Isolated congenital hypogonadotropic hypogonadism

Summary

Isolated congenital hypogonadotropic hypogonadism (MONDO:0016553) is a disease with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated congenital hypogonadotropic hypogonadism
Mondo ID	MONDO:0016553
Orphanet	238666
UMLS	C5679849
MedGen	1842176
GARD	0020643
Is cancer (heuristic)	no

Also known as: nonsyndromic congenital hypogonadotropic hypogonadism

Data availability: 2 ClinVar variants.

Disease family

An umbrella term covering 1 Mondo subtype.

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

Related subtypes (24): brachytelephalangy-dysmorphism-Kallmann syndrome, hypogonadotropic hypogonadism 7 with or without anosmia, 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, Moebius syndrome-axonal neuropathy-hypogonadotropic hypogonadism syndrome, hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome, Prader-Willi-like syndrome, Martsolf syndrome 1

Subtypes (1): congenital isolated adrenocorticotropic hormone deficiency

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

2 retrieved; paginated sample, class counts are floors:

2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16023	NM_000406.3(GNRHR):c.317A>G (p.Gln106Arg)	GNRHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2825275	NM_000406.3(GNRHR):c.351_352del (p.Ser118fs)	GNRHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNRHR	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GNRHR	HGNC:4421	ENSG00000109163	P30968	Gonadotropin-releasing hormone receptor	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).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GNRHR	GPCR	yes		GPCR_Rhodpsn, GphnRH_fam_rcpt, GPCR_Rhodpsn_7TM

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
adrenal tissue	1
male germ line stem cell (sensu Vertebrata) in testis	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNRHR	1,346

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNRHR	P30968	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Hormone ligand-binding receptors	1	951.7×	0.002	GNRHR
G alpha (q) signalling events	1	57.4×	0.017	GNRHR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
gonadotropin secretion	1	8426.0×	4e-04	GNRHR
cellular response to hormone stimulus	1	383.0×	0.004	GNRHR
G protein-coupled receptor signaling pathway	1	36.2×	0.028	GNRHR

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GNRHR	12	4

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
SUFUGOLIX	2	GNRHR
ACYLINE	2	GNRHR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GNRHR	302	Binding:248, Functional:54

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GNRHR	302

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

12 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
SUFUGOLIX	2	GNRHR
ACYLINE	2	GNRHR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GNRHR
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.