Hypogonadotropic hypogonadism 22 with or without anosmia

Summary

Hypogonadotropic hypogonadism 22 with or without anosmia (MONDO:0014461) is a disease caused by FEZF1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: FEZF1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 22 with or without anosmia
Mondo ID	MONDO:0014461
OMIM	616030
DOID	DOID:0090081
UMLS	C4014988
MedGen	863425
GARD	0016050
Is cancer (heuristic)	no

Also known as: FEZF1 hypogonadotropic hypogonadism · HH22 · hypogonadotropic hypogonadism 22 with or without anosmia · hypogonadotropic hypogonadism 22, with or without anosmia · hypogonadotropic hypogonadism caused by mutation in FEZF1

Data availability: 3 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Kallmann syndrome › hypogonadotropic hypogonadism 22 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 8 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

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

3 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1339088	NM_001024613.4(FEZF1):c.263C>T (p.Ala88Val)	FEZF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4845207	NM_001024613.4(FEZF1):c.721dup (p.Ile241fs)	FEZF1	Uncertain significance	criteria provided, single submitter
1192039	NM_001024613.4(FEZF1):c.801+10A>T	FEZF1	Benign/Likely 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
FEZF1	Strong	Autosomal recessive	hypogonadotropic hypogonadism 22 with or without anosmia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FEZF1	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
FEZF1	HGNC:22788	ENSG00000128610	A0PJY2	Fez family zinc finger protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FEZF1	Fez family zinc finger protein 1	Transcription repressor.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FEZF1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf

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
caudate nucleus	1
hypothalamus	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FEZF1	52	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, hypothalamus, caudate nucleus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FEZF1	939

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FEZF1	A0PJY2	56.91

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
forebrain anterior/posterior pattern specification	1	4213.0×	0.002	FEZF1
cell dedifferentiation	1	2808.7×	0.002	FEZF1
interneuron migration	1	1532.0×	0.002	FEZF1
olfactory bulb development	1	766.0×	0.004	FEZF1
central nervous system neuron differentiation	1	601.9×	0.004	FEZF1
regulation of neurogenesis	1	401.2×	0.005	FEZF1
positive regulation of neuron differentiation	1	198.3×	0.008	FEZF1
axon guidance	1	90.6×	0.015	FEZF1
negative regulation of cell population proliferation	1	42.1×	0.029	FEZF1
positive regulation of DNA-templated transcription	1	27.9×	0.039	FEZF1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	FEZF1

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
FEZF1	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	FEZF1

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)
FEZF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.