Hypogonadotropic hypogonadism 7 with or without anosmia
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Also known as HH7hypogonadotropic hypogonadism 7 without anosmia
Summary
Hypogonadotropic hypogonadism 7 with or without anosmia (MONDO:0007794) is a disease caused by GNRHR (GenCC Strong), with 18 cohort genes.
At a glance
- Causal gene: GNRHR (GenCC Strong)
- Cohort genes: 18
- ClinVar variants: 234
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | hypogonadotropic hypogonadism 7 with or without anosmia |
| Mondo ID | MONDO:0007794 |
| MeSH | C562785 |
| OMIM | 146110 |
| DOID | DOID:0090078 |
| SNOMED CT | 123953004 |
| UMLS | C0342384 |
| MedGen | 87440 |
| GARD | 0002897 |
| Is cancer (heuristic) | no |
Also known as: HH7 · hypogonadotropic hypogonadism 7 with or without anosmia · hypogonadotropic hypogonadism 7 without anosmia
Data availability: 234 ClinVar variants · 3 GenCC gene-disease records.
Disease family
Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › hypogonadism › hypogonadotropic hypogonadism › congenital hypogonadotropic hypogonadism › hypogonadotropic hypogonadism 7 with or without anosmia
Related subtypes (24): brachytelephalangy-dysmorphism-Kallmann syndrome, Prader-Willi syndrome, familial adrenal hypoplasia with absent pituitary luteinizing hormone, cerebellar ataxia-hypogonadism syndrome, CHARGE syndrome, ataxia-hypogonadism-choroidal dystrophy syndrome, Woodhouse-Sakati syndrome, Laurence-Moon syndrome, X-linked adrenal hypoplasia congenita, obesity due to prohormone convertase I deficiency, arhinia, choanal atresia, and microphthalmia, ANE syndrome, combined pituitary hormone deficiencies, genetic form, obesity due to congenital leptin deficiency, obesity due to leptin receptor gene deficiency, polyendocrine-polyneuropathy syndrome, hypogonadotropic hypogonadism-frontoparietal alopecia syndrome, hypogonadotropic hypogonadism-retinitis pigmentosa syndrome, Kallmann syndrome-heart disease syndrome, isolated congenital hypogonadotropic hypogonadism, Moebius syndrome-axonal neuropathy-hypogonadotropic hypogonadism syndrome, hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome, Prader-Willi-like syndrome, Martsolf syndrome 1
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
234 retrieved; paginated sample, class counts are floors:
117 uncertain significance, 23 likely benign, 18 pathogenic/likely pathogenic, 17 pathogenic, 17 benign, 15 benign/likely benign, 15 conflicting classifications of pathogenicity, 12 likely pathogenic
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 180157 | NM_000216.4(ANOS1):c.1369C>T (p.Arg457Ter) | ANOS1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 626905 | NM_001195305.3(BBIP1):c.109C>T (p.Gln37Ter) | BBIP1 | Pathogenic | no assertion criteria provided |
| 16282 | NM_023110.3(FGFR1):c.1864C>T (p.Arg622Ter) | FGFR1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 180153 | NM_023110.3(FGFR1):c.1916T>C (p.Ile639Thr) | FGFR1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 180154 | NM_023110.3(FGFR1):c.1037_1038del (p.Ser346fs) | FGFR1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 180156 | NM_023110.3(FGFR1):c.296A>G (p.Tyr99Cys) | FGFR1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 180160 | NM_023110.3(FGFR1):c.2059G>A (p.Gly687Arg) | FGFR1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 126540 | NM_000406.3(GNRHR):c.842C>T (p.Thr281Ile) | GNRHR | Pathogenic | no assertion criteria provided |
| 140610 | NM_000406.3(GNRHR):c.392T>C (p.Met131Thr) | GNRHR | Pathogenic | no assertion criteria provided |
| 140611 | NM_000406.3(GNRHR):c.806C>T (p.Thr269Met) | GNRHR | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1458023 | NM_000406.3(GNRHR):c.401T>G (p.Val134Gly) | GNRHR | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1519153 | NM_000406.3(GNRHR):c.797T>G (p.Leu266Arg) | GNRHR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 16023 | NM_000406.3(GNRHR):c.317A>G (p.Gln106Arg) | GNRHR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 16024 | NM_000406.3(GNRHR):c.785G>A (p.Arg262Gln) | GNRHR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 16026 | NM_000406.3(GNRHR):c.386C>A (p.Ala129Asp) | GNRHR | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 16027 | NM_000406.3(GNRHR):c.651C>A (p.Ser217Arg) | GNRHR | Pathogenic | no assertion criteria provided |
| 16028 | NM_000406.3(GNRHR):c.504T>A (p.Ser168Arg) | GNRHR | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 16029 | NM_000406.3(GNRHR):c.941T>A (p.Leu314Ter) | GNRHR | Pathogenic | no assertion criteria provided |
| 16030 | NM_000406.3(GNRHR):c.416G>A (p.Arg139His) | GNRHR | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 16032 | NM_000406.3(GNRHR):c.268G>A (p.Glu90Lys) | GNRHR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 16033 | NM_000406.3(GNRHR):c.523-1G>A | GNRHR | Pathogenic | criteria provided, single submitter |
| 16034 | NM_000406.3(GNRHR):c.511G>A (p.Ala171Thr) | GNRHR | Pathogenic | criteria provided, single submitter |
| 16036 | NM_000406.3(GNRHR):c.959C>T (p.Pro320Leu) | GNRHR | Pathogenic | no assertion criteria provided |
| 1675193 | NM_000406.3(GNRHR):c.415C>T (p.Arg139Cys) | GNRHR | Pathogenic | criteria provided, single submitter |
| 180147 | NM_000406.3(GNRHR):c.350T>G (p.Leu117Arg) | GNRHR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 189195 | NM_001012763.1(GNRHR):c.30_31delinsAA (p.Asn10_Gln11delinsLysLys) | GNRHR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 2151986 | NM_000406.3(GNRHR):c.784C>T (p.Arg262Trp) | GNRHR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 2577284 | NM_000406.3(GNRHR):c.35del (p.Asn12fs) | GNRHR | Pathogenic | criteria provided, single submitter |
| 2581289 | NM_000406.3(GNRHR):c.521A>G (p.Gln174Arg) | GNRHR | Pathogenic | criteria provided, single submitter |
| 2755816 | NM_000406.3(GNRHR):c.847T>C (p.Tyr283His) | GNRHR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 4 · Orphanet: 47 · 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 |
|---|---|---|---|---|
| GNRHR | Strong | Autosomal recessive | hypogonadotropic hypogonadism 7 with or without anosmia | 4 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| GNRHR | Orphanet:432 | Normosmic congenital hypogonadotropic hypogonadism |
| SEMA3E | Orphanet:138 | CHARGE syndrome |
| TAC3 | Orphanet:432 | Normosmic congenital hypogonadotropic hypogonadism |
| TACR3 | Orphanet:432 | Normosmic congenital hypogonadotropic hypogonadism |
| TACR3 | Orphanet:478 | Kallmann syndrome |
| WDR11 | Orphanet:432 | Normosmic congenital hypogonadotropic hypogonadism |
| WDR11 | Orphanet:478 | Kallmann syndrome |
| WDR11 | Orphanet:95496 | Pituitary stalk interruption syndrome |
| SPRY4 | Orphanet:363494 | Non-seminomatous germ cell tumor of testis |
| SPRY4 | Orphanet:432 | Normosmic congenital hypogonadotropic hypogonadism |
| SPRY4 | Orphanet:478 | Kallmann syndrome |
| PHIP | Orphanet:589905 | PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome |
| 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 |
| PNPLA6 | Orphanet:1173 | Cerebellar ataxia-hypogonadism syndrome |
| PNPLA6 | Orphanet:1180 | Ataxia-hypogonadism-choroidal dystrophy syndrome |
| PNPLA6 | Orphanet:139480 | Autosomal recessive spastic paraplegia type 39 |
| PNPLA6 | Orphanet:2377 | Laurence-Moon syndrome |
| PNPLA6 | Orphanet:3363 | Trichomegaly-retina pigmentary degeneration-dwarfism syndrome |
| RNF216 | Orphanet:1173 | Cerebellar ataxia-hypogonadism syndrome |
| FEZF1 | Orphanet:478 | Kallmann syndrome |
| CCDC141 | Orphanet:478 | Kallmann syndrome |
| BBIP1 | Orphanet:110 | Bardet-Biedl syndrome |
| POLR3B | Orphanet:85186 | Endosteal sclerosis-cerebellar hypoplasia syndrome |
| POLR3B | Orphanet:88637 | Hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome |
| 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 |
| HS6ST1 | Orphanet:432 | Normosmic congenital hypogonadotropic hypogonadism |
| HS6ST1 | Orphanet:478 | Kallmann syndrome |
| ANOS1 | Orphanet:478 | Kallmann syndrome |
Cohort genes → proteins
18 cohort genes, 18 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 18 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| GNRHR | HGNC:4421 | ENSG00000109163 | P30968 | Gonadotropin-releasing hormone receptor | gencc,clinvar |
| SEMA3E | HGNC:10727 | ENSG00000170381 | O15041 | Semaphorin-3E | clinvar |
| TAC3 | HGNC:11521 | ENSG00000166863 | Q9UHF0 | Tachykinin-3 | clinvar |
| TACR3 | HGNC:11528 | ENSG00000169836 | P29371 | Neuromedin-K receptor | clinvar |
| WDR11 | HGNC:13831 | ENSG00000120008 | Q9BZH6 | WD repeat-containing protein 11 | clinvar |
| SPRY4 | HGNC:15533 | ENSG00000187678 | Q9C004 | Protein sprouty homolog 4 | clinvar |
| PHIP | HGNC:15673 | ENSG00000146247 | Q8WWQ0 | PH-interacting protein | clinvar |
| PROKR2 | HGNC:15836 | ENSG00000101292 | Q8NFJ6 | Prokineticin receptor 2 | clinvar |
| PNPLA6 | HGNC:16268 | ENSG00000032444 | Q8IY17 | Patatin-like phospholipase domain-containing protein 6 | clinvar |
| RNF216 | HGNC:21698 | ENSG00000011275 | Q9NWF9 | E3 ubiquitin-protein ligase RNF216 | clinvar |
| FEZF1 | HGNC:22788 | ENSG00000128610 | A0PJY2 | Fez family zinc finger protein 1 | clinvar |
| CCDC141 | HGNC:26821 | ENSG00000163492 | Q6ZP82 | Coiled-coil domain-containing protein 141 | clinvar |
| BBIP1 | HGNC:28093 | ENSG00000214413 | A8MTZ0 | BBSome-interacting protein 1 | clinvar |
| POLR3B | HGNC:30348 | ENSG00000013503 | Q9NW08 | DNA-directed RNA polymerase III subunit RPC2 | clinvar |
| FGFR1 | HGNC:3688 | ENSG00000077782 | P11362 | Fibroblast growth factor receptor 1 | clinvar |
| HS6ST1 | HGNC:5201 | ENSG00000136720 | O60243 | Heparan-sulfate 6-O-sulfotransferase 1 | clinvar |
| ANOS1 | HGNC:6211 | ENSG00000011201 | P23352 | Anosmin-1 | clinvar |
| AXL | HGNC:905 | ENSG00000167601 | P30530 | Tyrosine-protein kinase receptor UFO | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| GNRHR | Gonadotropin-releasing hormone receptor | Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). |
| SEMA3E | Semaphorin-3E | Plays an important role in signaling via the cell surface receptor PLXND1. |
| TAC3 | Tachykinin-3 | Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles. |
| TACR3 | Neuromedin-K receptor | Receptor for the tachykinin neuromedin-K (neurokinin B), also able to bind and respond to tachynins substance K/neurokinin A and substance P. |
| WDR11 | WD repeat-containing protein 11 | Involved in the Hedgehog (Hh) signaling pathway, is essential for normal ciliogenesis. |
| SPRY4 | Protein sprouty homolog 4 | Suppresses the insulin receptor and EGFR-transduced MAPK signaling pathway, but does not inhibit MAPK activation by a constitutively active mutant Ras. |
| PHIP | PH-interacting protein | Probable regulator of the insulin and insulin-like growth factor signaling pathways. |
| PROKR2 | Prokineticin receptor 2 | Receptor for prokineticin 2. |
| PNPLA6 | Patatin-like phospholipase domain-containing protein 6 | Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho). |
| RNF216 | E3 ubiquitin-protein ligase RNF216 | E3 ubiquitin ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their ubiquitination. |
| FEZF1 | Fez family zinc finger protein 1 | Transcription repressor. |
| CCDC141 | Coiled-coil domain-containing protein 141 | Plays a critical role in cortical radial and GnRH neurons migration during brain development. |
| BBIP1 | BBSome-interacting protein 1 | The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia. |
| POLR3B | DNA-directed RNA polymerase III subunit RPC2 | Catalytic core component of RNA polymerase III (Pol III), a DNA-dependent RNA polymerase which synthesizes small non-coding RNAs using the four ribonucleoside triphosphates as substrates. |
| 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. |
| HS6ST1 | Heparan-sulfate 6-O-sulfotransferase 1 | 6-O-sulfation enzyme which catalyzes the transfer of sulfate from 3’-phosphoadenosine 5’-phosphosulfate (PAPS) to position 6 of the N-sulfoglucosamine residue (GlcNS) of heparan sulfate. |
| ANOS1 | Anosmin-1 | Has a dual branch-promoting and guidance activity, which may play an important role in the patterning of mitral and tufted cell collaterals to the olfactory cortex. |
| AXL | Tyrosine-protein kinase receptor UFO | Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding growth factor GAS6 and which is thus regulating many physiological processes including cell survival, cell proliferation, migratio… |
Protein-family classification
Druggable: 8 · Difficult: 4 · Unknown: 6 · Druggable fraction: 0.44
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 |
|---|---|---|---|
| Antibody/Immunoglobulin | 3 | 4.9× | 0.111 |
| GPCR | 3 | 4.0× | 0.111 |
| Kinase | 2 | 3.1× | 0.272 |
| Scaffold/PPI | 2 | 1.9× | 0.420 |
| Transcription factor | 2 | 0.9× | 0.791 |
| Other/Unknown | 6 | 0.6× | 0.985 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| GNRHR | GPCR | yes | GPCR_Rhodpsn, GphnRH_fam_rcpt, GPCR_Rhodpsn_7TM | |
| SEMA3E | Antibody/Immunoglobulin | yes | Semap_dom, Ig-like_dom, Immunoglobulin_dom | |
| TAC3 | Other/Unknown | no | Neurokinin-B/TAC3, Tachy_Neuro_lke_CS | |
| TACR3 | GPCR | yes | GPCR_Rhodpsn, NK3_rcpt, Neurokn_rcpt | |
| WDR11 | Scaffold/PPI | no | WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS | |
| SPRY4 | Other/Unknown | no | Sprouty, Sprouty_domain | |
| PHIP | Scaffold/PPI | no | Bromodomain, WD40_rpt, WD40/YVTN_repeat-like_dom_sf | |
| PROKR2 | GPCR | yes | GPCR_Rhodpsn, NPY_rcpt, GPCR_Rhodpsn_7TM | |
| PNPLA6 | Other/Unknown | no | cNMP-bd_dom, LysoPLipase_patatin_CS, PNPLA_dom | |
| RNF216 | Transcription factor | no | IBR_dom, Znf_RING/FYVE/PHD, TRIAD_supradom | |
| FEZF1 | Transcription factor | no | Znf_C2H2_type, Znf_C2H2_sf | |
| CCDC141 | Antibody/Immunoglobulin | yes | Spectrin_repeat, Ig_sub2, Ig_sub | |
| BBIP1 | Other/Unknown | no | BBIP10 | |
| POLR3B | Other/Unknown | no | DNA-dir_RNAP_su2_dom, RNA_pol_bsu_CS, RNA_pol_Rpb2_7 | |
| FGFR1 | Kinase | yes | 2.7.10.1 | Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2 |
| HS6ST1 | Other/Unknown | no | Sulfotransferase, Heparan_SO4-6-sulfoTrfase, P-loop_NTPase | |
| ANOS1 | Antibody/Immunoglobulin | yes | FN3_dom, WAP_dom, Ig-like_fold | |
| AXL | Kinase | yes | 2.7.10.1 | Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub |
Expression context
Cohort genes with no expression data: 0.
16 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) | 18 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| male germ line stem cell (sensu Vertebrata) in testis | 3 |
| calcaneal tendon | 3 |
| cortical plate | 3 |
| adrenal tissue | 2 |
| hypothalamus | 2 |
| secondary oocyte | 2 |
| epithelium of nasopharynx | 2 |
| ventricular zone | 2 |
| ganglionic eminence | 2 |
| buccal mucosa cell | 2 |
| stromal cell of endometrium | 2 |
| adenohypophysis | 1 |
| blood vessel layer | 1 |
| decidua | 1 |
| placenta | 1 |
| primordial germ cell in gonad | 1 |
| nasopharynx | 1 |
| ascending aorta | 1 |
| left coronary artery | 1 |
| right lung | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| GNRHR | 121 | tissue_specific | yes | adrenal tissue, adenohypophysis, male germ line stem cell (sensu Vertebrata) in testis |
| SEMA3E | 197 | broad | marker | cortical plate, calcaneal tendon, blood vessel layer |
| TAC3 | 162 | broad | marker | decidua, primordial germ cell in gonad, placenta |
| TACR3 | 43 | tissue_specific | marker | cortical plate, secondary oocyte, hypothalamus |
| WDR11 | 287 | ubiquitous | marker | epithelium of nasopharynx, nasopharynx, calcaneal tendon |
| SPRY4 | 219 | ubiquitous | marker | left coronary artery, right lung, ascending aorta |
| PHIP | 302 | ubiquitous | marker | bronchial epithelial cell, epithelium of bronchus, ventricular zone |
| PROKR2 | 32 | tissue_specific | yes | cortical plate, ganglionic eminence, ventricular zone |
| PNPLA6 | 276 | ubiquitous | marker | granulocyte, metanephros cortex, upper lobe of left lung |
| RNF216 | 278 | ubiquitous | marker | male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis |
| FEZF1 | 52 | tissue_specific | marker | male germ line stem cell (sensu Vertebrata) in testis, hypothalamus, caudate nucleus |
| CCDC141 | 149 | broad | marker | heart left ventricle, adrenal tissue, right atrium auricular region |
| BBIP1 | 288 | ubiquitous | marker | epithelium of nasopharynx, buccal mucosa cell, sperm |
| POLR3B | 247 | ubiquitous | marker | secondary oocyte, esophagus squamous epithelium, endothelial cell |
| FGFR1 | 292 | ubiquitous | marker | buccal mucosa cell, stromal cell of endometrium, calcaneal tendon |
| HS6ST1 | 258 | ubiquitous | marker | kidney epithelium, pancreatic ductal cell, ganglionic eminence |
| ANOS1 | 268 | broad | marker | visceral pleura, hair follicle, skeletal muscle tissue of rectus abdominis |
| AXL | 290 | ubiquitous | marker | synovial joint, saphenous vein, stromal cell of endometrium |
Protein interactions among cohort
Intra-cohort edges: 27.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| POLR3B | 5,712 |
| FGFR1 | 5,693 |
| AXL | 4,443 |
| PHIP | 3,057 |
| PNPLA6 | 2,676 |
| GNRHR | 1,346 |
| RNF216 | 1,268 |
| CCDC141 | 1,255 |
| ANOS1 | 1,182 |
| SPRY4 | 1,118 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| ANOS1 | CCDC141 | string_interaction |
| ANOS1 | FEZF1 | string_interaction |
| ANOS1 | FGFR1 | biogrid_interaction, intact, string_interaction |
| ANOS1 | GNRHR | string_interaction |
| ANOS1 | HS6ST1 | string_interaction |
| ANOS1 | PROKR2 | string_interaction |
| ANOS1 | TAC3 | string_interaction |
| ANOS1 | TACR3 | string_interaction |
| CCDC141 | FEZF1 | string_interaction |
| CCDC141 | HS6ST1 | string_interaction |
| CCDC141 | PROKR2 | string_interaction |
| CCDC141 | TACR3 | string_interaction |
| FEZF1 | GNRHR | string_interaction |
| FEZF1 | HS6ST1 | string_interaction |
| FEZF1 | PROKR2 | string_interaction |
| FEZF1 | TAC3 | string_interaction |
| FEZF1 | TACR3 | string_interaction |
| FGFR1 | GNRHR | string_interaction |
| FGFR1 | PROKR2 | string_interaction |
| FGFR1 | SPRY4 | string_interaction |
| FGFR1 | TACR3 | string_interaction |
| GNRHR | TAC3 | string_interaction |
| HS6ST1 | PROKR2 | string_interaction |
| HS6ST1 | TACR3 | string_interaction |
| PNPLA6 | RNF216 | string_interaction |
| PROKR2 | TAC3 | string_interaction |
| TAC3 | TACR3 | intact, string_interaction |
Structural data
PDB: 12 · AlphaFold-only: 6 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| PHIP | Q8WWQ0 | 146 |
| FGFR1 | P11362 | 83 |
| POLR3B | Q9NW08 | 29 |
| RNF216 | Q9NWF9 | 4 |
| AXL | P30530 | 4 |
| TACR3 | P29371 | 3 |
| TAC3 | Q9UHF0 | 2 |
| WDR11 | Q9BZH6 | 2 |
| GNRHR | P30968 | 1 |
| SPRY4 | Q9C004 | 1 |
| BBIP1 | A8MTZ0 | 1 |
| ANOS1 | P23352 | 1 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| HS6ST1 | O60243 | 87.28 |
| SEMA3E | O15041 | 84.62 |
| PROKR2 | Q8NFJ6 | 78.50 |
| CCDC141 | Q6ZP82 | 72.36 |
| PNPLA6 | Q8IY17 | 69.75 |
| FEZF1 | A0PJY2 | 56.91 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 60. Enrichment computed across 18 evidence-associated genes (15 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 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Tachykinin receptors bind tachykinins | 2 | 253.8× | 0.001 | TAC3, TACR3 |
| G alpha (q) signalling events | 4 | 15.3× | 0.003 | GNRHR, TAC3, TACR3, PROKR2 |
| FGFR1c ligand binding and activation | 2 | 101.5× | 0.003 | FGFR1, ANOS1 |
| Negative regulation of FGFR1 signaling | 2 | 49.1× | 0.011 | FGFR1, ANOS1 |
| Signaling by FGFR1 amplification mutants | 1 | 380.7× | 0.026 | FGFR1 |
| FGFR1 ligand binding and activation | 1 | 380.7× | 0.026 | ANOS1 |
| FGFR1c and Klotho ligand binding and activation | 1 | 190.3× | 0.039 | FGFR1 |
| Signaling by plasma membrane FGFR1 fusions | 1 | 190.3× | 0.039 | FGFR1 |
| Glycerophospholipid catabolism | 1 | 108.8× | 0.061 | PNPLA6 |
| Epithelial-Mesenchymal Transition (EMT) during gastrulation | 1 | 95.2× | 0.063 | FGFR1 |
| FGFR1b ligand binding and activation | 1 | 84.6× | 0.064 | FGFR1 |
| Signaling by activated point mutants of FGFR1 | 1 | 63.4× | 0.072 | FGFR1 |
| Hormone ligand-binding receptors | 1 | 63.4× | 0.072 | GNRHR |
| Signaling by FGFR1 | 1 | 54.4× | 0.075 | ANOS1 |
| Phospholipase C-mediated cascade: FGFR1 | 1 | 44.8× | 0.075 | FGFR1 |
| RNA Polymerase III Chain Elongation | 1 | 42.3× | 0.075 | POLR3B |
| Other semaphorin interactions | 1 | 40.1× | 0.075 | SEMA3E |
| Downstream signaling of activated FGFR1 | 1 | 36.2× | 0.075 | FGFR1 |
| Signal transduction by L1 | 1 | 34.6× | 0.075 | FGFR1 |
| PI-3K cascade:FGFR1 | 1 | 34.6× | 0.075 | FGFR1 |
| BBSome-mediated cargo-targeting to cilium | 1 | 33.1× | 0.075 | BBIP1 |
| SHC-mediated cascade:FGFR1 | 1 | 33.1× | 0.075 | FGFR1 |
| RNA Polymerase III Transcription Termination | 1 | 33.1× | 0.075 | POLR3B |
| RHOBTB2 GTPase cycle | 1 | 31.7× | 0.075 | PHIP |
| FRS-mediated FGFR1 signaling | 1 | 30.4× | 0.075 | FGFR1 |
| RNA Polymerase III Transcription Initiation From Type 2 Promoter | 1 | 28.2× | 0.075 | POLR3B |
| RNA Polymerase III Transcription Initiation From Type 1 Promoter | 1 | 27.2× | 0.075 | POLR3B |
| RNA Polymerase III Transcription Initiation From Type 3 Promoter | 1 | 27.2× | 0.075 | POLR3B |
| Formation of paraxial mesoderm | 1 | 27.2× | 0.075 | FGFR1 |
| Semaphorin interactions | 1 | 26.2× | 0.075 | SEMA3E |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 18 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| tachykinin receptor signaling pathway | 2 | 208.1× | 0.005 | TAC3, TACR3 |
| vagina development | 2 | 170.2× | 0.005 | TACR3, AXL |
| erythrocyte homeostasis | 2 | 144.0× | 0.005 | BBIP1, AXL |
| positive regulation of blood pressure | 2 | 117.0× | 0.006 | TAC3, TACR3 |
| cell maturation | 2 | 49.3× | 0.027 | FGFR1, AXL |
| cellular response to hormone stimulus | 2 | 42.6× | 0.027 | GNRHR, PROKR2 |
| axon guidance | 3 | 15.1× | 0.027 | SEMA3E, FEZF1, ANOS1 |
| gonadotropin secretion | 1 | 468.1× | 0.031 | GNRHR |
| vitamin D3 metabolic process | 1 | 468.1× | 0.031 | FGFR1 |
| positive regulation of mitotic cell cycle DNA replication | 1 | 468.1× | 0.031 | FGFR1 |
| positive regulation of parathyroid hormone secretion | 1 | 468.1× | 0.031 | FGFR1 |
| regulation of extrinsic apoptotic signaling pathway in absence of ligand | 1 | 468.1× | 0.031 | FGFR1 |
| positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | 3 | 13.1× | 0.031 | SEMA3E, FGFR1, AXL |
| regulation of phosphate transport | 1 | 312.1× | 0.033 | FGFR1 |
| forebrain cell migration | 1 | 312.1× | 0.033 | AXL |
| fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development | 1 | 312.1× | 0.033 | FGFR1 |
| regulation of lateral mesodermal cell fate specification | 1 | 312.1× | 0.033 | FGFR1 |
| negative regulation of lymphocyte activation | 1 | 312.1× | 0.033 | AXL |
| phospholipase C-activating tachykinin receptor signaling pathway | 1 | 234.1× | 0.033 | TACR3 |
| forebrain anterior/posterior pattern specification | 1 | 234.1× | 0.033 | FEZF1 |
| ventricular zone neuroblast division | 1 | 234.1× | 0.033 | FGFR1 |
| negative regulation of fibroblast growth factor production | 1 | 234.1× | 0.033 | FGFR1 |
| positive regulation of phospholipase activity | 1 | 187.2× | 0.033 | FGFR1 |
| regulation of interferon-beta production | 1 | 187.2× | 0.033 | RNF216 |
| positive regulation of luteinizing hormone secretion | 1 | 187.2× | 0.033 | TACR3 |
| positive regulation of pinocytosis | 1 | 187.2× | 0.033 | AXL |
| regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling | 1 | 187.2× | 0.033 | FGFR1 |
| diphosphate metabolic process | 1 | 187.2× | 0.033 | FGFR1 |
| receptor localization to non-motile cilium | 1 | 187.2× | 0.033 | BBIP1 |
| obsolete vesicle tethering to Golgi | 1 | 187.2× | 0.033 | WDR11 |
Therapeutics
Drug target analysis
Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 4 · Undrugged: 14
Druggability breadth: 8 of 18 evidence-associated genes (44%) 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 |
|---|---|
| GNRHR | GONADORELIN |
| TACR3 | APREPITANT |
| FGFR1 | PONATINIB |
| AXL | GILTERITINIB |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| FGFR1 | 93 | 4 |
| AXL | 59 | 4 |
| GNRHR | 12 | 4 |
| TACR3 | 9 | 4 |
| SEMA3E | 0 | 0 |
| TAC3 | 0 | 0 |
| WDR11 | 0 | 0 |
| SPRY4 | 0 | 0 |
| PHIP | 0 | 0 |
| PROKR2 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| GONADORELIN | 4 | GNRHR |
| CETRORELIX | 4 | GNRHR |
| LEUPROLIDE | 4 | GNRHR |
| ELAGOLIX | 4 | GNRHR |
| ABARELIX | 4 | GNRHR |
| RELUGOLIX | 4 | GNRHR |
| LINZAGOLIX | 4 | GNRHR |
| DEGARELIX | 4 | GNRHR |
| ELAGOLIX SODIUM | 4 | GNRHR |
| GANIRELIX ACETATE | 4 | GNRHR |
| APREPITANT | 4 | TACR3 |
| FEZOLINETANT | 4 | TACR3 |
| PONATINIB | 4 | FGFR1 |
| PEMIGATINIB | 4 | FGFR1 |
| NINTEDANIB | 4 | AXL, FGFR1 |
| FEDRATINIB | 4 | AXL, FGFR1 |
| TIVOZANIB | 4 | FGFR1 |
| LENVATINIB | 4 | FGFR1 |
| AXITINIB | 4 | AXL, FGFR1 |
| SORAFENIB | 4 | AXL, FGFR1 |
| NICLOSAMIDE | 4 | FGFR1 |
| INFIGRATINIB PHOSPHATE | 4 | FGFR1 |
| INFIGRATINIB | 4 | FGFR1 |
| REGORAFENIB | 4 | FGFR1 |
| ENTRECTINIB | 4 | AXL, FGFR1 |
| CABOZANTINIB | 4 | AXL, FGFR1 |
| CAPIVASERTIB | 4 | FGFR1 |
| VANDETANIB | 4 | AXL, FGFR1 |
| NINTEDANIB ESYLATE | 4 | FGFR1 |
| BRIGATINIB | 4 | 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 |
| AXL | 701 | Binding:698, Functional:3 |
| GNRHR | 302 | Binding:248, Functional:54 |
| TACR3 | 266 | Binding:217, Functional:48, ADMET:1 |
| PHIP | 17 | Binding:17 |
| PROKR2 | 9 | Functional:5, Binding:4 |
| TAC3 | 1 | Binding:1 |
| PNPLA6 | 1 | Binding:1 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| FGFR1 | 2.7.10.1 | receptor protein-tyrosine kinase |
| AXL | 2.7.10.1 | receptor protein-tyrosine kinase |
Cohort genes with high screening signal
≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.
| Symbol | ChEMBL assays |
|---|---|
| GNRHR | 302 |
| TACR3 | 266 |
| FGFR1 | 1,465 |
| AXL | 701 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 18; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
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) |
|---|---|---|
| GONADORELIN | 4 | GNRHR |
| CETRORELIX | 4 | GNRHR |
| LEUPROLIDE | 4 | GNRHR |
| ELAGOLIX | 4 | GNRHR |
| ABARELIX | 4 | GNRHR |
| RELUGOLIX | 4 | GNRHR |
| LINZAGOLIX | 4 | GNRHR |
| DEGARELIX | 4 | GNRHR |
| ELAGOLIX SODIUM | 4 | GNRHR |
| GANIRELIX ACETATE | 4 | GNRHR |
| APREPITANT | 4 | TACR3 |
| FEZOLINETANT | 4 | TACR3 |
| PONATINIB | 4 | FGFR1 |
| PEMIGATINIB | 4 | FGFR1 |
| NINTEDANIB | 4 | AXL, FGFR1 |
| FEDRATINIB | 4 | AXL, FGFR1 |
| TIVOZANIB | 4 | FGFR1 |
| LENVATINIB | 4 | FGFR1 |
| AXITINIB | 4 | AXL, FGFR1 |
| SORAFENIB | 4 | AXL, FGFR1 |
| NICLOSAMIDE | 4 | FGFR1 |
| INFIGRATINIB PHOSPHATE | 4 | FGFR1 |
| INFIGRATINIB | 4 | FGFR1 |
| REGORAFENIB | 4 | FGFR1 |
| ENTRECTINIB | 4 | AXL, FGFR1 |
| CABOZANTINIB | 4 | AXL, FGFR1 |
| CAPIVASERTIB | 4 | FGFR1 |
| VANDETANIB | 4 | AXL, FGFR1 |
| NINTEDANIB ESYLATE | 4 | FGFR1 |
| BRIGATINIB | 4 | FGFR1 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 4 | GNRHR, TACR3, FGFR1, AXL |
| B | Phased (≥1) drug, not yet approved | 0 | |
| C | Druggable family + PDB, no drug | 1 | ANOS1 |
| D | Druggable family + AlphaFold only, no drug | 3 | SEMA3E, PROKR2, CCDC141 |
| E | Difficult family or no structure, no drug | 10 | TAC3, WDR11, SPRY4, PHIP, PNPLA6, RNF216, FEZF1, BBIP1, POLR3B, HS6ST1 |
Undrugged target profiles
14 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| TAC3 | 1 | TACR3 |
| ANOS1 | 0 | FGFR1 |
| SEMA3E | 0 | — |
| WDR11 | 0 | — |
| SPRY4 | 0 | — |
| PHIP | 17 | — |
| PROKR2 | 9 | — |
| PNPLA6 | 1 | — |
| RNF216 | 0 | — |
| FEZF1 | 0 | — |
| CCDC141 | 0 | — |
| BBIP1 | 0 | — |
| POLR3B | 0 | — |
| HS6ST1 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.