Hypogonadotropic hypogonadism

Summary

Hypogonadotropic hypogonadism (MONDO:0018555) is a disease (an umbrella term covering 10 Mondo subtypes) caused by variants in KLB, PLXNA3, and SEMA3F, with 32 cohort genes and 79 clinical trials. The dominant Reactome pathway is G alpha (q) signalling events (8 cohort genes). Top therapeutic interventions include gonadorelin, testosterone, and clomiphene.

At a glance

• Causal genes: KLB (GenCC Strong), PLXNA3 (GenCC Strong), SEMA3F (GenCC Strong)
• Umbrella term: 10 Mondo subtypes
• Cohort genes: 32
• ClinVar variants: 90
• Phenotypes (HPO): 38
• Clinical trials: 79

Clinical features

Signs & symptoms

Clinical features (HPO)

38 HPO clinical features (Orphanet curated; top 38 by frequency):

HPO ID	Term	Frequency
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000044	Hypogonadotropic hypogonadism	Very frequent (80-99%)
HP:0000054	Micropenis	Very frequent (80-99%)
HP:0000118	Phenotypic abnormality	Very frequent (80-99%)
HP:0000134	Female hypogonadism	Very frequent (80-99%)
HP:0000786	Primary amenorrhea	Very frequent (80-99%)
HP:0000802	Impotence	Very frequent (80-99%)
HP:0001608	Abnormality of the voice	Very frequent (80-99%)
HP:0002231	Sparse body hair	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0003187	Breast hypoplasia	Very frequent (80-99%)
HP:0003782	Eunuchoid habitus	Very frequent (80-99%)
HP:0006610	Wide intermamillary distance	Very frequent (80-99%)
HP:0008187	Absence of secondary sex characteristics	Very frequent (80-99%)
HP:0008197	Absence of pubertal development	Very frequent (80-99%)
HP:0008734	Decreased testicular size	Very frequent (80-99%)
HP:0011961	Non-obstructive azoospermia	Very frequent (80-99%)
HP:0030019	Increased female libido	Very frequent (80-99%)
HP:0040171	Decreased serum testosterone concentration	Very frequent (80-99%)
HP:0000026	Male hypogonadism	Very frequent (80-99%)
HP:0000027	Azoospermia	Very frequent (80-99%)
HP:0000002	Abnormality of body height	Frequent (30-79%)
HP:0000013	Hypoplasia of the uterus	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000771	Gynecomastia	Frequent (30-79%)
HP:0000823	Delayed puberty	Frequent (30-79%)
HP:0000869	Secondary amenorrhea	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0008724	Hypoplasia of the ovary	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0002761	Generalized joint laxity	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0008527	Congenital sensorineural hearing impairment	Occasional (5-29%)
HP:0012385	Camptodactyly	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism
Mondo ID	MONDO:0018555
OMIM	147950
Orphanet	432
DOID	DOID:0090070, DOID:7455
NCIT	C113347
SNOMED CT	33927004
UMLS	C0271623
MedGen	82883
GARD	0016533
Is cancer (heuristic)	no

Also known as: central hypogonadism · congenital idiopathic hypogonadotropic hypogonadism · gonadotropic deficiency · hypogonadism, hypogonadotropic · hypogonadotropic hypogonadism · hypogonadotropic hypogonadism with or without anosmia · hypogonadotropism · isolated congenital gonadotropin deficiency · low gonadotropins (secondary hypogonadism) · nIHH · normosmic congenital hypogonadotropic hypogonadism · Normosmic idiopathic hypogonadotropic hypogonadism · secondary hypogonadism

Data availability: 90 ClinVar variants · 22 GenCC gene-disease records · 1 HPO phenotype.

Disease family

An umbrella term covering 10 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › hypogonadism › hypogonadotropic hypogonadism

Related subtypes (5): gonadal dysgenesis, eunuchism, hypogonadism, male, Slti-Salem syndrome, weinstein kliman scully syndrome

Subtypes (10): hypogonadotropic hypogonadism 23 with or without anosmia, hypogonadotropic hypogonadism 24 without anosmia, hypogonadotropic hypogonadism 10 with or without anosmia, hypogonadotropic hypogonadism 12 with or without anosmia, hypogonadotropic hypogonadism 13 with or without anosmia, congenital hypogonadotropic hypogonadism, Kallmann syndrome, hypogonadotropic hypogonadism 25 with anosmia, hypogonadotropic hypogonadism 26 with or without anosmia, hypogonadotropic hypogonadism 27 without anosmia

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

90 retrieved; paginated sample, class counts are floors:

40 uncertain significance, 19 conflicting classifications of pathogenicity, 12 pathogenic, 10 pathogenic/likely pathogenic, 4 likely pathogenic, 3 association, 1 likely benign, 1 affects

ClinVar	Variant (HGVS)	Gene	Classification	Review
3901104	NM_000216.4(ANOS1):c.856+1G>T	ANOS1	Pathogenic	criteria provided, single submitter
447606	NM_000216.4(ANOS1):c.1270C>T (p.Arg424Ter)	ANOS1	Pathogenic	criteria provided, multiple submitters, no conflicts
4540562	NM_000216.4(ANOS1):c.256T>A (p.Cys86Ser)	ANOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
658717	NM_000216.4(ANOS1):c.1449+1G>A	ANOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16282	NM_023110.3(FGFR1):c.1864C>T (p.Arg622Ter)	FGFR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3234159	NM_023110.3(FGFR1):c.1029G>A (p.Ala343=)	FGFR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3374752	NM_023110.3(FGFR1):c.1716C>G (p.Tyr572Ter)	FGFR1	Pathogenic	criteria provided, single submitter
4533350	NM_023110.3(FGFR1):c.729C>A (p.Tyr243Ter)	FGFR1	Pathogenic	criteria provided, single submitter
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
16030	NM_000406.3(GNRHR):c.416G>A (p.Arg139His)	GNRHR	Pathogenic	criteria provided, multiple submitters, no conflicts
3776762	NM_000406.3(GNRHR):c.742+2T>C	GNRHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5757	NM_032551.5(KISS1R):c.1195T>A (p.Ter399Arg)	KISS1R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2443311	NM_181303.2(NLGN3):c.366G>A (p.Trp122Ter)	NLGN3	Pathogenic	criteria provided, single submitter
1407649	NM_006941.4(SOX10):c.481C>T (p.Arg161Cys)	POLR2F	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31166	NM_018082.6(POLR3B):c.1568T>A (p.Val523Glu)	POLR3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3251948	NM_003108.4(SOX11):c.908C>A (p.Ser303Ter)	SOX11	Pathogenic	criteria provided, single submitter
3251953	NM_003108.4(SOX11):c.1032_1044del (p.Ser345fs)	SOX11	Pathogenic	criteria provided, single submitter
3251954	NM_003108.4(SOX11):c.251G>A (p.Gly84Asp)	SOX11	Pathogenic	criteria provided, single submitter
3248549	NM_001059.3(TACR3):c.1003C>T (p.Gln335Ter)	TACR3	Pathogenic	criteria provided, single submitter
66084	NM_001059.3(TACR3):c.824G>A (p.Trp275Ter)	TACR3	Pathogenic	criteria provided, multiple submitters, no conflicts
14026	NM_001059.3(TACR3):c.1057C>T (p.Pro353Ser)	TACR3-AS1	Pathogenic	criteria provided, multiple submitters, no conflicts
4796682	NM_017780.4(CHD7):c.2698-2A>G	CHD7	Likely pathogenic	criteria provided, single submitter
2505411	NM_023110.3(FGFR1):c.670G>C (p.Asp224His)	FGFR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3590756	NM_000406.3(GNRHR):c.469C>T (p.Gln157Ter)	GNRHR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3251956	NM_003108.4(SOX11):c.340C>T (p.Pro114Ser)	SOX11	Likely pathogenic	criteria provided, single submitter
255563	NM_000216.4(ANOS1):c.1600G>A (p.Val534Ile)	ANOS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1169510	NM_023110.3(FGFR1):c.66G>C (p.Arg22Ser)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1452079	NM_001083111.2(GNRH1):c.92G>A (p.Arg31His)	GNRH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2735146	NM_001083111.2(GNRH1):c.91C>T (p.Arg31Cys)	GNRH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 149 · Orphanet: 68 · 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	hypogonadotropic hypogonadism 2 with or without anosmia	36
KISS1R	Definitive	Autosomal recessive	hypogonadotropic hypogonadism 8 with or without anosmia	5
PROK2	Definitive	Semidominant	hypogonadotropic hypogonadism 4 with or without anosmia	7
PROKR2	Definitive	Autosomal dominant	hypogonadotropic hypogonadism 3 with or without anosmia	8
CHD7	Strong	Autosomal dominant	hypogonadotropic hypogonadism 5 with or without anosmia	8
FGF17	Strong	Autosomal dominant	hypogonadotropic hypogonadism 20 with or without anosmia	4
FGF8	Strong	Autosomal dominant	hypogonadotropic hypogonadism 6 with or without anosmia	9
GNRH1	Strong	Autosomal recessive	hypogonadotropic hypogonadism 12 with or without anosmia	5
GNRHR	Strong	Autosomal recessive	hypogonadotropic hypogonadism 7 with or without anosmia	4
KLB	Strong	Autosomal dominant	hypogonadotropic hypogonadism
NSMF	Strong	Autosomal dominant	hypogonadotropic hypogonadism 9 with or without anosmia	4
PHIP	Strong	Autosomal dominant	hypogonadotropic hypogonadism 14 with or without anosmia	15
PLXNA3	Strong	X-linked	hypogonadotropic hypogonadism
SEMA3F	Strong	Autosomal dominant	hypogonadotropic hypogonadism
TAC3	Strong	Autosomal recessive	hypogonadotropic hypogonadism 10 with or without anosmia	5
TACR3	Strong	Autosomal recessive	hypogonadotropic hypogonadism 11 with or without anosmia	5
WDR11	Strong	Autosomal dominant	hypogonadotropic hypogonadism 14 with or without anosmia	10
KISS1	Moderate	Autosomal recessive	hypogonadotropic hypogonadism 13 with or without anosmia	4
SPRY4	Moderate	Autosomal dominant	hypogonadotropic hypogonadism 17 with or without anosmia	5
DUSP6	Supportive	Autosomal dominant	hypogonadotropic hypogonadism	5
HS6ST1	Supportive	Autosomal dominant	hypogonadotropic hypogonadism	5
CCDC141	Limited	Autosomal dominant	hypogonadotropic hypogonadism	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
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
PROK2	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
PROK2	Orphanet:478	Kallmann syndrome
CHD7	Orphanet:138	CHARGE syndrome
CHD7	Orphanet:39041	Omenn syndrome
CHD7	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
CHD7	Orphanet:478	Kallmann syndrome
CCDC141	Orphanet:478	Kallmann syndrome
FGF8	Orphanet:220386	Semilobar holoprosencephaly
FGF8	Orphanet:280195	Septopreoptic holoprosencephaly
FGF8	Orphanet:280200	Microform holoprosencephaly
FGF8	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
FGF8	Orphanet:478	Kallmann syndrome
FGF8	Orphanet:93924	Lobar holoprosencephaly
FGF8	Orphanet:93925	Alobar holoprosencephaly
FGF8	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
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
GNRH1	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
GNRHR	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
KISS1R	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
KISS1R	Orphanet:650077	Genetic central precocious puberty in female
KISS1R	Orphanet:650097	Genetic central precocious puberty in male
SPRY4	Orphanet:363494	Non-seminomatous germ cell tumor of testis
SPRY4	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism

Cohort genes → proteins

32 cohort genes, 31 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	32

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SEMA3F	HGNC:10728	ENSG00000001617	Q13275	Semaphorin-3F	gencc,clinvar
TAC3	HGNC:11521	ENSG00000166863	Q9UHF0	Tachykinin-3	gencc,clinvar
TACR3	HGNC:11528	ENSG00000169836	P29371	Neuromedin-K receptor	gencc,clinvar
WDR11	HGNC:13831	ENSG00000120008	Q9BZH6	WD repeat-containing protein 11	gencc,clinvar
KLB	HGNC:15527	ENSG00000134962	Q86Z14	Beta-klotho	gencc,clinvar
PHIP	HGNC:15673	ENSG00000146247	Q8WWQ0	PH-interacting protein	gencc,clinvar
PROKR2	HGNC:15836	ENSG00000101292	Q8NFJ6	Prokineticin receptor 2	gencc,clinvar
PROK2	HGNC:18455	ENSG00000163421	Q9HC23	Prokineticin-2	gencc,clinvar
CHD7	HGNC:20626	ENSG00000171316	Q9P2D1	ATP-dependent chromatin remodeler CHD7	gencc,clinvar
CCDC141	HGNC:26821	ENSG00000163492	Q6ZP82	Coiled-coil domain-containing protein 141	gencc,clinvar
FGF8	HGNC:3686	ENSG00000107831	P55075	Fibroblast growth factor 8	gencc,clinvar
FGFR1	HGNC:3688	ENSG00000077782	P11362	Fibroblast growth factor receptor 1	gencc,clinvar
GNRH1	HGNC:4419	ENSG00000147437	P01148	Progonadoliberin-1	gencc,clinvar
GNRHR	HGNC:4421	ENSG00000109163	P30968	Gonadotropin-releasing hormone receptor	gencc,clinvar
KISS1R	HGNC:4510	ENSG00000116014	Q969F8	KiSS-1 receptor	gencc,clinvar
PLXNA3	HGNC:9101	ENSG00000130827	P51805	Plexin-A3	gencc,clinvar
SPRY4	HGNC:15533	ENSG00000187678	Q9C004	Protein sprouty homolog 4	gencc
NSMF	HGNC:29843	ENSG00000165802	Q6X4W1	NMDA receptor synaptonuclear signaling and neuronal migration factor	gencc
DUSP6	HGNC:3072	ENSG00000139318	Q16828	Dual specificity protein phosphatase 6	gencc
FGF17	HGNC:3673	ENSG00000158815	O60258	Fibroblast growth factor 17	gencc
HS6ST1	HGNC:5201	ENSG00000136720	O60243	Heparan-sulfate 6-O-sulfotransferase 1	gencc
KISS1	HGNC:6341	ENSG00000170498	Q15726	Metastasis-suppressor KiSS-1	gencc
SOX11	HGNC:11191	ENSG00000176887	P35716	Transcription factor SOX-11	clinvar
NLGN3	HGNC:14289	ENSG00000196338	Q9NZ94	Neuroligin-3	clinvar
IL17RD	HGNC:17616	ENSG00000144730	Q8NFM7	Interleukin-17 receptor D	clinvar
POU6F2	HGNC:21694	ENSG00000106536	P78424	POU domain, class 6, transcription factor 2	clinvar
POLR3B	HGNC:30348	ENSG00000013503	Q9NW08	DNA-directed RNA polymerase III subunit RPC2	clinvar
TACR3-AS1	HGNC:55593	ENSG00000251577		TACR3 antisense RNA 1	clinvar
ANOS1	HGNC:6211	ENSG00000011201	P23352	Anosmin-1	clinvar
LHB	HGNC:6584	ENSG00000104826	P01229	Lutropin subunit beta	clinvar
NHLH2	HGNC:7818	ENSG00000177551	Q02577	Helix-loop-helix protein 2	clinvar
POLR2F	HGNC:9193	ENSG00000100142	P61218	DNA-directed RNA polymerases I, II, and III subunit RPABC2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SEMA3F	Semaphorin-3F	May play a role in cell motility and cell adhesion.
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.
KLB	Beta-klotho	Contributes to the transcriptional repression of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis.
PHIP	PH-interacting protein	Probable regulator of the insulin and insulin-like growth factor signaling pathways.
PROKR2	Prokineticin receptor 2	Receptor for prokineticin 2.
PROK2	Prokineticin-2	May function as an output molecule from the suprachiasmatic nucleus (SCN) that transmits behavioral circadian rhythm.
CHD7	ATP-dependent chromatin remodeler CHD7	ATP-dependent chromatin-remodeling factor, slides nucleosomes along DNA; nucleosome sliding requires ATP.
CCDC141	Coiled-coil domain-containing protein 141	Plays a critical role in cortical radial and GnRH neurons migration during brain development.
FGF8	Fibroblast growth factor 8	Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration.
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.
GNRH1	Progonadoliberin-1	Stimulates the secretion of gonadotropins; it stimulates the secretion of both luteinizing and follicle-stimulating hormones.
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).
KISS1R	KiSS-1 receptor	Receptor for kisspeptins (kisspeptin-10, kisspeptin-13, kisspeptin-14 and metastin/kisspeptin-54).
PLXNA3	Plexin-A3	Coreceptor for SEMA3A and SEMA3F.
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.
NSMF	NMDA receptor synaptonuclear signaling and neuronal migration factor	Couples NMDA-sensitive glutamate receptor signaling to the nucleus and triggers long-lasting changes in the cytoarchitecture of dendrites and spine synapse processes.
DUSP6	Dual specificity protein phosphatase 6	Dual specificity protein phosphatase, which mediates dephosphorylation and inactivation of MAP kinases.
FGF17	Fibroblast growth factor 17	Plays an important role in the regulation of embryonic development and as signaling molecule in the induction and patterning of the embryonic brain.
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.
KISS1	Metastasis-suppressor KiSS-1	Kisspeptins are ligands for the G-protein coupled receptor KISS1R/GPR54.
SOX11	Transcription factor SOX-11	Transcription factor that acts as a transcriptional activator.
NLGN3	Neuroligin-3	Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.
IL17RD	Interleukin-17 receptor D	Feedback inhibitor of fibroblast growth factor mediated Ras-MAPK signaling and ERK activation.
POU6F2	POU domain, class 6, transcription factor 2	Probable transcription factor likely to be involved in early steps in the differentiation of amacrine and ganglion cells.
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.
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.
LHB	Lutropin subunit beta	Promotes spermatogenesis and ovulation by stimulating the testes and ovaries to synthesize steroids.
NHLH2	Helix-loop-helix protein 2	Transcription factor which binds the E box motif 5’-CA[TC][AG]TG-3'.
POLR2F	DNA-directed RNA polymerases I, II, and III subunit RPABC2	DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.

Protein-family classification

Druggable: 10 · Difficult: 5 · Unknown: 17 · Druggable fraction: 0.31

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	4	3.6×	0.150
GPCR	4	3.0×	0.150
Phosphatase	1	2.6×	0.744
Scaffold/PPI	2	1.1×	0.762
Other/Unknown	17	0.9×	0.762
Kinase	1	0.9×	0.762
Transcription factor	3	0.8×	0.762

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SEMA3F	Antibody/Immunoglobulin	yes		Semap_dom, Ig_sub2, Ig_sub
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
KLB	Other/Unknown	no		Glyco_hydro_1, GH_hydrolase_sf
PHIP	Scaffold/PPI	no		Bromodomain, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
PROKR2	GPCR	yes		GPCR_Rhodpsn, NPY_rcpt, GPCR_Rhodpsn_7TM
PROK2	Other/Unknown	no		Prokineticin, Prokineticin_domain
CHD7	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
CCDC141	Antibody/Immunoglobulin	yes		Spectrin_repeat, Ig_sub2, Ig_sub
FGF8	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
FGFR1	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
GNRH1	Other/Unknown	no		GnRH, Gonadoliberin_I_precursor, Gonadoliberin
GNRHR	GPCR	yes		GPCR_Rhodpsn, GphnRH_fam_rcpt, GPCR_Rhodpsn_7TM
KISS1R	GPCR	yes		GPCR_Rhodpsn, KiSS_1_rcpt, GPCR_Rhodpsn_7TM
PLXNA3	Antibody/Immunoglobulin	yes		Semap_dom, Plexin_repeat, IPT_dom
SPRY4	Other/Unknown	no		Sprouty, Sprouty_domain
NSMF	Other/Unknown	no		NSMF, IQ_SCN5A_C
DUSP6	Phosphatase	yes	3.1.3.16	Dual-sp_phosphatase_cat-dom, Tyr_Pase_dom, Rhodanese-like_dom
FGF17	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
HS6ST1	Other/Unknown	no		Sulfotransferase, Heparan_SO4-6-sulfoTrfase, P-loop_NTPase
KISS1	Other/Unknown	no		Metastasis-suppressor_KiSS-1
SOX11	Transcription factor	no		HMG_box_dom, SOX-12/11/4, HMG_box_dom_sf
NLGN3	Other/Unknown	no		Nlgn, CarbesteraseB, Carboxylesterase_B_CS
IL17RD	Other/Unknown	no		SEFIR_dom, IL17R_D_N, Toll_tir_struct_dom_sf
POU6F2	Transcription factor	no		POU_dom, HD, Homeodomain-like_sf
POLR3B	Other/Unknown	no		DNA-dir_RNAP_su2_dom, RNA_pol_bsu_CS, RNA_pol_Rpb2_7
TACR3-AS1	Other/Unknown	no
ANOS1	Antibody/Immunoglobulin	yes		FN3_dom, WAP_dom, Ig-like_fold
LHB	Other/Unknown	no		Gonadotropin_bsu, Glyco_hormone_CN, Gonadotropin_bsu_CS
NHLH2	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, TAL-like
POLR2F	Other/Unknown	no		Pol_omega/Rpo6/RPB6, Rpo6/Rpb6, DNA-dir_RNA_polK_14-18kDa_CS

Expression context

Cohort genes with no expression data: 0.

24 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)	32
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	5
cortical plate	5
secondary oocyte	4
buccal mucosa cell	4
ventricular zone	4
ganglionic eminence	3
male germ line stem cell (sensu Vertebrata) in testis	3
adenohypophysis	3
lower esophagus mucosa	2
placenta	2
calcaneal tendon	2
epithelium of bronchus	2
adrenal tissue	2
stromal cell of endometrium	2
tibial nerve	2
endothelial cell	2
right hemisphere of cerebellum	2
prefrontal cortex	2
cervix squamous epithelium	1
gingival epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SEMA3F	289	ubiquitous	marker	cervix squamous epithelium, gingival epithelium, lower esophagus mucosa
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
KLB	146	broad	marker	sperm, buccal mucosa cell, liver
PHIP	302	ubiquitous	marker	bronchial epithelial cell, epithelium of bronchus, ventricular zone
PROKR2	32	tissue_specific	yes	cortical plate, ganglionic eminence, ventricular zone
PROK2	159	broad	marker	blood, bone marrow, trabecular bone tissue
CHD7	269	ubiquitous	marker	secondary oocyte, cerebellar vermis, sural nerve
CCDC141	149	broad	marker	heart left ventricle, adrenal tissue, right atrium auricular region
FGF8	109	tissue_specific	yes	primordial germ cell in gonad, metanephric glomerulus, endometrium epithelium
FGFR1	292	ubiquitous	marker	buccal mucosa cell, stromal cell of endometrium, calcaneal tendon
GNRH1	181	tissue_specific	yes	tibial nerve, lower esophagus mucosa, male germ line stem cell (sensu Vertebrata) in testis
GNRHR	121	tissue_specific	yes	adrenal tissue, adenohypophysis, male germ line stem cell (sensu Vertebrata) in testis
KISS1R	109	broad	yes	pons, buccal mucosa cell, endothelial cell
PLXNA3	204	ubiquitous	marker	adenohypophysis, stromal cell of endometrium, right hemisphere of cerebellum
SPRY4	219	ubiquitous	marker	left coronary artery, right lung, ascending aorta
NSMF	251	ubiquitous	marker	cortical plate, anterior cingulate cortex, cingulate cortex
DUSP6	296	ubiquitous	marker	parotid gland, pericardium, monocyte
FGF17	154	tissue_specific	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
HS6ST1	258	ubiquitous	marker	kidney epithelium, pancreatic ductal cell, ganglionic eminence
KISS1	105	tissue_specific	marker	placenta, right lobe of liver, epithelium of bronchus
SOX11	93	broad	marker	ganglionic eminence, cortical plate, embryo
NLGN3	181	broad	marker	cortical plate, ventricular zone, prefrontal cortex
IL17RD	236	broad	yes	secondary oocyte, oocyte, mammary duct
POU6F2	108	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, ventricular zone
POLR3B	247	ubiquitous	marker	secondary oocyte, esophagus squamous epithelium, endothelial cell
TACR3-AS1	46		yes	primordial germ cell in gonad, prefrontal cortex, cortex of kidney
ANOS1	268	broad	marker	visceral pleura, hair follicle, skeletal muscle tissue of rectus abdominis
LHB	158	tissue_specific	yes	adenohypophysis, pituitary gland, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 87.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLR3B	5,712
FGFR1	5,693
CHD7	4,819
FGF8	4,536
FGF17	3,908
PHIP	3,057
DUSP6	2,421
NLGN3	2,122
SOX11	2,090
KISS1	2,056

Intra-cohort edges

A	B	Sources
ANOS1	CCDC141	string_interaction
ANOS1	CHD7	string_interaction
ANOS1	FGF8	string_interaction
ANOS1	FGFR1	biogrid_interaction, intact, string_interaction
ANOS1	GNRH1	string_interaction
ANOS1	GNRHR	string_interaction
ANOS1	HS6ST1	string_interaction
ANOS1	KISS1R	string_interaction
ANOS1	NSMF	string_interaction
ANOS1	PROK2	string_interaction
ANOS1	PROKR2	string_interaction
ANOS1	TAC3	string_interaction
ANOS1	TACR3	string_interaction
CCDC141	HS6ST1	string_interaction
CCDC141	NSMF	string_interaction
CCDC141	PROKR2	string_interaction
CCDC141	TACR3	string_interaction
CHD7	GNRHR	string_interaction
CHD7	KISS1	string_interaction
CHD7	KISS1R	string_interaction
CHD7	NSMF	string_interaction
CHD7	PROK2	string_interaction
CHD7	PROKR2	string_interaction
CHD7	TAC3	string_interaction
CHD7	TACR3	string_interaction
DUSP6	SPRY4	string_interaction
FGF17	FGF8	intact
FGF17	FGFR1	string_interaction
FGF17	KLB	string_interaction
FGF8	FGFR1	biogrid_interaction, intact, string_interaction
FGF8	IL17RD	string_interaction
FGF8	NSMF	string_interaction
FGF8	PROK2	string_interaction
FGF8	SPRY4	string_interaction
FGF8	WDR11	biogrid_interaction
FGFR1	GNRHR	string_interaction
FGFR1	KISS1R	string_interaction
FGFR1	KLB	biogrid_interaction, intact, string_interaction
FGFR1	NSMF	string_interaction
FGFR1	PROK2	string_interaction
FGFR1	PROKR2	string_interaction
FGFR1	SPRY4	string_interaction
FGFR1	TACR3	string_interaction
GNRH1	GNRHR	string_interaction
GNRH1	KISS1	string_interaction
GNRH1	KISS1R	string_interaction
GNRH1	LHB	string_interaction
GNRH1	NSMF	string_interaction
GNRH1	PROK2	string_interaction
GNRH1	PROKR2	string_interaction

Structural data

PDB: 19 · AlphaFold-only: 12 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PHIP	Q8WWQ0	146
FGFR1	P11362	83
POLR2F	P61218	60
POLR3B	Q9NW08	29
KISS1R	Q969F8	6
KLB	Q86Z14	5
SOX11	P35716	4
TACR3	P29371	3
CHD7	Q9P2D1	3
TAC3	Q9UHF0	2
WDR11	Q9BZH6	2
GNRH1	P01148	2
DUSP6	Q16828	2
KISS1	Q15726	2
FGF8	P55075	1
GNRHR	P30968	1
SPRY4	Q9C004	1
NLGN3	Q9NZ94	1
ANOS1	P23352	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HS6ST1	O60243	87.28
FGF17	O60258	86.39
PLXNA3	P51805	84.77
LHB	P01229	84.33
SEMA3F	Q13275	84.06
PROKR2	Q8NFJ6	78.50
NHLH2	Q02577	77.76
CCDC141	Q6ZP82	72.36
IL17RD	Q8NFM7	69.68
PROK2	Q9HC23	69.22
NSMF	Q6X4W1	65.71
POU6F2	P78424	48.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 197. Enrichment computed across 32 evidence-associated genes (24 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 24 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
G alpha (q) signalling events	8	19.1×	8e-07	TAC3, TACR3, PROKR2, PROK2, GNRH1, GNRHR, KISS1R, KISS1
FGFR1c ligand binding and activation	4	126.9×	2e-06	FGF8, FGFR1, FGF17, ANOS1
Negative regulation of FGFR1 signaling	4	61.4×	3e-05	FGF8, FGFR1, FGF17, ANOS1
Signaling by activated point mutants of FGFR1	3	119.0×	6e-05	FGF8, FGFR1, FGF17
Hormone ligand-binding receptors	3	119.0×	6e-05	GNRH1, GNRHR, LHB
PI3K Cascade	4	45.3×	6e-05	KLB, FGF8, FGFR1, FGF17
FGFR4 ligand binding and activation	3	102.0×	8e-05	KLB, FGF8, FGF17
Phospholipase C-mediated cascade; FGFR4	3	95.2×	9e-05	KLB, FGF8, FGF17
Phospholipase C-mediated cascade: FGFR1	3	84.0×	1e-04	FGF8, FGFR1, FGF17
PI-3K cascade:FGFR4	3	71.4×	2e-04	KLB, FGF8, FGF17
Downstream signaling of activated FGFR1	3	68.0×	2e-04	FGF8, FGFR1, FGF17
SHC-mediated cascade:FGFR4	3	68.0×	2e-04	KLB, FGF8, FGF17
PI-3K cascade:FGFR1	3	64.9×	2e-04	FGF8, FGFR1, FGF17
SHC-mediated cascade:FGFR1	3	62.1×	2e-04	FGF8, FGFR1, FGF17
FRS-mediated FGFR4 signaling	3	62.1×	2e-04	KLB, FGF8, FGF17
FRS-mediated FGFR1 signaling	3	57.1×	2e-04	FGF8, FGFR1, FGF17
Negative regulation of FGFR4 signaling	3	51.0×	3e-04	KLB, FGF8, FGF17
Constitutive Signaling by Aberrant PI3K in Cancer	4	21.1×	4e-04	KLB, FGF8, FGFR1, FGF17
Signaling by FGFR	3	43.3×	4e-04	KLB, ANOS1, POLR2F
Tachykinin receptors bind tachykinins	2	158.6×	6e-04	TAC3, TACR3
Signaling by FGFR1 in disease	3	36.6×	7e-04	FGF8, FGFR1, FGF17
FGFR3b ligand binding and activation	2	135.9×	8e-04	FGF8, FGF17
Signaling by FGFR2 in disease	3	33.2×	8e-04	FGF8, FGF17, POLR2F
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	4	16.1×	8e-04	KLB, FGF8, FGFR1, FGF17
Signaling by activated point mutants of FGFR3	2	79.3×	0.002	FGF8, FGF17
Peptide ligand-binding receptors	4	12.4×	0.002	PROKR2, PROK2, KISS1R, KISS1
FGFR3c ligand binding and activation	2	73.2×	0.002	FGF8, FGF17
FGFR2c ligand binding and activation	2	73.2×	0.002	FGF8, FGF17
Phospholipase C-mediated cascade; FGFR3	2	73.2×	0.002	FGF8, FGF17
FGFRL1 modulation of FGFR1 signaling	2	73.2×	0.002	FGF8, FGF17

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 31 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of luteinizing hormone secretion	2	217.4×	0.003	TACR3, KISS1
trigeminal nerve structural organization	2	181.2×	0.003	SEMA3F, PLXNA3
chordate embryonic development	2	181.2×	0.003	CHD7, FGFR1
positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway	2	181.2×	0.003	KLB, FGFR1
positive regulation of stem cell proliferation	3	51.0×	0.003	FGF8, FGFR1, SOX11
branchiomotor neuron axon guidance	2	135.9×	0.004	SEMA3F, PLXNA3
tachykinin receptor signaling pathway	2	120.8×	0.004	TAC3, TACR3
facial nerve structural organization	2	120.8×	0.004	SEMA3F, PLXNA3
positive regulation of hormone secretion	2	108.7×	0.004	KISS1R, SOX11
negative regulation of axon extension involved in axon guidance	2	108.7×	0.004	SEMA3F, PLXNA3
axon extension involved in axon guidance	2	98.8×	0.004	SEMA3F, PLXNA3
neuroepithelial cell differentiation	2	98.8×	0.004	FGF8, SOX11
fibroblast growth factor receptor signaling pathway	3	27.6×	0.004	FGF8, FGFR1, FGF17
G protein-coupled receptor signaling pathway	6	7.0×	0.004	PROKR2, PROK2, GNRHR, KISS1R, KISS1, LHB
branching involved in salivary gland morphogenesis	2	90.6×	0.005	FGF8, FGFR1
organ induction	2	77.7×	0.006	FGF8, FGFR1
positive regulation of blood pressure	2	68.0×	0.007	TAC3, TACR3
lung morphogenesis	2	68.0×	0.007	FGF8, SOX11
aorta morphogenesis	2	57.2×	0.010	CHD7, FGF8
neuropeptide signaling pathway	3	16.6×	0.013	TAC3, PROK2, KISS1R
motor neuron axon guidance	2	45.3×	0.015	FGF8, PLXNA3
negative chemotaxis	2	41.8×	0.015	SEMA3F, PLXNA3
regulation of cell migration	3	15.2×	0.015	FGF8, PLXNA3, FGF17
MAPK cascade	3	14.8×	0.015	FGF8, FGFR1, DUSP6
embryonic hindlimb morphogenesis	2	37.5×	0.018	CHD7, FGF8
positive regulation of mitotic nuclear division	2	35.1×	0.020	PHIP, FGF8
right ventricular compact myocardium morphogenesis	1	543.6×	0.021	CHD7
pallium development	1	543.6×	0.021	FGF8
negative regulation of immature T cell proliferation	1	543.6×	0.021	GNRH1
negative regulation of transcription regulatory region DNA binding	1	543.6×	0.021	SOX11

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 4 · Phased (≥1): 4 · Undrugged: 28

Druggability breadth: 9 of 32 evidence-associated genes (28%) 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
TACR3	APREPITANT
FGFR1	PONATINIB
GNRHR	GONADORELIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR1	93	4
GNRHR	12	4
TACR3	9	4
KISS1R	3	3
SEMA3F	0	0
TAC3	0	0
WDR11	0	0
KLB	0	0
PHIP	0	0
PROKR2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
APREPITANT	4	TACR3
FEZOLINETANT	4	TACR3
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
GONADORELIN	4	GNRHR
CETRORELIX	4	GNRHR
LEUPROLIDE	4	GNRHR

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
GNRHR	302	Binding:248, Functional:54
TACR3	266	Binding:217, Functional:48, ADMET:1
KISS1R	48	Binding:24, Functional:24
DUSP6	38	Binding:37, ADMET:1
PHIP	17	Binding:17
PROKR2	9	Functional:5, Binding:4
TAC3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FGFR1	2.7.10.1	receptor protein-tyrosine kinase
DUSP6	3.1.3.16, 3.1.3.48	protein-serine/threonine phosphatase, protein-tyrosine-phosphatase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TACR3	266
FGFR1	1,465
GNRHR	302

Pharmacogenomics

Cohort genes with a PharmGKB record: 31; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

29 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)
APREPITANT	4	TACR3
FEZOLINETANT	4	TACR3
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
CETRORELIX	4	GNRHR
LEUPROLIDE	4	GNRHR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	TACR3, FGFR1, GNRHR
B	Phased (≥1) drug, not yet approved	1	KISS1R
C	Druggable family + PDB, no drug	2	DUSP6, ANOS1
D	Druggable family + AlphaFold only, no drug	4	SEMA3F, PROKR2, CCDC141, PLXNA3
E	Difficult family or no structure, no drug	22	TAC3, WDR11, KLB, PHIP, PROK2, CHD7, FGF8, GNRH1, SPRY4, NSMF (+12 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TAC3	1	TACR3, KISS1R
KLB	0	FGFR1
FGF8	0	FGFR1
GNRH1	0	GNRHR, KISS1R
NSMF	0	TACR3, KISS1R
FGF17	0	FGFR1
KISS1	0	KISS1R, TACR3, GNRHR
ANOS1	0	FGFR1
LHB	0	GNRHR
SEMA3F	0	—
WDR11	0	—
PHIP	17	—
PROKR2	9	—
PROK2	0	—
CHD7	0	—
CCDC141	0	—
PLXNA3	0	—
SPRY4	0	—
DUSP6	38	—
HS6ST1	0	—
SOX11	0	—
NLGN3	0	—
IL17RD	0	—
POU6F2	0	—
POLR3B	0	—
TACR3-AS1	0	—
NHLH2	0	—
POLR2F	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 79.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	22
PHASE2	21
PHASE3	13
PHASE1	13
PHASE4	9
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00328926	PHASE4	TERMINATED	Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT01454011	PHASE4	COMPLETED	The Effect of Testosterone Replacement on the High Density Lipoprotein Cholesterol Subgroups
NCT01601327	PHASE4	COMPLETED	Effects of Medications in Patients With Hypogonadism
NCT02310074	PHASE4	UNKNOWN	Efficacy and Safety of Pulsatile Gonadotropin Releasing Hormone Pump Treatment in Patients With Idiopathic Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03490513	PHASE4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
NCT04456296	PHASE4	COMPLETED	A Study of the Effect of Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT05205837	PHASE4	TERMINATED	A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial
NCT06561594	PHASE3	NOT_YET_RECRUITING	To Evaluate Recombinant Human Follicle Stimulating Hormone-CTP Fusion Protein Injection or Placebo Combined With Chorionic Gonadotropin for Injection
NCT00467870	PHASE3	COMPLETED	Long-term Safety Study of Intramuscular Injections of 750 mg and 1000 mg Testosterone Undecanoate in Hypogonadal Men
NCT00962637	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal™ Treatment in Men With Secondary Hypogonadism
NCT01067365	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal Treatment in Men With Secondary Hypogonadism
NCT01532414	PHASE3	COMPLETED	Phase III Study to Evaluated Morning Testosterone Normalization in Men With Secondary Hypogonadism
NCT01534208	PHASE3	COMPLETED	Safety Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01709331	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adult Men With Hypogonadotropic Hypogonadism (HH) (P07937)
NCT01739582	PHASE3	COMPLETED	An Extension Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01739595	PHASE3	COMPLETED	Phase III Study to Evaluate Morning Testosterone Normalization in Overweight Men With Secondary Hypogonadism
NCT01993212	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT01993225	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT02110368	PHASE3	COMPLETED	Bioequivalence Study of Test and Reference Testosterone Topical Gel, 1.62% Metered Pump in Testosterone Deficient Adult Male Subjects Under Fasting Conditions
NCT03019575	PHASE3	COMPLETED	Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adolescent Males With Hypogonadotropic Hypogonadism (HH) (MK-8962-043)
NCT01894308	PHASE2	NOT_YET_RECRUITING	A Dose Ranging Study to Examine TDS-Testosterone 5%
NCT02733133	PHASE2	NOT_YET_RECRUITING	Product Transference Study of Testagen™ TDS®-Testosterone
NCT05896293	PHASE2	RECRUITING	Kisspeptin Administration Subcutaneously to Patients With IHH
NCT07224438	PHASE2	RECRUITING	Kisspeptin Administration Subcutaneously to Patients With Hypothalamic Amenorrhea
NCT00193661	PHASE2	COMPLETED	Observation Study of T-Gel (1%) in Treatment of Adolescent Boys With Hypogonadism
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00697814	PHASE2	COMPLETED	Clomiphene in Males With Prolactinomas and Persistent Hypogonadism
NCT00706719	PHASE2	COMPLETED	To Evaluate Sperm Parameters in Men With Secondary Hypogonadism Previously Treated With Topical Testosterone
NCT00911586	PHASE2	COMPLETED	Pharmacokinetic Study to Determine Time to Steady-state
NCT01155518	PHASE2	TERMINATED	Hypogonadism in Young Men With Type 2 Diabetes
NCT01191320	PHASE2	COMPLETED	Study to Evaluate the Efficacy of Androxal in Controlling Blood Glucose in Men With Type-2 Diabetes Mellitus
NCT01270841	PHASE2	COMPLETED	Normalization of Morning Testosterone Levels in Men With Secondary Hypogonadism
NCT01386606	PHASE2	COMPLETED	The Effect on Androxal Versus Androgel on Morning Testosterone in Men With Secondary Hypogonadism (Low Testosterone)
NCT02154477	PHASE1/PHASE2	COMPLETED	Effect of Intranasal Insulin on LH Concentrations in Man
NCT02369796	PHASE2	TERMINATED	A Phase 2a Pharmacodynamic Study of TAK-448 in Participants With Hypogonadotropic Hypogonadism
NCT02443090	PHASE2	UNKNOWN	Safety and Efficacy Study of Oral Fispemifene for the Treatment of Sexual Dysfunction in Hypogonadal Men
NCT02651688	PHASE2	COMPLETED	A Multi-Center Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters With Diet and Exercise in Conjunction With Treatment With 12.5 mg or 25 mg Enclomiphene
NCT02730169	PHASE2	COMPLETED	Safety and Efficacy of BGS649 in Male Obese Subjects With Hypogonadotropic Hypogonadism

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
GONADORELIN	4	10
TESTOSTERONE	4	7
CLOMIPHENE	4	4
GONADOTROPIN, CHORIONIC	4	4
ANASTROZOLE	4	2
CORIFOLLITROPIN ALFA	4	2
TESTOSTERONE UNDECANOATE	4	2
DYDROGESTERONE	4	1
LETROZOLE	4	1
LUTROPIN ALFA	4	1
MENOTROPINS	4	1
ENCLOMIPHENE	3	20
ESTROGEN	3	1
KISSPEPTIN	2	8
FISPEMIFENE	2	1
TAK-448	2	1
CHEMBL2370644	0	6
CHEMBL4746472	0	4
CHEMBL1233255	0	3