46,XX ovarian dysgenesis-short stature syndrome

Summary

46,XX ovarian dysgenesis-short stature syndrome (MONDO:0014520) is a disease caused by MCM9 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MCM9 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	46,XX ovarian dysgenesis-short stature syndrome
Mondo ID	MONDO:0014520
OMIM	616185
Orphanet	444048
DOID	DOID:0080496
UMLS	C4015409
MedGen	863846
GARD	0017760
Is cancer (heuristic)	no

Also known as: ODG4 · ovarian dysgenesis 4

Data availability: 14 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inherited primary ovarian failure › 46,XX ovarian dysgenesis-short stature syndrome

Related subtypes (40): blepharophimosis, ptosis, and epicanthus inversus syndrome, congenital lipoid adrenal hyperplasia due to STAR deficency, ataxia telangiectasia, classic galactosemia, 46 XX gonadal dysgenesis, premature ovarian failure 2A, premature ovarian failure 2B, premature ovarian failure 1, Satoyoshi syndrome, premature ovarian failure 3, osteosclerosis-ichthyosis-premature ovarian failure syndrome, premature ovarian failure 5, premature ovarian failure 6, premature ovarian failure 7, aromatase deficiency, premature ovarian failure 8, premature ovarian failure 9, premature ovarian failure 11, premature ovarian failure 12, Perrault syndrome, trisomy X, Turner syndrome, tetrasomy X, X small rings, premature ovarian failure 17, premature ovarian failure 18, premature ovarian failure 20, premature ovarian failure 19, premature ovarian failure 16, premature ovarian failure 13, premature ovarian failure 10, premature ovarian failure 14, premature ovarian failure 15, premature ovarian failure 4, premature ovarian failure 21, premature ovarian failure 22, premature ovarian failure 23, premature ovarian failure 24, premature ovarian failure 25, premature ovarian failure 26

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

14 retrieved; paginated sample, class counts are floors:

4 likely pathogenic, 3 uncertain significance, 3 pathogenic, 2 pathogenic/likely pathogenic, 1 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
156587	NM_017696.3(MCM9):c.1732+2T>C	MCM9	Pathogenic	criteria provided, single submitter
156588	NM_017696.3(MCM9):c.394C>T (p.Arg132Ter)	MCM9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709346	NM_017696.3(MCM9):c.1151-1G>A	MCM9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3254813	NM_017696.3(MCM9):c.672_673delinsC (p.Glu225fs)	MCM9	Pathogenic	criteria provided, single submitter
417973	NM_017696.3(MCM9):c.1483G>T (p.Glu495Ter)	MCM9	Pathogenic	no assertion criteria provided
3254812	NM_017696.3(MCM9):c.1529-7C>G	MCM9	Likely pathogenic	criteria provided, single submitter
3779839	NM_017696.3(MCM9):c.1556G>A (p.Trp519Ter)	MCM9	Likely pathogenic	criteria provided, single submitter
3779840	NM_017696.3(MCM9):c.139_140del (p.Leu47fs)	MCM9	Likely pathogenic	criteria provided, single submitter
3897556	NM_017696.3(MCM9):c.754C>T (p.Gln252Ter)	MCM9	Likely pathogenic	criteria provided, single submitter
1299227	NM_017696.3(MCM9):c.503G>A (p.Arg168Gln)	MCM9	Uncertain significance	criteria provided, multiple submitters, no conflicts
4538451	NM_017696.3(MCM9):c.163G>A (p.Gly55Arg)	MCM9	Uncertain significance	no assertion criteria provided
812138	NM_017696.3(MCM9):c.220C>T (p.Arg74Ter)	MCM9	Uncertain significance	criteria provided, single submitter
1321160	NM_017696.3(MCM9):c.1673G>C (p.Cys558Ser)	MCM9	Benign	criteria provided, single submitter
789184	NM_017696.3(MCM9):c.1272G>A (p.Arg424=)	MCM9	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
MCM9	Definitive	Autosomal recessive	premature ovarian failure 10	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MCM9	Orphanet:444048	46,XX ovarian dysgenesis-short stature 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
MCM9	HGNC:21484	ENSG00000111877	Q9NXL9	DNA helicase MCM9	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MCM9	DNA helicase MCM9	Component of the MCM8-MCM9 complex, which is involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MCM9	Other/Unknown	no		MCM_dom, AAA+_ATPase, NA-bd_OB-fold

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
bronchial epithelial cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MCM9	233	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MCM9	2,092

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCM9	Q9NXL9	6

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
recombinational interstrand cross-link repair	1	8426.0×	4e-04	MCM9
mismatch repair involved in maintenance of fidelity involved in DNA-dependent DNA replication	1	8426.0×	4e-04	MCM9
female gamete generation	1	802.5×	0.002	MCM9
protein localization to chromatin	1	581.1×	0.003	MCM9
double-strand break repair via homologous recombination	1	156.0×	0.008	MCM9
DNA damage response	1	53.5×	0.019	MCM9

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
MCM9	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	MCM9

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)
MCM9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.