Congenital hypogonadotropic hypogonadism

Summary

Congenital hypogonadotropic hypogonadism (MONDO:0015770) is a disease (an umbrella term covering 25 Mondo subtypes) caused by ARHGAP35 (GenCC Strong), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: ARHGAP35 (GenCC Strong)
• Umbrella term: 25 Mondo subtypes
• Cohort genes: 3
• ClinVar variants: 8
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital hypogonadotropic hypogonadism
Mondo ID	MONDO:0015770
Orphanet	174590
ICD-11	1752075408
NCIT	C120162
SNOMED CT	722944006
UMLS	C3899503
MedGen	859097
GARD	0020135
Is cancer (heuristic)	no

Data availability: 8 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 25 Mondo subtypes.

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

Related subtypes (9): 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, Kallmann syndrome, hypogonadotropic hypogonadism 25 with anosmia, hypogonadotropic hypogonadism 26 with or without anosmia, hypogonadotropic hypogonadism 27 without anosmia

Subtypes (25): 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, 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

8 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
3896706	NM_004098.4(EMX2):c.332C>A (p.Ser111Ter)	EMX2OS	Pathogenic	criteria provided, single submitter
3896705	NM_004098.4(EMX2):c.595A>C (p.Lys199Gln)	EMX2	Likely pathogenic	criteria provided, single submitter
593850	NM_004098.4(EMX2):c.653G>A (p.Gly218Asp)	EMX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3896707	NM_004098.4(EMX2):c.173C>A (p.Ala58Asp)	EMX2	Uncertain significance	criteria provided, single submitter
3896708	NM_004098.4(EMX2):c.569G>A (p.Ser190Asn)	EMX2	Uncertain significance	criteria provided, single submitter
3896710	NM_004098.4(EMX2):c.22C>A (p.Arg8Ser)	EMX2	Uncertain significance	criteria provided, single submitter
3896709	NM_004098.4(EMX2):c.115G>T (p.Ala39Ser)	EMX2	Likely benign	criteria provided, single submitter
3896711	NM_004098.4(EMX2):c.524A>C (p.Lys175Thr)	EMX2	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
ARHGAP35	Strong	Autosomal dominant	congenital hypogonadotropic hypogonadism	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EMX2	Orphanet:485275	Acquired schizencephaly

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
ARHGAP35	HGNC:4591	ENSG00000160007	Q9NRY4	Rho GTPase-activating protein 35	gencc
EMX2OS	HGNC:18511	ENSG00000229847		EMX2 opposite strand/antisense RNA	clinvar
EMX2	HGNC:3341	ENSG00000170370	Q04743	Homeobox protein EMX2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARHGAP35	Rho GTPase-activating protein 35	Rho GTPase-activating protein (GAP).
EMX2	Homeobox protein EMX2	Transcription factor, which in cooperation with EMX1, acts to generate the boundary between the roof and archipallium in the developing brain.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARHGAP35	Other/Unknown	no		RhoGAP_dom, Small_GTPase, FF_domain
EMX2OS	Other/Unknown	no
EMX2	Transcription factor	no		HTH_motif, HD, Homeodomain-like_sf

Expression context

Cohort genes with no expression data: 0.

3 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
caput epididymis	2
corpus epididymis	2
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
kidney epithelium	1
cauda epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARHGAP35	277	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, middle temporal gyrus
EMX2OS	205	broad	marker	corpus epididymis, kidney epithelium, caput epididymis
EMX2	203	broad	marker	corpus epididymis, caput epididymis, cauda epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARHGAP35	1,649
EMX2	1,515
EMX2OS	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ARHGAP35	Q9NRY4	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EMX2	Q04743	67.26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. 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
Sema4D mediated inhibition of cell attachment and migration	1	713.8×	0.018	ARHGAP35
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	1	407.9×	0.018	ARHGAP35
Formation of the nephric duct	1	317.2×	0.018	EMX2
RND1 GTPase cycle	1	132.8×	0.019	ARHGAP35
RND3 GTPase cycle	1	129.8×	0.019	ARHGAP35
RND2 GTPase cycle	1	129.8×	0.019	ARHGAP35
RHOD GTPase cycle	1	102.0×	0.019	ARHGAP35
RHOJ GTPase cycle	1	100.2×	0.019	ARHGAP35
RHOQ GTPase cycle	1	90.6×	0.019	ARHGAP35
RHOB GTPase cycle	1	77.2×	0.019	ARHGAP35
RHOG GTPase cycle	1	74.2×	0.019	ARHGAP35
RHOC GTPase cycle	1	73.2×	0.019	ARHGAP35
RAC2 GTPase cycle	1	63.4×	0.020	ARHGAP35
RAC3 GTPase cycle	1	59.5×	0.020	ARHGAP35
RHOA GTPase cycle	1	37.3×	0.029	ARHGAP35
CDC42 GTPase cycle	1	36.1×	0.029	ARHGAP35
RAC1 GTPase cycle	1	30.5×	0.032	ARHGAP35

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
stereocilium bundle organization	1	4213.0×	0.004	EMX2
forebrain cell migration	1	2808.7×	0.004	EMX2
establishment or maintenance of actin cytoskeleton polarity	1	2106.5×	0.004	ARHGAP35
neuron projection guidance	1	2106.5×	0.004	ARHGAP35
regulation of actin polymerization or depolymerization	1	1404.3×	0.005	ARHGAP35
cerebral cortex regionalization	1	1203.7×	0.005	EMX2
ureter morphogenesis	1	1053.2×	0.005	EMX2
central nervous system neuron axonogenesis	1	936.2×	0.005	ARHGAP35
cell proliferation in forebrain	1	648.1×	0.006	EMX2
negative regulation of vascular permeability	1	561.7×	0.006	ARHGAP35
wound healing, spreading of cells	1	561.7×	0.006	ARHGAP35
axonal fasciculation	1	468.1×	0.006	ARHGAP35
regulation of axonogenesis	1	443.5×	0.006	ARHGAP35
regulation of cell size	1	383.0×	0.006	ARHGAP35
negative regulation of Rho protein signal transduction	1	383.0×	0.006	ARHGAP35
positive regulation of cilium assembly	1	383.0×	0.006	ARHGAP35
mammary gland development	1	324.1×	0.006	ARHGAP35
dentate gyrus development	1	312.1×	0.006	EMX2
camera-type eye development	1	179.3×	0.010	ARHGAP35
forebrain development	1	175.5×	0.010	ARHGAP35
Rho protein signal transduction	1	123.9×	0.013	ARHGAP35
neural tube closure	1	93.6×	0.017	ARHGAP35
anterior/posterior pattern specification	1	90.6×	0.017	EMX2
regulation of actin cytoskeleton organization	1	78.8×	0.018	ARHGAP35
regulation of small GTPase mediated signal transduction	1	72.0×	0.019	ARHGAP35
positive regulation of neuron projection development	1	68.5×	0.019	ARHGAP35
neuron migration	1	66.9×	0.019	EMX2
regulation of cell shape	1	61.5×	0.020	ARHGAP35
central nervous system development	1	57.7×	0.021	EMX2
neuron differentiation	1	50.1×	0.023	EMX2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ARHGAP35	0	0
EMX2OS	0	0
EMX2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ARHGAP35	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	ARHGAP35, EMX2OS, EMX2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ARHGAP35	1	—
EMX2OS	0	—
EMX2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01914172	Not specified	COMPLETED	Health Needs of Patients With Kallmann Syndrome