Hypogonadotropic hypogonadism 12 with or without anosmia

Summary

Hypogonadotropic hypogonadism 12 with or without anosmia (MONDO:0013914) is a disease caused by GNRH1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GNRH1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 12 with or without anosmia
Mondo ID	MONDO:0013914
MeSH	C535764
OMIM	227200, 614841
DOID	DOID:0090072
UMLS	C1856897
MedGen	347328
GARD	0000276
Is cancer (heuristic)	no

Also known as: eunuchoidism familial hypogonadotropic · eunuchoidism, familial hypogonadotropic · familial hypogonadotropic eunuchoidism · FIGD · gonadotropin deficiency familial idiopathic · HH12 · hypogonadotropic hypogonadism 12 with or without anosmia

Data availability: 21 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 › hypogonadotropic hypogonadism 12 with or without anosmia

Related subtypes (9): hypogonadotropic hypogonadism 23 with or without anosmia, hypogonadotropic hypogonadism 24 without anosmia, hypogonadotropic hypogonadism 10 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

21 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 4 conflicting classifications of pathogenicity, 2 benign, 2 likely benign, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
14417	NM_001083111.2(GNRH1):c.18dup (p.Leu7fs)	GNRH1	Pathogenic	no assertion criteria provided
156555	NM_001083111.2(GNRH1):c.87del (p.Leu30fs)	GNRH1	Likely pathogenic	criteria provided, single submitter
1452079	NM_001083111.2(GNRH1):c.92G>A (p.Arg31His)	GNRH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362650	NM_001083111.2(GNRH1):c.237+8A>C	GNRH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362651	NM_001083111.2(GNRH1):c.177A>G (p.Gln59=)	GNRH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
734969	NM_001083111.2(GNRH1):c.141G>C (p.Glu47Asp)	GNRH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362649	NM_001083111.2(GNRH1):c.238-12T>C	GNRH1	Uncertain significance	criteria provided, single submitter
362654	NM_001083111.2(GNRH1):c.-1-110A>G	GNRH1	Uncertain significance	criteria provided, single submitter
362655	NM_001083111.2(GNRH1):c.-1-140G>A	GNRH1	Uncertain significance	criteria provided, single submitter
362658	NM_001083111.2(GNRH1):c.-2+194C>A	GNRH1	Uncertain significance	criteria provided, single submitter
4849461	NM_001083111.2(GNRH1):c.21_23del (p.Leu8del)	GNRH1	Uncertain significance	criteria provided, single submitter
908878	NM_001083111.2(GNRH1):c.-2+59G>T	GNRH1	Uncertain significance	criteria provided, single submitter
908879	NM_000825.3(GNRH1):c.-984C>G	GNRH1	Uncertain significance	criteria provided, single submitter
908880	NM_000825.3(GNRH1):c.-1198G>A	GNRH1	Uncertain significance	criteria provided, single submitter
909738	NM_000825.3(GNRH1):c.-1316C>T	GNRH1	Uncertain significance	criteria provided, single submitter
909739	NM_000825.3(GNRH1):c.-1624G>A	GNRH1	Uncertain significance	criteria provided, single submitter
911829	NM_001083111.2(GNRH1):c.210T>A (p.Ser70=)	GNRH1	Uncertain significance	criteria provided, single submitter
362652	NM_001083111.2(GNRH1):c.47G>C (p.Trp16Ser)	GNRH1	Benign	criteria provided, multiple submitters, no conflicts
362657	NM_001083111.2(GNRH1):c.-2+388T>C	GNRH1	Likely benign	criteria provided, multiple submitters, no conflicts
362659	NM_001083111.2(GNRH1):c.-2+5A>C	GNRH1	Likely benign	criteria provided, single submitter
788272	NM_001083111.2(GNRH1):c.183C>T (p.Phe61=)	GNRH1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
GNRH1	Strong	Autosomal recessive	hypogonadotropic hypogonadism 12 with or without anosmia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNRH1	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
GNRH1	HGNC:4419	ENSG00000147437	P01148	Progonadoliberin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GNRH1	Progonadoliberin-1	Stimulates the secretion of gonadotropins; it stimulates the secretion of both luteinizing and follicle-stimulating hormones.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GNRH1	Other/Unknown	no		GnRH, Gonadoliberin_I_precursor, Gonadoliberin

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
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNRH1	181	tissue_specific	yes	tibial nerve, lower esophagus mucosa, 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
GNRH1	1,779

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNRH1	P01148	2

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	GNRH1
G alpha (q) signalling events	1	57.4×	0.017	GNRH1

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
negative regulation of immature T cell proliferation	1	16852.0×	7e-04	GNRH1
response to prolactin	1	8426.0×	7e-04	GNRH1
regulation of ovarian follicle development	1	8426.0×	7e-04	GNRH1
regulation of signaling	1	5617.3×	8e-04	GNRH1
response to potassium ion	1	2106.5×	0.001	GNRH1
male sex determination	1	1404.3×	0.001	GNRH1
response to prostaglandin E	1	1404.3×	0.001	GNRH1
estrous cycle	1	1404.3×	0.001	GNRH1
negative regulation of neuron migration	1	1404.3×	0.001	GNRH1
response to steroid hormone	1	842.6×	0.002	GNRH1
response to testosterone	1	468.1×	0.003	GNRH1
female pregnancy	1	210.7×	0.007	GNRH1
response to ethanol	1	146.5×	0.009	GNRH1
response to lipopolysaccharide	1	124.8×	0.010	GNRH1
regulation of gene expression	1	83.4×	0.014	GNRH1
cell-cell signaling	1	69.6×	0.016	GNRH1
negative regulation of apoptotic process	1	34.8×	0.030	GNRH1
signal transduction	1	16.1×	0.062	GNRH1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GNRH1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	GNRH1

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)
GNRH1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.