Hypogonadotropic hypogonadism 11 with or without anosmia

Summary

Hypogonadotropic hypogonadism 11 with or without anosmia (MONDO:0013913) is a disease caused by TACR3 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: TACR3 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 50

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 11 with or without anosmia
Mondo ID	MONDO:0013913
OMIM	614840
DOID	DOID:0090071
UMLS	C3553844
MedGen	766758
GARD	0015851
Is cancer (heuristic)	no

Also known as: HH11 · hypogonadotropic hypogonadism 11 with or without anosmia · hypogonadotropic hypogonadism caused by mutation in TACR3 · TACR3 hypogonadotropic hypogonadism

Data availability: 50 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Kallmann syndrome › hypogonadotropic hypogonadism 11 with or without anosmia

Related subtypes (17): hypogonadotropic hypogonadism 2 with or without anosmia, hypogonadotropic hypogonadism 3 with or without anosmia, hypogonadotropic hypogonadism 1 with or without anosmia, hypogonadotropic hypogonadism 4 with or without anosmia, hypogonadotropic hypogonadism 5 with or without anosmia, hypogonadotropic hypogonadism 6 with or without anosmia, hypogonadotropic hypogonadism 8 with or without anosmia, hypogonadotropic hypogonadism 9 with or without anosmia, hypogonadotropic hypogonadism 14 with or without anosmia, hypogonadotropic hypogonadism 15 with or without anosmia, hypogonadotropic hypogonadism 16 with or without anosmia, hypogonadotropic hypogonadism 17 with or without anosmia, hypogonadotropic hypogonadism 18 with or without anosmia, hypogonadotropic hypogonadism 19 with or without anosmia, hypogonadotropic hypogonadism 20 with or without anosmia, hypogonadotropic hypogonadism 21 with or without anosmia, hypogonadotropic hypogonadism 22 with or 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

50 retrieved; paginated sample, class counts are floors:

26 uncertain significance, 7 conflicting classifications of pathogenicity, 5 pathogenic, 4 benign/likely benign, 3 likely pathogenic, 3 benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
14025	NM_001059.3(TACR3):c.278G>A (p.Gly93Asp)	TACR3	Pathogenic	no assertion criteria provided
4755273	NM_001059.3(TACR3):c.1029G>A (p.Trp343Ter)	TACR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4849262	NM_001059.3(TACR3):c.19del (p.Ala7fs)	TACR3	Pathogenic	criteria provided, single submitter
66084	NM_001059.3(TACR3):c.824G>A (p.Trp275Ter)	TACR3	Pathogenic	criteria provided, multiple submitters, no conflicts
66085	NM_001059.3(TACR3):c.766T>C (p.Tyr256His)	TACR3	Pathogenic	no assertion criteria provided
818214	NM_001059.3(TACR3):c.737+1G>A	TACR3	Pathogenic/Likely 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
4849278	NM_023110.3(FGFR1):c.2144A>T (p.Glu715Val)	FGFR1	Likely pathogenic	criteria provided, single submitter
183684	NM_001059.3(TACR3):c.692C>T (p.Thr231Ile)	TACR3	Likely pathogenic	criteria provided, single submitter
3896750	NM_001059.3(TACR3):c.247_267del (p.Trp83_Ser89del)	TACR3	Likely pathogenic	criteria provided, single submitter
347113	NM_001059.3(TACR3):c.579C>T (p.Pro193=)	TACR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347117	NM_001059.3(TACR3):c.-20G>A	TACR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
586774	NM_001059.3(TACR3):c.1321C>T (p.Arg441Cys)	TACR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
726953	NM_001059.3(TACR3):c.138C>T (p.Asp46=)	TACR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
902915	NM_001059.3(TACR3):c.1225A>G (p.Met409Val)	TACR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347106	NM_001059.3(TACR3):c.1290G>A (p.Thr430=)	TACR3-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347107	NM_001059.3(TACR3):c.1246A>T (p.Asn416Tyr)	TACR3-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1298967	NM_001059.3(TACR3):c.1234G>A (p.Val412Met)	TACR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
347105	NM_001059.3(TACR3):c.1311T>C (p.Asn437=)	TACR3	Uncertain significance	criteria provided, single submitter
347109	NM_001059.3(TACR3):c.1188G>A (p.Arg396=)	TACR3	Uncertain significance	criteria provided, single submitter
347111	NM_001059.3(TACR3):c.737C>T (p.Thr246Ile)	TACR3	Uncertain significance	criteria provided, single submitter
347112	NM_001059.3(TACR3):c.703G>A (p.Val235Met)	TACR3	Uncertain significance	criteria provided, single submitter
347114	NM_001059.3(TACR3):c.114G>T (p.Glu38Asp)	TACR3	Uncertain significance	criteria provided, single submitter
347115	NM_001059.3(TACR3):c.-10A>T	TACR3	Uncertain significance	criteria provided, single submitter
347116	NM_001059.3(TACR3):c.-20G>C	TACR3	Uncertain significance	criteria provided, single submitter
347118	NM_001059.3(TACR3):c.-86C>A	TACR3	Uncertain significance	criteria provided, single submitter
347120	NM_001059.3(TACR3):c.-111C>A	TACR3	Uncertain significance	criteria provided, single submitter
419840	NM_001059.3(TACR3):c.918G>A (p.Met306Ile)	TACR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
4531915	NM_001059.3(TACR3):c.1034C>A (p.Ala345Glu)	TACR3	Uncertain significance	criteria provided, single submitter
900359	NM_001059.3(TACR3):c.1206C>T (p.Thr402=)	TACR3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 19 · 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
TACR3	Strong	Autosomal recessive	hypogonadotropic hypogonadism 11 with or without anosmia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TACR3	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
TACR3	Orphanet:478	Kallmann 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

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TACR3	HGNC:11528	ENSG00000169836	P29371	Neuromedin-K receptor	gencc,clinvar
FGFR1	HGNC:3688	ENSG00000077782	P11362	Fibroblast growth factor receptor 1	clinvar
TACR3-AS1	HGNC:55593	ENSG00000251577		TACR3 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Kinase	1	9.2×	0.180
GPCR	1	8.0×	0.180
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TACR3	GPCR	yes		GPCR_Rhodpsn, NK3_rcpt, Neurokn_rcpt
FGFR1	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
TACR3-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
hypothalamus	1
secondary oocyte	1
buccal mucosa cell	1
calcaneal tendon	1
stromal cell of endometrium	1
cortex of kidney	1
prefrontal cortex	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TACR3	43	tissue_specific	marker	cortical plate, secondary oocyte, hypothalamus
FGFR1	292	ubiquitous	marker	buccal mucosa cell, stromal cell of endometrium, calcaneal tendon
TACR3-AS1	46		yes	primordial germ cell in gonad, prefrontal cortex, cortex of kidney

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGFR1	5,693
TACR3	945
TACR3-AS1	0

Intra-cohort edges

A	B	Sources
FGFR1	TACR3	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGFR1	P11362	83
TACR3	P29371	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by FGFR1 amplification mutants	1	2855.0×	0.006	FGFR1
FGFR1c and Klotho ligand binding and activation	1	1427.5×	0.006	FGFR1
Signaling by plasma membrane FGFR1 fusions	1	1427.5×	0.006	FGFR1
Tachykinin receptors bind tachykinins	1	951.7×	0.006	TACR3
Epithelial-Mesenchymal Transition (EMT) during gastrulation	1	713.8×	0.006	FGFR1
FGFR1b ligand binding and activation	1	634.4×	0.006	FGFR1
Signaling by activated point mutants of FGFR1	1	475.8×	0.007	FGFR1
FGFR1c ligand binding and activation	1	380.7×	0.007	FGFR1
Phospholipase C-mediated cascade: FGFR1	1	335.9×	0.007	FGFR1
Downstream signaling of activated FGFR1	1	271.9×	0.007	FGFR1
Signal transduction by L1	1	259.6×	0.007	FGFR1
PI-3K cascade:FGFR1	1	259.6×	0.007	FGFR1
SHC-mediated cascade:FGFR1	1	248.3×	0.007	FGFR1
FRS-mediated FGFR1 signaling	1	228.4×	0.007	FGFR1
Formation of paraxial mesoderm	1	203.9×	0.008	FGFR1
Negative regulation of FGFR1 signaling	1	184.2×	0.008	FGFR1
Signaling by FGFR1 in disease	1	146.4×	0.009	FGFR1
PI3K Cascade	1	135.9×	0.009	FGFR1
NCAM signaling for neurite out-growth	1	135.9×	0.009	FGFR1
Constitutive Signaling by Aberrant PI3K in Cancer	1	63.4×	0.019	FGFR1
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	48.4×	0.023	FGFR1
PIP3 activates AKT signaling	1	33.4×	0.032	FGFR1
RAF/MAP kinase cascade	1	30.5×	0.034	FGFR1
G alpha (q) signalling events	1	28.7×	0.035	TACR3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
vitamin D3 metabolic process	1	4213.0×	0.004	FGFR1
positive regulation of mitotic cell cycle DNA replication	1	4213.0×	0.004	FGFR1
positive regulation of parathyroid hormone secretion	1	4213.0×	0.004	FGFR1
regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	4213.0×	0.004	FGFR1
regulation of phosphate transport	1	2808.7×	0.004	FGFR1
fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development	1	2808.7×	0.004	FGFR1
regulation of lateral mesodermal cell fate specification	1	2808.7×	0.004	FGFR1
phospholipase C-activating tachykinin receptor signaling pathway	1	2106.5×	0.004	TACR3
ventricular zone neuroblast division	1	2106.5×	0.004	FGFR1
negative regulation of fibroblast growth factor production	1	2106.5×	0.004	FGFR1
positive regulation of phospholipase activity	1	1685.2×	0.004	FGFR1
positive regulation of luteinizing hormone secretion	1	1685.2×	0.004	TACR3
regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling	1	1685.2×	0.004	FGFR1
diphosphate metabolic process	1	1685.2×	0.004	FGFR1
chordate embryonic development	1	1404.3×	0.004	FGFR1
positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway	1	1404.3×	0.004	FGFR1
cementum mineralization	1	1203.7×	0.004	FGFR1
positive regulation of uterine smooth muscle contraction	1	1053.2×	0.004	TACR3
tachykinin receptor signaling pathway	1	936.2×	0.004	TACR3
auditory receptor cell development	1	936.2×	0.004	FGFR1
regulation of feeding behavior	1	936.2×	0.004	TACR3
regulation of dopamine metabolic process	1	842.6×	0.004	TACR3
paraxial mesoderm development	1	842.6×	0.004	FGFR1
lung-associated mesenchyme development	1	842.6×	0.004	FGFR1
response to sodium phosphate	1	842.6×	0.004	FGFR1
conditioned place preference	1	842.6×	0.004	TACR3
outer ear morphogenesis	1	766.0×	0.004	FGFR1
vagina development	1	766.0×	0.004	TACR3
branching involved in salivary gland morphogenesis	1	702.2×	0.004	FGFR1
positive regulation of flagellated sperm motility	1	648.1×	0.004	TACR3

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR1	93	4
TACR3	9	4
TACR3-AS1	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
SERLOPITANT	3	TACR3
LINIFANIB	3	FGFR1
SEMAXANIB	3	FGFR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FGFR1	1,465	Binding:1428, Functional:24, ADMET:13
TACR3	266	Binding:217, Functional:48, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FGFR1	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
TACR3	266
FGFR1	1,465

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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)
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
SERLOPITANT	3	TACR3
LINIFANIB	3	FGFR1
SEMAXANIB	3	FGFR1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TACR3, FGFR1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TACR3-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TACR3-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.