Gonadal dysgenesis

Summary

Gonadal dysgenesis (MONDO:0001967) is a disease (an umbrella term covering 5 Mondo subtypes) with 5 cohort genes and 4 clinical trials.

At a glance

• Umbrella term: 5 Mondo subtypes
• Cohort genes: 5
• ClinVar variants: 4
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	gonadal dysgenesis
Mondo ID	MONDO:0001967
MeSH	D006059
DOID	DOID:14447
NCIT	C61420
SNOMED CT	205681004
UMLS	C0018051
MedGen	9075
GARD	0002538
Is cancer (heuristic)	no

Data availability: 4 ClinVar variants · 1 GenCC gene-disease record · 2 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › hypogonadism › gonadal dysgenesis

Related subtypes (5): eunuchism, hypogonadism, male, hypogonadotropic hypogonadism, Slti-Salem syndrome, weinstein kliman scully syndrome

Subtypes (5): testicular dysgenesis syndrome, 46 XX gonadal dysgenesis, 46,XY complete gonadal dysgenesis, 45,X/46,XY mixed gonadal dysgenesis, Turner syndrome

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

4 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
336482	NM_000145.4(FSHR):c.1330G>A (p.Ala444Thr)	FSHR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
693064	NC_012920.1(MT-ATP6):m.9049G>A	MT-ATP6	Uncertain significance	reviewed by expert panel
805947	NC_012920.1(MT-TE):m.14724G>A	MT-TE	Uncertain significance	reviewed by expert panel
1683718	NM_024426.6(WT1):c.1321G>C (p.Asp441His)	WT1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 20 · 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
SMC1B	Limited	Autosomal dominant	gonadal dysgenesis

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WT1	Orphanet:220	Denys-Drash syndrome
WT1	Orphanet:242	46,XY complete gonadal dysgenesis
WT1	Orphanet:251510	46,XY partial gonadal dysgenesis
WT1	Orphanet:3097	Meacham syndrome
WT1	Orphanet:347	Frasier syndrome
WT1	Orphanet:654	Nephroblastoma
WT1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
WT1	Orphanet:83469	Desmoplastic small round cell tumor
WT1	Orphanet:893	WAGR syndrome
FSHR	Orphanet:243	46,XX gonadal dysgenesis
FSHR	Orphanet:64739	Ovarian hyperstimulation syndrome
MT-ATP6	Orphanet:104	Leber hereditary optic neuropathy
MT-ATP6	Orphanet:225154	Familial infantile bilateral striatal necrosis
MT-ATP6	Orphanet:254913	Isolated ATP synthase deficiency
MT-ATP6	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ATP6	Orphanet:320360	MT-ATP6-related mitochondrial spastic paraplegia
MT-ATP6	Orphanet:397750	Periodic paralysis with later-onset distal motor neuropathy
MT-ATP6	Orphanet:644	NARP syndrome
MT-TE	Orphanet:254864	Mitochondrial myopathy with reversible cytochrome C oxidase deficiency
MT-TE	Orphanet:2596	Myopathy and diabetes mellitus

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMC1B	HGNC:11112	ENSG00000077935	Q8NDV3	Structural maintenance of chromosomes protein 1B	gencc
WT1	HGNC:12796	ENSG00000184937	P19544	Wilms tumor protein	clinvar
FSHR	HGNC:3969	ENSG00000170820	P23945	Follicle-stimulating hormone receptor	clinvar
MT-ATP6	HGNC:7414	ENSG00000198899	P00846	ATP synthase F(0) complex subunit a	clinvar
MT-TE	HGNC:7479	ENSG00000210194		mitochondrially encoded tRNA-Glu (GAA/G)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMC1B	Structural maintenance of chromosomes protein 1B	Meiosis-specific component of cohesin complex.
WT1	Wilms tumor protein	Transcription factor that plays an important role in cellular development and cell survival.
FSHR	Follicle-stimulating hormone receptor	G protein-coupled receptor for follitropin, the follicle-stimulating hormone.
MT-ATP6	ATP synthase F(0) complex subunit a	Subunit a, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of th…

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

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	4.8×	0.576
Transcription factor	1	1.6×	0.608
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMC1B	Other/Unknown	no		RecF/RecN/SMC_N, SMC_hinge, SMC
WT1	Transcription factor	no		Wilms_tumour_N, Znf_C2H2_type, Znf_C2H2_sf
FSHR	GPCR	yes		GPCR_Rhodpsn, LRRNT, Gphrmn_rcpt_fam
MT-ATP6	Other/Unknown	no		ATP_synth_F0_asu, ATP_synth_F0_asu_AS, F0_ATP_A_sf
MT-TE	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

5 cohort genes 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
apex of heart	2
left testis	1
right testis	1
germinal epithelium of ovary	1
metanephric glomerulus	1
renal glomerulus	1
lower esophagus mucosa	1
descending thoracic aorta	1
left uterine tube	1
mucosa of stomach	1
skeletal muscle tissue	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMC1B	31	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis
WT1	168	broad	marker	germinal epithelium of ovary, renal glomerulus, metanephric glomerulus
FSHR	98	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, lower esophagus mucosa, apex of heart
MT-ATP6	134	ubiquitous	marker	mucosa of stomach, left uterine tube, descending thoracic aorta
MT-TE	118	broad	marker	skeletal muscle tissue, sural nerve, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WT1	3,938
SMC1B	2,962
MT-ATP6	2,869
FSHR	1,667
MT-TE	0

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WT1	P19544	28
MT-ATP6	P00846	10
FSHR	P23945	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SMC1B	Q8NDV3	83.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Hormone ligand-binding receptors	1	237.9×	0.031	FSHR
Nephron development	1	219.6×	0.031	WT1
Transcriptional regulation of testis differentiation	1	178.4×	0.031	WT1
Formation of ATP by chemiosmotic coupling	1	142.8×	0.031	MT-ATP6
Cristae formation	1	86.5×	0.041	MT-ATP6
Meiosis	1	71.4×	0.042	SMC1B
Reproduction	1	47.6×	0.053	SMC1B
Mitochondrial biogenesis	1	42.0×	0.053	MT-ATP6
Meiotic synapsis	1	35.2×	0.054	SMC1B
Negative Regulation of CDH1 Gene Transcription	1	30.1×	0.054	WT1
Mitochondrial protein degradation	1	28.6×	0.054	MT-ATP6
Mitochondrial translation termination	1	27.4×	0.054	MT-ATP6
Aerobic respiration and respiratory electron transport	1	22.1×	0.062	MT-ATP6
G alpha (s) signalling events	1	18.3×	0.069	FSHR
Organelle biogenesis and maintenance	1	16.5×	0.071	MT-ATP6
Cell Cycle	1	9.0×	0.120	SMC1B
Metabolism of proteins	1	3.1×	0.302	MT-ATP6
Metabolism	1	2.9×	0.302	MT-ATP6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
gonad development	2	561.7×	4e-04	WT1, FSHR
regulation of acetylcholine metabolic process	1	4213.0×	0.004	FSHR
negative regulation of metanephric glomerular mesangial cell proliferation	1	4213.0×	0.004	WT1
primary ovarian follicle growth	1	2106.5×	0.004	FSHR
regulation of animal organ formation	1	2106.5×	0.004	WT1
regulation of platelet-derived growth factor receptor signaling pathway	1	2106.5×	0.004	FSHR
adrenal cortex formation	1	2106.5×	0.004	WT1
visceral serous pericardium development	1	2106.5×	0.004	WT1
posterior mesonephric tubule development	1	2106.5×	0.004	WT1
positive regulation of metanephric ureteric bud development	1	2106.5×	0.004	WT1
male gonad development	2	78.0×	0.004	WT1, FSHR
follicle-stimulating hormone signaling pathway	1	1404.3×	0.005	FSHR
obsolete regulation of protein kinase A signaling	1	1053.2×	0.005	FSHR
positive regulation of heart growth	1	1053.2×	0.005	WT1
metanephric S-shaped body morphogenesis	1	1053.2×	0.005	WT1
negative regulation of female gonad development	1	1053.2×	0.005	WT1
thorax and anterior abdomen determination	1	842.6×	0.005	WT1
regulation of hormone metabolic process	1	842.6×	0.005	FSHR
cardiac muscle cell fate commitment	1	842.6×	0.005	WT1
metanephric epithelium development	1	842.6×	0.005	WT1
Sertoli cell proliferation	1	702.2×	0.006	FSHR
cellular response to gonadotropin stimulus	1	702.2×	0.006	WT1
intracellular water homeostasis	1	601.9×	0.006	FSHR
metanephric mesenchyme development	1	601.9×	0.006	WT1
tissue development	1	468.1×	0.007	WT1
diaphragm development	1	468.1×	0.007	WT1
sex determination	1	421.3×	0.007	WT1
transcytosis	1	421.3×	0.007	FSHR
positive regulation of male gonad development	1	421.3×	0.007	WT1
glomerular basement membrane development	1	383.0×	0.007	WT1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMC1B	0	0
WT1	0	0
FSHR	0	0
MT-ATP6	0	0
MT-TE	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
FSHR	43	Functional:26, Binding:17
MT-ATP6	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	1	FSHR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	SMC1B, WT1, MT-ATP6, MT-TE

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SMC1B	0	—
WT1	0	—
FSHR	43	—
MT-ATP6	1	—
MT-TE	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	2
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00001221	PHASE2	COMPLETED	Effect of Biosynthetic Growth Hormone and/or Ethinyl Estradiol on Adult Height in Patients With Turner Syndrome
NCT00001253	PHASE2	COMPLETED	The Effects of Estrogen on Cognition in Girls With Turner Syndrome
NCT04189406	Not specified	UNKNOWN	Turner Syndrome Minipuberty Study
NCT06687252	Not specified	COMPLETED	Retrospective Analysis of the Neonatal Management of Patients with an Antenatal Diagnosis of Genital Development Variation At the Hospital of Lyon