Hypogonadotropic hypogonadism 8 with or without anosmia

Summary

Hypogonadotropic hypogonadism 8 with or without anosmia (MONDO:0013910) is a disease caused by KISS1R (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: KISS1R (GenCC Definitive)
• 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 8 with or without anosmia
Mondo ID	MONDO:0013910
OMIM	614837
DOID	DOID:0090074
UMLS	C3553841
MedGen	766755
GARD	0015849
Is cancer (heuristic)	no

Also known as: HH8 · hypogonadotropic hypogonadism 8 with or without anosmia · hypogonadotropic hypogonadism caused by mutation in KISS1R · KISS1R hypogonadotropic hypogonadism

Data availability: 16 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 8 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 9 with or without anosmia, hypogonadotropic hypogonadism 11 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

16 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
2637681	NC_000019.9:g.(?917332)(921006_?)del	KISS1R	Pathogenic	criteria provided, single submitter
5759	NM_032551.5(KISS1R):c.305T>C (p.Leu102Pro)	KISS1R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
281944	NM_032551.5(KISS1R):c.890G>T (p.Arg297Leu)	KISS1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
5760	NM_032551.5(KISS1R):c.1157G>C (p.Arg386Pro)	KISS1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028963	NM_032551.5(KISS1R):c.749T>A (p.Leu250Gln)	KISS1R	Uncertain significance	criteria provided, single submitter
1339093	NM_032551.5(KISS1R):c.82A>C (p.Asn28His)	KISS1R	Uncertain significance	criteria provided, single submitter
2455181	NM_032551.5(KISS1R):c.1112C>T (p.Ala371Val)	KISS1R	Uncertain significance	criteria provided, multiple submitters, no conflicts
3062119	NM_032551.5(KISS1R):c.233A>G (p.Asn78Ser)	KISS1R	Uncertain significance	criteria provided, single submitter
3584223	NM_032551.5(KISS1R):c.244+6del	KISS1R	Uncertain significance	criteria provided, single submitter
4086213	NM_032551.5(KISS1R):c.572G>A (p.Cys191Tyr)	KISS1R	Uncertain significance	criteria provided, single submitter
4293841	NM_032551.5(KISS1R):c.793G>T (p.Val265Leu)	KISS1R	Uncertain significance	criteria provided, single submitter
50861	NM_032551.5(KISS1R):c.581C>A (p.Ala194Asp)	KISS1R	Uncertain significance	criteria provided, single submitter
1590131	NM_032551.5(KISS1R):c.18G>A (p.Thr6=)	KISS1R	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
286524	NM_032551.5(KISS1R):c.24A>G (p.Gly8=)	KISS1R	Benign	criteria provided, multiple submitters, no conflicts
379860	NM_032551.5(KISS1R):c.1155G>A (p.Ala385=)	KISS1R	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
447660	NM_032551.5(KISS1R):c.1091T>A (p.Leu364His)	KISS1R	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · 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
KISS1R	Definitive	Autosomal recessive	hypogonadotropic hypogonadism 8 with or without anosmia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KISS1R	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
KISS1R	Orphanet:650077	Genetic central precocious puberty in female
KISS1R	Orphanet:650097	Genetic central precocious puberty in male

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
KISS1R	HGNC:4510	ENSG00000116014	Q969F8	KiSS-1 receptor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KISS1R	KiSS-1 receptor	Receptor for kisspeptins (kisspeptin-10, kisspeptin-13, kisspeptin-14 and metastin/kisspeptin-54).

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)
KISS1R	GPCR	yes		GPCR_Rhodpsn, KiSS_1_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
buccal mucosa cell	1
endothelial cell	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KISS1R	109	broad	yes	pons, buccal mucosa cell, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KISS1R	811

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KISS1R	Q969F8	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Class A/1 (Rhodopsin-like receptors)	1	74.2×	0.029	KISS1R
Peptide ligand-binding receptors	1	74.2×	0.029	KISS1R
GPCR ligand binding	1	64.2×	0.029	KISS1R
G alpha (q) signalling events	1	57.4×	0.029	KISS1R
GPCR downstream signalling	1	43.4×	0.029	KISS1R
Signaling by GPCR	1	40.1×	0.029	KISS1R
Signal Transduction	1	10.2×	0.098	KISS1R

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
positive regulation of hormone secretion	1	1685.2×	0.002	KISS1R
neuropeptide signaling pathway	1	172.0×	0.009	KISS1R
G protein-coupled receptor signaling pathway	1	36.2×	0.028	KISS1R

Therapeutics

Drug target analysis

Approved (phase 4): 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KISS1R	3	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KISSPEPTIN-10	3	KISS1R
BENZETHONIUM CHLORIDE	2	KISS1R
TAK-448	2	KISS1R

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KISS1R	48	Binding:24, Functional:24

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

3 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)
KISSPEPTIN-10	3	KISS1R
BENZETHONIUM CHLORIDE	2	KISS1R
TAK-448	2	KISS1R

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	1	KISS1R
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.