46 XX gonadal dysgenesis

Summary

46 XX gonadal dysgenesis (MONDO:0009299) is a disease (an umbrella term covering 11 Mondo subtypes) with 10 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Umbrella term: 11 Mondo subtypes
• Cohort genes: 10
• ClinVar variants: 4
• Phenotypes (HPO): 25

Clinical features

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0000133	Gonadal dysgenesis	Obligate (100%)
HP:0008209	Premature ovarian insufficiency	Obligate (100%)
HP:0000144	Decreased fertility	Very frequent (80-99%)
HP:0000786	Primary amenorrhea	Very frequent (80-99%)
HP:0000823	Delayed puberty	Very frequent (80-99%)
HP:0000837	Increased circulating gonadotropin level	Very frequent (80-99%)
HP:0008214	Decreased serum estradiol	Very frequent (80-99%)
HP:0009888	Abnormality of secondary sexual hair	Very frequent (80-99%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0002225	Sparse pubic hair	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0004349	Reduced bone mineral density	Frequent (30-79%)
HP:0005625	Osteoporosis of vertebrae	Frequent (30-79%)
HP:0008684	Aplasia/hypoplasia of the uterus	Frequent (30-79%)
HP:0010311	Aplasia/Hypoplasia of the breasts	Frequent (30-79%)
HP:0010464	Streak ovary	Frequent (30-79%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000869	Secondary amenorrhea	Occasional (5-29%)
HP:0001939	Abnormality of metabolism/homeostasis	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0000062	Ambiguous genitalia	Excluded (0%)
HP:0000252	Microcephaly	Very rare (<1-4%)
HP:0001166	Arachnodactyly	Very rare (<1-4%)
HP:0001251	Ataxia	Very rare (<1-4%)
HP:0002206	Pulmonary fibrosis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	46 XX gonadal dysgenesis
Mondo ID	MONDO:0009299
MeSH	D023961
OMIM	233300
Orphanet	243
DOID	DOID:14450
ICD-11	1742528605
NCIT	C120197
SNOMED CT	95198001
UMLS	C0685837
MedGen	146899
GARD	0005671
Is cancer (heuristic)	no

Also known as: 46,XX complete gonadal dysgenesis · 46,XX gonadal dysgenesis · 46,XX ovarian dysgenesis · 46,XX pure gonadal dysgenesis · follicular stimulating hormone-resistant ovaries · FSH-RO · hypergonadotropic ovarian dysgenesis · XX female gonadal dysgenesis · XX-GD

Data availability: 4 ClinVar variants · 9 GenCC gene-disease records · 1 cell line.

Disease family

An umbrella term covering 11 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › hypogonadism › gonadal dysgenesis › 46 XX gonadal dysgenesis

Related subtypes (4): testicular dysgenesis syndrome, 46,XY complete gonadal dysgenesis, 45,X/46,XY mixed gonadal dysgenesis, Turner syndrome

Subtypes (11): ovarian dysgenesis 2, SERKAL syndrome, ovarian dysgenesis 3, ovarian dysgenesis 7, ovarian dysgenesis 1, ovarian dysgenesis 9, ovarian dysgenesis 10, ovarian dysgenesis 8, ovarian dysgenesis 5, ovarian dysgenesis 6, ovarian dysgenesis 11

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:

1 uncertain significance, 1 likely pathogenic, 1 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
432184	NM_020191.4(MRPS22):c.878+1G>T	MRPS22	Pathogenic	criteria provided, multiple submitters, no conflicts
3780497	NM_016556.4(PSMC3IP):c.310C>T (p.Gln104Ter)	PSMC3IP	Likely pathogenic	criteria provided, single submitter
441255	NM_020191.4(MRPS22):c.605G>A (p.Arg202His)	MRPS22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3778907	NM_001717.4(BNC1):c.2116G>A (p.Val706Met)	BNC1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 58 · Orphanet: 19 · 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
BMP15	Strong	X-linked	ovarian dysgenesis 2	4
FSHR	Strong	Autosomal recessive	ovarian dysgenesis 1	5
MRPS22	Strong	Autosomal recessive	ovarian dysgenesis 7	7
NUP107	Strong	Autosomal recessive	ovarian dysgenesis 6	11
PSMC3IP	Strong	Autosomal recessive	ovarian dysgenesis 3	4
SPIDR	Moderate	Autosomal recessive	ovarian dysgenesis 9	5
ASIC2	Supportive	Autosomal dominant	46 XX gonadal dysgenesis	4
BNC1	Supportive	Autosomal dominant	46 XX gonadal dysgenesis	4
NR5A1	Supportive	Autosomal dominant	46,XY complete gonadal dysgenesis	12
POLR3H	Supportive	Autosomal dominant	46 XX gonadal dysgenesis	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BNC1	Orphanet:243	46,XX gonadal dysgenesis
MRPS22	Orphanet:137908	Hypotonia with lactic acidemia and hyperammonemia
MRPS22	Orphanet:243	46,XX gonadal dysgenesis
PSMC3IP	Orphanet:243	46,XX gonadal dysgenesis
BMP15	Orphanet:243	46,XX gonadal dysgenesis
BMP15	Orphanet:398987	Malignant teratoma of ovary
SPIDR	Orphanet:243	46,XX gonadal dysgenesis
NUP107	Orphanet:2065	Galloway-Mowat syndrome
NUP107	Orphanet:243	46,XX gonadal dysgenesis
NUP107	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
POLR3H	Orphanet:243	46,XX gonadal dysgenesis
FSHR	Orphanet:243	46,XX gonadal dysgenesis
FSHR	Orphanet:64739	Ovarian hyperstimulation syndrome
NR5A1	Orphanet:2138	46,XX ovotesticular difference of sex development
NR5A1	Orphanet:242	46,XY complete gonadal dysgenesis
NR5A1	Orphanet:243	46,XX gonadal dysgenesis
NR5A1	Orphanet:251510	46,XY partial gonadal dysgenesis
NR5A1	Orphanet:393	46,XX testicular difference of sex development
NR5A1	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BNC1	HGNC:1081	ENSG00000169594	Q01954	Zinc finger protein basonuclin-1	gencc,clinvar
MRPS22	HGNC:14508	ENSG00000175110	P82650	Small ribosomal subunit protein mS22	gencc,clinvar
PSMC3IP	HGNC:17928	ENSG00000131470	Q9P2W1	Homologous-pairing protein 2 homolog	gencc,clinvar
ASIC2	HGNC:99	ENSG00000108684	Q16515	Acid-sensing ion channel 2	gencc,clinvar
BMP15	HGNC:1068	ENSG00000130385	O95972	Bone morphogenetic protein 15	gencc
SPIDR	HGNC:28971	ENSG00000164808	Q14159	DNA repair-scaffolding protein	gencc
NUP107	HGNC:29914	ENSG00000111581	P57740	Nuclear pore complex protein Nup107	gencc
POLR3H	HGNC:30349	ENSG00000100413	Q9Y535	DNA-directed RNA polymerase III subunit RPC8	gencc
FSHR	HGNC:3969	ENSG00000170820	P23945	Follicle-stimulating hormone receptor	gencc
NR5A1	HGNC:7983	ENSG00000136931	Q13285	Steroidogenic factor 1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BNC1	Zinc finger protein basonuclin-1	Transcriptional activator.
PSMC3IP	Homologous-pairing protein 2 homolog	Plays an important role in meiotic recombination.
ASIC2	Acid-sensing ion channel 2	Forms pH-gated trimeric sodium channels that act as postsynaptic excitatory sensors in the nervous system.
BMP15	Bone morphogenetic protein 15	May be involved in follicular development.
SPIDR	DNA repair-scaffolding protein	Plays a role in DNA double-strand break (DBS) repair via homologous recombination (HR).
NUP107	Nuclear pore complex protein Nup107	Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance.
POLR3H	DNA-directed RNA polymerase III subunit RPC8	DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.
FSHR	Follicle-stimulating hormone receptor	G protein-coupled receptor for follitropin, the follicle-stimulating hormone.
NR5A1	Steroidogenic factor 1	Transcriptional activator.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 6 · 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
Nuclear receptor	1	38.6×	0.128
GPCR	1	2.4×	0.657
Scaffold/PPI	1	1.7×	0.657
Other/Unknown	6	1.1×	0.657
Transcription factor	1	0.8×	0.725

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BNC1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Disconnected-like
MRPS22	Other/Unknown	no		Ribosomal_mS22
PSMC3IP	Other/Unknown	no		Hop2_WH_dom, WH-like_DNA-bd_sf, LZ3wCH
ASIC2	Other/Unknown	no		ENaC, ENaC_chordates, ENaC_CS
BMP15	Other/Unknown	no		TGF-b_C, TGF-beta-like, TGFb_CS
SPIDR	Scaffold/PPI	no		DUF4502, DUF4503, DNA_repair-scaffolding
NUP107	Other/Unknown	no		Nup84/Nup107
POLR3H	Other/Unknown	no		RNAP_E/RPC8, Rpb7-like_N, NA-bd_OB-fold
FSHR	GPCR	yes		GPCR_Rhodpsn, LRRNT, Gphrmn_rcpt_fam
NR5A1	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt

Expression context

Cohort genes with no expression data: 0.

8 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)	1
broad (>20)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right adrenal gland	2
right adrenal gland cortex	2
anterior cingulate cortex	2
prefrontal cortex	2
oocyte	2
secondary oocyte	2
germinal epithelium of ovary	1
parietal pleura	1
primordial germ cell in gonad	1
adrenal tissue	1
left testis	1
right testis	1
tendon of biceps brachii	1
cingulate cortex	1
pancreatic ductal cell	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
right uterine tube	1
ventricular zone	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BNC1	117	broad	marker	germinal epithelium of ovary, parietal pleura, primordial germ cell in gonad
MRPS22	289	ubiquitous	marker	adrenal tissue, right adrenal gland, right adrenal gland cortex
PSMC3IP	268	ubiquitous	marker	tendon of biceps brachii, left testis, right testis
ASIC2	131	tissue_specific	marker	prefrontal cortex, cingulate cortex, anterior cingulate cortex
BMP15	8		yes	secondary oocyte, oocyte, pancreatic ductal cell
SPIDR	285	ubiquitous	marker	right hemisphere of cerebellum, right uterine tube, cerebellar hemisphere
NUP107	283	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
POLR3H	232	ubiquitous	marker	prefrontal cortex, anterior cingulate cortex, right frontal lobe
FSHR	98	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, lower esophagus mucosa, apex of heart
NR5A1	77	tissue_specific	yes	right adrenal gland cortex, right adrenal gland, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NUP107	3,524
MRPS22	2,985
NR5A1	2,146
FSHR	1,667
POLR3H	1,630
BMP15	1,566
ASIC2	1,493
PSMC3IP	1,212
SPIDR	652
BNC1	471

Intra-cohort edges

A	B	Sources
BMP15	FSHR	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPS22	P82650	77
POLR3H	Q9Y535	29
NUP107	P57740	7
NR5A1	Q13285	6
FSHR	P23945	5
ASIC2	Q16515	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PSMC3IP	Q9P2W1	92.45
BMP15	O95972	72.64
SPIDR	Q14159	62.19
BNC1	Q01954	54.85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 81. Enrichment computed across 10 evidence-associated genes (9 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 9 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	105.7×	0.073	FSHR
Transcriptional regulation of testis differentiation	1	79.3×	0.073	NR5A1
Resolution of D-Loop Structures	1	70.5×	0.073	SPIDR
RNA Polymerase III Chain Elongation	1	70.5×	0.073	POLR3H
Transcriptional regulation of pluripotent stem cells	1	60.4×	0.073	NR5A1
RNA Polymerase III Transcription Termination	1	55.2×	0.073	POLR3H
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	47.0×	0.073	POLR3H
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	45.3×	0.073	POLR3H
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	45.3×	0.073	POLR3H
Postmitotic nuclear pore complex (NPC) reformation	1	45.3×	0.073	NUP107
IPs transport between nucleus and cytosol	1	42.3×	0.073	NUP107
IP3 and IP4 transport between cytosol and nucleus	1	42.3×	0.073	NUP107
IP6 and IP7 transport between cytosol and nucleus	1	42.3×	0.073	NUP107
Transport of Ribonucleoproteins into the Host Nucleus	1	39.6×	0.073	NUP107
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	39.6×	0.073	NUP107
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	39.6×	0.073	NUP107
NEP/NS2 Interacts with the Cellular Export Machinery	1	38.5×	0.073	NUP107
Nuclear import of Rev protein	1	37.3×	0.073	NUP107
Vpr-mediated nuclear import of PICs	1	37.3×	0.073	NUP107
SUMOylation of intracellular receptors	1	37.3×	0.073	NR5A1
RNA Polymerase III Transcription Initiation	1	37.3×	0.073	POLR3H
Transport of the SLBP independent Mature mRNA	1	36.2×	0.073	NUP107
SUMOylation of SUMOylation proteins	1	36.2×	0.073	NUP107
RNA Polymerase III Transcription	1	36.2×	0.073	POLR3H
Transport of the SLBP Dependant Mature mRNA	1	35.2×	0.073	NUP107
Rev-mediated nuclear export of HIV RNA	1	35.2×	0.073	NUP107
Nuclear Pore Complex (NPC) Disassembly	1	34.3×	0.073	NUP107
Homology Directed Repair	1	34.3×	0.073	SPIDR
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	34.3×	0.073	SPIDR
Resolution of D-loop Structures through Holliday Junction Intermediates	1	33.4×	0.073	SPIDR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
female gonad development	3	240.7×	2e-05	NUP107, FSHR, NR5A1
female gamete generation	2	160.5×	0.003	BMP15, FSHR
meiotic joint molecule formation	1	1685.2×	0.009	PSMC3IP
meiotic strand invasion involved in reciprocal meiotic recombination	1	1685.2×	0.009	PSMC3IP
regulation of acetylcholine metabolic process	1	1685.2×	0.009	FSHR
regulation of establishment of protein localization to chromosome	1	1685.2×	0.009	SPIDR
hormone-mediated signaling pathway	2	80.2×	0.009	FSHR, NR5A1
primary ovarian follicle growth	1	842.6×	0.011	FSHR
regulation of systemic arterial blood pressure by aortic arch baroreceptor feedback	1	842.6×	0.011	ASIC2
primary sex determination	1	842.6×	0.011	NR5A1
regulation of platelet-derived growth factor receptor signaling pathway	1	842.6×	0.011	FSHR
post-transcriptional tethering of RNA polymerase II gene DNA at nuclear periphery	1	561.7×	0.011	NUP107
follicle-stimulating hormone signaling pathway	1	561.7×	0.011	FSHR
response to gonadotropin-releasing hormone	1	561.7×	0.011	NR5A1
positive regulation of oocyte maturation	1	561.7×	0.011	BNC1
male gonad development	2	31.2×	0.011	FSHR, NR5A1
regulation of transcription by RNA polymerase I	1	421.3×	0.013	BNC1
obsolete regulation of protein kinase A signaling	1	421.3×	0.013	FSHR
negative regulation of female gonad development	1	421.3×	0.013	NR5A1
regulation of hormone metabolic process	1	337.0×	0.014	FSHR
cellular response to camptothecin	1	337.0×	0.014	SPIDR
detection of mechanical stimulus involved in sensory perception	1	280.9×	0.016	ASIC2
Sertoli cell proliferation	1	280.9×	0.016	FSHR
transcription initiation at RNA polymerase III promoter	1	240.7×	0.017	POLR3H
intracellular water homeostasis	1	240.7×	0.017	FSHR
luteinization	1	187.2×	0.018	NR5A1
tissue development	1	187.2×	0.018	NR5A1
nephron development	1	187.2×	0.018	NUP107
sex determination	1	168.5×	0.018	NR5A1
transcytosis	1	168.5×	0.018	FSHR

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 10

Druggability breadth: 3 of 10 evidence-associated genes (30%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BNC1	0	0
MRPS22	0	0
PSMC3IP	0	0
ASIC2	0	0
BMP15	0	0
SPIDR	0	0
NUP107	0	0
POLR3H	0	0
FSHR	0	0
NR5A1	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
NR5A1	88	Binding:84, Functional:4
FSHR	43	Functional:26, Binding:17
MRPS22	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; 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	2	FSHR, NR5A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	8	BNC1, MRPS22, PSMC3IP, ASIC2, BMP15, SPIDR, NUP107, POLR3H

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BNC1	0	—
MRPS22	1	—
PSMC3IP	0	—
ASIC2	0	—
BMP15	0	—
SPIDR	0	—
NUP107	0	—
POLR3H	0	—
FSHR	43	—
NR5A1	88	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.