Hypogonadotropic hypogonadism 23 with or without anosmia

Summary

Hypogonadotropic hypogonadism 23 with or without anosmia (MONDO:0009223) is a disease caused by LHB (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: LHB (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 23 with or without anosmia
Mondo ID	MONDO:0009223
MeSH	C537919
OMIM	228300
Orphanet	325448
DOID	DOID:0090091
SNOMED CT	8829008
UMLS	C0271582
MedGen	82881
GARD	0010127
Is cancer (heuristic)	no

Also known as: 46,XY disorder of sex development due to LHB deficiency · 46,XY disorder of sex development due to luteinizing hormone subunit beta deficiency · 46,XY DSD due to LHB deficiency · 46,XY DSD due to luteinizing hormone subunit beta deficiency · eunuchoidism with spermatogenesis, normal FSH and low or normal interstitial cell-stimulating hormone (ICSH) · fertile eunuch syndrome · HH23 · hypogonadotropic hypogonadism 23 without anosmia · hypogonadotropic hypogonadism caused by mutation in LHB · Leydig cell hypoplasia due to LHB deficiency · Leydig cell hypoplasia due to luteinizing hormone subunit beta deficiency · LHB hypogonadotropic hypogonadism · Pasqualini syndrome

Data availability: 16 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 23 with or without anosmia

Related subtypes (9): 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

16 retrieved; paginated sample, class counts are floors:

7 benign, 6 pathogenic, 1 likely benign, 1 benign/likely benign, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
14413	NM_000894.3(LHB):c.221A>G (p.Gln74Arg)	LHB	Pathogenic	no assertion criteria provided
14416	NM_000894.3(LHB):c.167G>A (p.Gly56Asp)	LHB	Pathogenic	no assertion criteria provided
189290	NM_000894.3(LHB):c.183+1G>C	LHB	Pathogenic	no assertion criteria provided
189291	NM_000894.3(LHB):c.88_96del (p.His30_Ile32del)	LHB	Pathogenic	no assertion criteria provided
189292	NM_000894.3(LHB):c.28_39del (p.Leu10_Leu13del)	LHB	Pathogenic	no assertion criteria provided
189293	NM_000894.3(LHB):c.183+1G>T	LHB	Pathogenic	no assertion criteria provided
818213	NM_000894.3(LHB):c.286G>A (p.Val96Met)	LHB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1253699	NM_000894.3(LHB):c.183+18del	LHB	Benign	criteria provided, multiple submitters, no conflicts
1258177	NM_000894.3(LHB):c.285T>C (p.Gly95=)	LHB	Benign	criteria provided, multiple submitters, no conflicts
14415	NM_000894.3(LHB):c.364G>A (p.Gly122Ser)	LHB	Likely benign	criteria provided, multiple submitters, no conflicts
518301	NM_000894.3(LHB):c.183+11T>C	LHB	Benign	criteria provided, multiple submitters, no conflicts
518302	NM_000894.3(LHB):c.132A>C (p.Pro44=)	LHB	Benign	criteria provided, multiple submitters, no conflicts
518303	NM_000894.3(LHB):c.114C>G (p.Val38=)	LHB	Benign	criteria provided, multiple submitters, no conflicts
518304	NM_000894.3(LHB):c.16-26T>C	LHB	Benign	criteria provided, multiple submitters, no conflicts
769028	NM_000894.3(LHB):c.233C>A (p.Thr78Asn)	LHB	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
769029	NM_000894.3(LHB):c.15+9A>G	LHB	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
LHB	Strong	Autosomal recessive	hypogonadotropic hypogonadism 23 with or without anosmia	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LHB	Orphanet:325448	Leydig cell hypoplasia due to LHB deficiency

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
LHB	HGNC:6584	ENSG00000104826	P01229	Lutropin subunit beta	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LHB	Lutropin subunit beta	Promotes spermatogenesis and ovulation by stimulating the testes and ovaries to synthesize steroids.

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)
LHB	Other/Unknown	no		Gonadotropin_bsu, Glyco_hormone_CN, Gonadotropin_bsu_CS

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
pituitary gland	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LHB	158	tissue_specific	yes	adenohypophysis, pituitary gland, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LHB	564

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LHB	P01229	84.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. 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
Mineralocorticoid biosynthesis	1	1427.5×	0.004	LHB
Peptide hormone biosynthesis	1	1427.5×	0.004	LHB
Reactions specific to the complex N-glycan synthesis pathway	1	1142.0×	0.004	LHB
Androgen biosynthesis	1	1038.2×	0.004	LHB
Glycoprotein hormones	1	951.7×	0.004	LHB
Hormone ligand-binding receptors	1	951.7×	0.004	LHB
N-glycan antennae elongation in the medial/trans-Golgi	1	571.0×	0.005	LHB
Metabolism of steroid hormones	1	519.1×	0.005	LHB
Peptide hormone metabolism	1	271.9×	0.009	LHB
Metabolism of steroids	1	137.6×	0.016	LHB
Transport to the Golgi and subsequent modification	1	102.9×	0.019	LHB
Class A/1 (Rhodopsin-like receptors)	1	74.2×	0.023	LHB
G alpha (s) signalling events	1	73.2×	0.023	LHB
GPCR ligand binding	1	64.2×	0.024	LHB
Asparagine N-linked glycosylation	1	60.1×	0.024	LHB
GPCR downstream signalling	1	43.4×	0.032	LHB
Signaling by GPCR	1	40.1×	0.032	LHB
Metabolism of lipids	1	31.6×	0.039	LHB
Post-translational protein modification	1	19.2×	0.060	LHB
Metabolism of proteins	1	12.4×	0.089	LHB
Metabolism	1	11.6×	0.090	LHB
Signal Transduction	1	10.2×	0.098	LHB

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
progesterone biosynthetic process	1	3370.4×	0.002	LHB
hormone-mediated signaling pathway	1	401.2×	0.007	LHB
male gonad development	1	156.0×	0.013	LHB
cell-cell signaling	1	69.6×	0.022	LHB
G protein-coupled receptor signaling pathway	1	36.2×	0.033	LHB
signal transduction	1	16.1×	0.062	LHB

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
LHB	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	LHB

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)
LHB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.