Ovarian dysgenesis 3

Summary

Ovarian dysgenesis 3 (MONDO:0013689) is a disease caused by PSMC3IP (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: PSMC3IP (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 13

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ovarian dysgenesis 3
Mondo ID	MONDO:0013689
OMIM	614324
DOID	DOID:0080495
UMLS	C3280471
MedGen	482101
GARD	0018041
Is cancer (heuristic)	no

Also known as: 46 XX gonadal dysgenesis caused by mutation in PSMC3IP · ODG3 · ovarian dysgenesis 3 · ovarian dysgenesis type 3 · PSMC3IP 46 XX gonadal dysgenesis

Data availability: 13 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › hypogonadism › gonadal dysgenesis › 46 XX gonadal dysgenesis › ovarian dysgenesis 3

Related subtypes (10): ovarian dysgenesis 2, SERKAL syndrome, 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

13 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
30741	NM_016556.4(PSMC3IP):c.600_602del	MLX	Pathogenic	no assertion criteria provided
812136	NM_016556.4(PSMC3IP):c.614del (p.Glu205fs)	MLX	Pathogenic	criteria provided, single submitter
3901233	PSMC3IP, TYR163TER	PSMC3IP	Pathogenic	no assertion criteria provided
3901234	PSMC3IP, 2-BP INS, 430GA	PSMC3IP	Pathogenic	no assertion criteria provided
3901235	PSMC3IP, 2-BP DEL, 496CT	PSMC3IP	Pathogenic	no assertion criteria provided
3901236	D90H	PSMC3IP	Pathogenic	no assertion criteria provided
3901237	c.597+1G-T	PSMC3IP	Pathogenic	no assertion criteria provided
3901240	NM_016556.4(PSMC3IP):c.215T>C (p.Phe72Ser)	PSMC3IP	Pathogenic	no assertion criteria provided
3342726	NM_016556.4(PSMC3IP):c.203AGA[1] (p.Lys69del)	PSMC3IP	Likely pathogenic	criteria provided, single submitter
1501945	NM_016556.4(PSMC3IP):c.189G>T (p.Lys63Asn)	PSMC3IP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
375625	NM_001330078.2(NRXN1):c.162G>A (p.Met54Ile)	NRXN1	Uncertain significance	criteria provided, single submitter
801407	NM_016556.4(PSMC3IP):c.-35C>T	PSMC3IP	Uncertain significance	criteria provided, single submitter
1285798	NM_016556.4(PSMC3IP):c.338-15C>G	PSMC3IP	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · 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
PSMC3IP	Strong	Autosomal recessive	ovarian dysgenesis 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PSMC3IP	Orphanet:243	46,XX gonadal dysgenesis
MLX	Orphanet:3287	Takayasu arteritis
NRXN1	Orphanet:600663	NRXN1-related severe neurodevelopmental disorder-motor stereotypies-chronic constipation-sleep-wake cycle disturbance

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PSMC3IP	HGNC:17928	ENSG00000131470	Q9P2W1	Homologous-pairing protein 2 homolog	gencc,clinvar
MLX	HGNC:11645	ENSG00000108788	Q9UH92	Max-like protein X	clinvar
NRXN1	HGNC:8008	ENSG00000179915	P58400	Neurexin-1-beta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PSMC3IP	Homologous-pairing protein 2 homolog	Plays an important role in meiotic recombination.
MLX	Max-like protein X	Transcription regulator.
NRXN1	Neurexin-1-beta	Neuronal cell surface protein involved in cell recognition and cell adhesion by forming intracellular junctions through binding to neuroligins.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PSMC3IP	Other/Unknown	no		Hop2_WH_dom, WH-like_DNA-bd_sf, LZ3wCH
MLX	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, Max-like/E-box_TFs
NRXN1	Other/Unknown	no		Laminin_G, Neurexin-like, ConA-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right testis	1
tendon of biceps brachii	1
oocyte	1
parotid gland	1
secondary oocyte	1
cortical plate	1
middle temporal gyrus	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSMC3IP	268	ubiquitous	marker	tendon of biceps brachii, left testis, right testis
MLX	294	ubiquitous	marker	oocyte, secondary oocyte, parotid gland
NRXN1	222	broad	marker	sural nerve, cortical plate, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PSMC3IP	1,212
MLX	893
NRXN1	120

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NRXN1	P58400	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PSMC3IP	Q9P2W1	92.45
MLX	Q9UH92	73.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ChREBP activates metabolic gene expression	1	423.0×	0.014	MLX
Neurexins and neuroligins	1	65.6×	0.028	NRXN1
Integration of energy metabolism	1	58.6×	0.028	MLX
Non-integrin membrane-ECM interactions	1	51.4×	0.028	NRXN1
Meiotic recombination	1	43.3×	0.028	PSMC3IP
Metabolism	1	3.9×	0.237	MLX

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
meiotic joint molecule formation	1	5617.3×	0.002	PSMC3IP
meiotic strand invasion involved in reciprocal meiotic recombination	1	5617.3×	0.002	PSMC3IP
obsolete positive regulation of cAMP-mediated signaling	1	5617.3×	0.002	NRXN1
protein-containing complex assembly involved in synapse maturation	1	5617.3×	0.002	NRXN1
positive regulation of presynaptic active zone assembly	1	5617.3×	0.002	NRXN1
guanylate kinase-associated protein clustering	1	2808.7×	0.004	NRXN1
neuroligin clustering involved in postsynaptic membrane assembly	1	1872.4×	0.004	NRXN1
positive regulation of neuromuscular synaptic transmission	1	1872.4×	0.004	NRXN1
negative regulation of filopodium assembly	1	1123.5×	0.004	NRXN1
gamma-aminobutyric acid receptor clustering	1	1123.5×	0.004	NRXN1
NMDA glutamate receptor clustering	1	1123.5×	0.004	NRXN1
gephyrin clustering involved in postsynaptic density assembly	1	1123.5×	0.004	NRXN1
AMPA selective glutamate receptor signaling pathway	1	1123.5×	0.004	NRXN1
postsynaptic density protein 95 clustering	1	936.2×	0.004	NRXN1
neuronal signal transduction	1	802.5×	0.004	NRXN1
postsynaptic membrane assembly	1	802.5×	0.004	NRXN1
NMDA selective glutamate receptor signaling pathway	1	802.5×	0.004	NRXN1
positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway	1	802.5×	0.004	NRXN1
cerebellar granule cell differentiation	1	702.2×	0.004	NRXN1
vocal learning	1	702.2×	0.004	NRXN1
receptor localization to synapse	1	702.2×	0.004	NRXN1
positive regulation of synapse maturation	1	624.1×	0.004	NRXN1
presynaptic membrane assembly	1	561.7×	0.005	NRXN1
positive regulation of fibroblast growth factor receptor signaling pathway	1	510.7×	0.005	NRXN1
synaptic vesicle clustering	1	468.1×	0.005	NRXN1
neuron cell-cell adhesion	1	330.4×	0.007	NRXN1
positive regulation of synaptic transmission, GABAergic	1	330.4×	0.007	NRXN1
vocalization behavior	1	295.6×	0.007	NRXN1
protein localization to synapse	1	255.3×	0.008	NRXN1
neurotransmitter secretion	1	234.1×	0.009	NRXN1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MLX	1	1
PSMC3IP	0	0
NRXN1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GDC-0152	1	MLX

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MLX	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
GDC-0152	1	MLX

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	1	MLX
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	PSMC3IP, NRXN1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PSMC3IP	0	—
NRXN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.