Hypogonadotropic hypogonadism 26 with or without anosmia

Summary

Hypogonadotropic hypogonadism 26 with or without anosmia (MONDO:0030534) is a disease caused by TCF12 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TCF12 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 13

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 26 with or without anosmia
Mondo ID	MONDO:0030534
OMIM	619718
UMLS	C5676903
MedGen	1811919
GARD	0025597
Is cancer (heuristic)	no

Also known as: HH26

Data availability: 13 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 26 with or without 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 25 with 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

13 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
2582606	NM_207037.2(TCF12):c.1490_1491del (p.Ser497fs)	TCF12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4293067	NM_207037.2(TCF12):c.797dup (p.Tyr266Ter)	TCF12	Pathogenic	criteria provided, single submitter
871064	NM_207037.2(TCF12):c.1453C>T (p.Arg485Ter)	TCF12	Pathogenic	criteria provided, multiple submitters, no conflicts
2431576	NM_207037.2(TCF12):c.1621_1622del (p.Glu541fs)	TCF12	Likely pathogenic	criteria provided, single submitter
2572612	NM_207037.2(TCF12):c.222+1G>A	TCF12	Likely pathogenic	criteria provided, single submitter
3382394	NM_207037.2(TCF12):c.465dup (p.Tyr156fs)	TCF12	Likely pathogenic	criteria provided, single submitter
3382735	NM_207037.2(TCF12):c.1924del (p.Ile643fs)	TCF12	Likely pathogenic	criteria provided, single submitter
3577491	NM_207037.2(TCF12):c.1376T>A (p.Leu459Ter)	TCF12	Likely pathogenic	criteria provided, single submitter
3764696	NM_207037.2(TCF12):c.1727C>A (p.Ser576Ter)	TCF12	Likely pathogenic	criteria provided, single submitter
4082053	NM_207037.2(TCF12):c.654_657del (p.Ser219fs)	TCF12	Likely pathogenic	no assertion criteria provided
1192534	NM_207037.2(TCF12):c.1807C>T (p.Arg603Trp)	TCF12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3892611	NM_207037.2(TCF12):c.316A>C (p.Asn106His)	TCF12	Uncertain significance	criteria provided, single submitter
263279	NM_207037.2(TCF12):c.1950C>T (p.Val650=)	TCF12	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 2 · 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
TCF12	Strong	Autosomal dominant	hypogonadotropic hypogonadism 26 with or without anosmia	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCF12	Orphanet:209916	Extraskeletal myxoid chondrosarcoma
TCF12	Orphanet:35099	Non-syndromic bicoronal craniosynostosis

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
TCF12	HGNC:11623	ENSG00000140262	Q99081	Transcription factor 12	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TCF12	Transcription factor 12	Transcriptional regulator.

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)
TCF12	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, NeuroDiff_E-box_TFs

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
ganglionic eminence	1
periodontal ligament	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TCF12	295	ubiquitous	marker	periodontal ligament, ventricular zone, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TCF12	1,978

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TCF12	Q99081	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
TGFBR3 expression	1	456.8×	0.007	TCF12
Myogenesis	1	380.7×	0.007	TCF12
NGF-stimulated transcription	1	285.5×	0.007	TCF12
Negative Regulation of CDH1 Gene Transcription	1	120.2×	0.011	TCF12
CHD1 and CHD2 subfamily	1	108.8×	0.011	TCF12
RUNX1 regulates transcription of genes involved in differentiation of HSCs	1	95.2×	0.011	TCF12

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
response to gonadotropin-releasing hormone	1	5617.3×	0.002	TCF12
positive regulation of neuron differentiation	1	198.3×	0.020	TCF12
muscle organ development	1	166.8×	0.020	TCF12
gene expression	1	79.9×	0.031	TCF12
immune response	1	47.1×	0.036	TCF12
nervous system development	1	45.9×	0.036	TCF12
positive regulation of gene expression	1	38.7×	0.037	TCF12
cell differentiation	1	29.1×	0.043	TCF12
positive regulation of transcription by RNA polymerase II	1	14.9×	0.075	TCF12
regulation of transcription by RNA polymerase II	1	11.7×	0.086	TCF12

Therapeutics

Drug target analysis

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

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
TCF12	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
TCF12	1	Binding:1

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	TCF12

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)
TCF12	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.