process | 1 | 1532.0× | 0.006 | G6PD |
| trachea morphogenesis | 1 | 1532.0× | 0.006 | SHH |
| right lung development | 1 | 1532.0× | 0.006 | SHH |
| left lung development | 1 | 1532.0× | 0.006 | SHH |
| primary prostatic bud elongation | 1 | 1532.0× | 0.006 | SHH |
| regulation of prostatic bud formation | 1 | 1532.0× | 0.006 | SHH |
| obsolete regulation of mesenchymal cell proliferation involved in prostate gland development | 1 | 1532.0× | 0.006 | SHH |
| mesenchymal smoothened signaling pathway involved in prostate gland development | 1 | 1532.0× | 0.006 | SHH |
| positive regulation of sclerotome development | 1 | 1532.0× | 0.006 | SHH |
| tracheoesophageal septum formation | 1 | 1532.0× | 0.006 | SHH |
| negative regulation of ureter smooth muscle cell differentiation | 1 | 1532.0× | 0.006 | SHH |
| positive regulation of ureter smooth muscle cell differentiation | 1 | 1532.0× | 0.006 | SHH |
| negative regulation of kidney smooth muscle cell differentiation | 1 | 1532.0× | 0.006 | SHH |
| positive regulation of kidney smooth muscle cell differentiation | 1 | 1532.0× | 0.006 | SHH |
| embryonic limb morphogenesis | 2 | 73.0× | 0.006 | SHH, FGFR1 |
| inner ear development | 2 | 68.1× | 0.006 | SHH, SOX2 |
| camera-type eye development | 2 | 65.2× | 0.006 | HESX1, SHH |
Therapeutics
Drug target analysis
Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 8
Druggability breadth: 5 of 11 evidence-associated genes (45%) 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 |
|---|---|
| FGFR1 | PONATINIB |
| SHH | VISMODEGIB |
| G6PD | BREXANOLONE |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| FGFR1 | 93 | 4 |
| G6PD | 8 | 4 |
| SHH | 1 | 4 |
| HESX1 | 0 | 0 |
| SOX2 | 0 | 0 |
| SOX3 | 0 | 0 |
| PROKR2 | 0 | 0 |
| ARNT2 | 0 | 0 |
| OTX2 | 0 | 0 |
| ARID1A | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| PONATINIB | 4 | FGFR1 |
| PEMIGATINIB | 4 | FGFR1 |
| NINTEDANIB | 4 | FGFR1 |
| FEDRATINIB | 4 | FGFR1 |
| TIVOZANIB | 4 | FGFR1 |
| LENVATINIB | 4 | FGFR1 |
| AXITINIB | 4 | FGFR1 |
| SORAFENIB | 4 | FGFR1 |
| NICLOSAMIDE | 4 | FGFR1 |
| INFIGRATINIB PHOSPHATE | 4 | FGFR1 |
| INFIGRATINIB | 4 | FGFR1 |
| REGORAFENIB | 4 | FGFR1 |
| ENTRECTINIB | 4 | FGFR1 |
| CABOZANTINIB | 4 | FGFR1 |
| CAPIVASERTIB | 4 | FGFR1 |
| VANDETANIB | 4 | FGFR1 |
| NINTEDANIB ESYLATE | 4 | FGFR1 |
| BRIGATINIB | 4 | FGFR1 |
| ERDAFITINIB | 4 | FGFR1 |
| UPADACITINIB | 4 | FGFR1 |
| FUTIBATINIB | 4 | FGFR1 |
| PAZOPANIB | 4 | FGFR1 |
| SUNITINIB | 4 | FGFR1 |
| DASATINIB | 4 | FGFR1 |
| MIDOSTAURIN | 4 | FGFR1 |
| VISMODEGIB | 4 | SHH |
| BREXANOLONE | 4 | G6PD |
| APOMORPHINE HYDROCHLORIDE | 4 | G6PD |
| PRASTERONE | 4 | G6PD |
| LINIFANIB | 3 | FGFR1 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 2.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| FGFR1 | 1,465 | Binding:1428, Functional:24, ADMET:13 |
| G6PD | 49 | Binding:46, ADMET:2, Functional:1 |
| SHH | 27 | Binding:23, Functional:4 |
| PROKR2 | 9 | Functional:5, Binding:4 |
| ARID1A | 6 | Binding:6 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| FGFR1 | 2.7.10.1 | receptor protein-tyrosine kinase |
| G6PD | 1.1.1.49 | glucose-6-phosphate dehydrogenase (NADP+) |
Cohort genes with high screening signal
≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.
| Symbol | ChEMBL assays |
|---|---|
| FGFR1 | 1,465 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 11; with CPIC/DPWG dosing guidelines: 1.
Cohort genes with a CPIC/DPWG dosing guideline
| Symbol | CPIC guidelines |
|---|---|
| G6PD | 1 |
Chemical tractability of cohort targets
30 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) |
|---|---|---|
| PONATINIB | 4 | FGFR1 |
| PEMIGATINIB | 4 | FGFR1 |
| NINTEDANIB | 4 | FGFR1 |
| FEDRATINIB | 4 | FGFR1 |
| TIVOZANIB | 4 | FGFR1 |
| LENVATINIB | 4 | FGFR1 |
| AXITINIB | 4 | FGFR1 |
| SORAFENIB | 4 | FGFR1 |
| NICLOSAMIDE | 4 | FGFR1 |
| INFIGRATINIB PHOSPHATE | 4 | FGFR1 |
| INFIGRATINIB | 4 | FGFR1 |
| REGORAFENIB | 4 | FGFR1 |
| ENTRECTINIB | 4 | FGFR1 |
| CABOZANTINIB | 4 | FGFR1 |
| CAPIVASERTIB | 4 | FGFR1 |
| VANDETANIB | 4 | FGFR1 |
| NINTEDANIB ESYLATE | 4 | FGFR1 |
| BRIGATINIB | 4 | FGFR1 |
| ERDAFITINIB | 4 | FGFR1 |
| UPADACITINIB | 4 | FGFR1 |
| FUTIBATINIB | 4 | FGFR1 |
| PAZOPANIB | 4 | FGFR1 |
| SUNITINIB | 4 | FGFR1 |
| DASATINIB | 4 | FGFR1 |
| MIDOSTAURIN | 4 | FGFR1 |
| VISMODEGIB | 4 | SHH |
| BREXANOLONE | 4 | G6PD |
| APOMORPHINE HYDROCHLORIDE | 4 | G6PD |
| PRASTERONE | 4 | G6PD |
| LINIFANIB | 3 | FGFR1 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 3 | FGFR1, SHH, G6PD |
| B | Phased (≥1) drug, not yet approved | 0 | |
| C | Druggable family + PDB, no drug | 0 | |
| D | Druggable family + AlphaFold only, no drug | 1 | PROKR2 |
| E | Difficult family or no structure, no drug | 7 | HESX1, SOX2, SOX3, ARNT2, OTX2, ARID1A, RALGAPB |
Undrugged target profiles
8 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| HESX1 | 0 | — |
| SOX2 | 0 | — |
| SOX3 | 0 | — |
| PROKR2 | 9 | — |
| ARNT2 | 0 | — |
| OTX2 | 0 | — |
| ARID1A | 6 | — |
| RALGAPB | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 4.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| Not specified | 2 |
| PHASE4 | 1 |
| PHASE3 | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT00140413 | PHASE4 | COMPLETED | Endocrine Dysfunction and Growth Hormone Deficiency in Children With Optic Nerve Hypoplasia |
| NCT06760546 | PHASE3 | RECRUITING | A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756) |
| NCT05717855 | Not specified | COMPLETED | Screening of Septo-optic Dysplasia During a Fetal Examination at 16-20 Weeks of Gestation |
| NCT06262152 | Not specified | UNKNOWN | Sleep Profile of Patients With Septo-optic Dysplasia |
Drugs tested across these trials (top 30)
| Molecule | Max phase | Trials referencing |
|---|---|---|
| SETMELANOTIDE | 4 | 1 |
| CHEMBL4067491 | 0 | 1 |