Hypogonadotropic hypogonadism 25 with anosmia

Summary

Hypogonadotropic hypogonadism 25 with anosmia (MONDO:0030010) is a disease caused by NDNF (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: NDNF (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 25 with anosmia
Mondo ID	MONDO:0030010
OMIM	618841
UMLS	C5394246
MedGen	1717461
GARD	0016387
Is cancer (heuristic)	no

Also known as: HH25 · HYPOGONADOTROPIC HYPOGONADISM 25 WITH ANOSMIA · hypogonadotropic hypogonadism 25 with anosmia

Data availability: 15 ClinVar variants · 2 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 25 with 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 12 with or without anosmia, hypogonadotropic hypogonadism 13 with or without anosmia, congenital hypogonadotropic hypogonadism, Kallmann syndrome, 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

15 retrieved; paginated sample, class counts are floors:

6 benign, 4 uncertain significance, 3 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
834069	NM_024574.4(NDNF):c.184A>T (p.Lys62Ter)	NDNF	Pathogenic	no assertion criteria provided
834070	NM_024574.4(NDNF):c.381del (p.Tyr128fs)	NDNF	Pathogenic	no assertion criteria provided
834071	NM_024574.4(NDNF):c.1406G>A (p.Trp469Ter)	NDNF	Pathogenic	no assertion criteria provided
1709811	NM_024574.4(NDNF):c.1159del (p.Ile387fs)	NDNF	Likely pathogenic	criteria provided, single submitter
4292410	NM_024574.4(NDNF):c.551_552del (p.Val184fs)	NDNF	Likely pathogenic	criteria provided, single submitter
1802269	NM_024574.4(NDNF):c.44_45delinsCT (p.Leu15Pro)	NDNF	Uncertain significance	criteria provided, single submitter
3185942	NM_024574.4(NDNF):c.1021A>G (p.Lys341Glu)	NDNF	Uncertain significance	criteria provided, multiple submitters, no conflicts
3255171	NM_024574.4(NDNF):c.825A>C (p.Lys275Asn)	NDNF	Uncertain significance	criteria provided, multiple submitters, no conflicts
4056642	NM_024574.4(NDNF):c.676_677insGAGA (p.Ala226fs)	NDNF	Uncertain significance	criteria provided, single submitter
1244379	NM_024574.4(NDNF):c.1567C>T (p.Leu523=)	NDNF	Benign	criteria provided, multiple submitters, no conflicts
1321859	NM_024574.4(NDNF):c.1392A>G (p.Ser464=)	NDNF	Benign	criteria provided, multiple submitters, no conflicts
1321860	NM_024574.4(NDNF):c.1035A>C (p.Leu345=)	NDNF	Benign	criteria provided, multiple submitters, no conflicts
1321861	NM_024574.4(NDNF):c.939T>C (p.Asp313=)	NDNF	Benign	criteria provided, multiple submitters, no conflicts
1321862	NM_024574.4(NDNF):c.435A>G (p.Leu145=)	NDNF	Benign	criteria provided, multiple submitters, no conflicts
1321863	NM_024574.4(NDNF):c.186G>A (p.Lys62=)	NDNF	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
NDNF	Strong	Autosomal dominant	hypogonadotropic hypogonadism 25 with anosmia	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDNF	Orphanet:478	Kallmann syndrome

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
NDNF	HGNC:26256	ENSG00000173376	Q8TB73	Protein NDNF	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDNF	Protein NDNF	Secretory protein that plays a role in various cellular processes.

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NDNF	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, NDNF

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephric glomerulus	1
renal glomerulus	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDNF	230	broad	marker	renal glomerulus, metanephric glomerulus, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDNF	673

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NDNF	Q8TB73	78.58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
gonadotrophin-releasing hormone neuronal migration to the hypothalamus	1	2808.7×	0.003	NDNF
vascular wound healing	1	1872.4×	0.003	NDNF
obsolete nitric oxide mediated signal transduction	1	1296.3×	0.003	NDNF
cellular response to fibroblast growth factor stimulus	1	543.6×	0.004	NDNF
positive regulation of cell-substrate adhesion	1	495.6×	0.004	NDNF
negative regulation of endothelial cell apoptotic process	1	495.6×	0.004	NDNF
response to ischemia	1	251.5×	0.007	NDNF
positive regulation of neuron projection development	1	137.0×	0.010	NDNF
neuron migration	1	133.8×	0.010	NDNF
extracellular matrix organization	1	122.1×	0.010	NDNF
cellular response to hypoxia	1	121.2×	0.010	NDNF
negative regulation of neuron apoptotic process	1	110.9×	0.010	NDNF
angiogenesis	1	62.4×	0.016	NDNF

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
NDNF	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	1	NDNF
E	Difficult family or no structure, no drug	0

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)
NDNF	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.