46,XX ovotesticular disorder of sex development

Summary

46,XX ovotesticular disorder of sex development (MONDO:0016281) is a disease with 4 cohort genes. The dominant Reactome pathway is Transcriptional regulation of testis differentiation (3 cohort genes).

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 4
• Phenotypes (HPO): 14

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		500	Worldwide	Validated
Prevalence at birth	1-9 / 100 000	2.5	Worldwide	Validated
Point prevalence	1-9 / 100 000		Europe	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000008	Abnormal morphology of female internal genitalia	Very frequent (80-99%)
HP:0000022	Abnormality of male internal genitalia	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000046	Small scrotum	Very frequent (80-99%)
HP:0000047	Hypospadias	Very frequent (80-99%)
HP:0000048	Bifid scrotum	Very frequent (80-99%)
HP:0000062	Ambiguous genitalia	Very frequent (80-99%)
HP:0000130	Abnormality of the uterus	Very frequent (80-99%)
HP:0000144	Decreased fertility	Very frequent (80-99%)
HP:0000147	Polycystic ovaries	Very frequent (80-99%)
HP:0008736	Hypoplasia of penis	Very frequent (80-99%)
HP:0010459	True hermaphroditism	Very frequent (80-99%)
HP:0012856	Abnormal scrotal rugation	Very frequent (80-99%)
HP:0100779	Urogenital sinus anomaly	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	46,XX ovotesticular disorder of sex development
Mondo ID	MONDO:0016281
MeSH	D050090
Orphanet	2138
NCIT	C127167
SNOMED CT	18978002
UMLS	C5679613
MedGen	1814438
GARD	0016585
Is cancer (heuristic)	no

Also known as: 46,XX ovotesticular DSD · ovotesticular differences of sex development · ovotesticular disorders of sex development · ovotesticular DSD

Data availability: 4 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › disorder of sexual differentiation › 46,XX ovotesticular disorder of sex development

Related subtypes (7): gynecomastia disorder, true hermaphroditism, 46,XX disorder of sex development, sex chromosome disorder of sex development, 46 XY differences of sex development, indeterminate sex and/or pseudohermaphroditism, MCM9-related gametogenic failure

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 46 · Orphanet: 22 · 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
NR5A1	Moderate	Autosomal recessive	46,XX disorder of sex development	12
SOX9	Supportive	Autosomal dominant	46,XX ovotesticular disorder of sex development	13
SRY	Supportive	Autosomal dominant	46,XX ovotesticular disorder of sex development	8
SOX3	Limited	X-linked	46,XX ovotesticular disorder of sex development	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOX3	Orphanet:3157	Septo-optic dysplasia spectrum
SOX3	Orphanet:393	46,XX testicular difference of sex development
SOX3	Orphanet:67045	X-linked intellectual disability with isolated growth hormone deficiency
SOX3	Orphanet:79495	X-linked congenital generalized hypertrichosis
SOX3	Orphanet:90695	Non-acquired panhypopituitarism
SOX9	Orphanet:140	Campomelic dysplasia
SOX9	Orphanet:2138	46,XX ovotesticular difference of sex development
SOX9	Orphanet:242	46,XY complete gonadal dysgenesis
SOX9	Orphanet:251510	46,XY partial gonadal dysgenesis
SOX9	Orphanet:393	46,XX testicular difference of sex development
SOX9	Orphanet:718	Isolated Pierre Robin sequence
SRY	Orphanet:1772	45,X/46,XY mixed gonadal dysgenesis
SRY	Orphanet:2138	46,XX ovotesticular difference of sex development
SRY	Orphanet:242	46,XY complete gonadal dysgenesis
SRY	Orphanet:251510	46,XY partial gonadal dysgenesis
SRY	Orphanet:393	46,XX testicular difference of sex development
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

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SOX3	HGNC:11199	ENSG00000134595	P41225	Transcription factor SOX-3	gencc
SOX9	HGNC:11204	ENSG00000125398	P48436	Transcription factor SOX-9	gencc
SRY	HGNC:11311	ENSG00000184895	Q05066	Sex-determining region Y protein	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)
SOX3	Transcription factor SOX-3	Transcription factor required during the formation of the hypothalamo-pituitary axis.
SOX9	Transcription factor SOX-9	Transcription factor that plays a key role in chondrocytes differentiation and skeletal development.
SRY	Sex-determining region Y protein	Transcriptional regulator that controls a genetic switch in male development.
NR5A1	Steroidogenic factor 1	Transcriptional activator.

Protein-family classification

Druggable: 1 · Difficult: 3 · Unknown: 0 · Druggable fraction: 0.25

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	96.5×	0.010
Transcription factor	3	6.2×	0.010

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOX3	Transcription factor	no		HMG_box_dom, SOX_fam, HMG_box_dom_sf
SOX9	Transcription factor	no		HMG_box_dom, Sox_N, HMG_box_dom_sf
SRY	Transcription factor	no		HMG_box_dom, SRY, HMG_box_dom_sf
NR5A1	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt

Expression context

Cohort genes with no expression data: 0.

2 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	2
embryo	1
ganglionic eminence	1
cranial nerve II	1
hair follicle	1
primordial germ cell in gonad	1
right testis	1
tendon of biceps brachii	1
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOX3	72	broad	marker	ventricular zone, ganglionic eminence, embryo
SOX9	274	ubiquitous	marker	ventricular zone, cranial nerve II, hair follicle
SRY	66	tissue_specific	yes	primordial germ cell in gonad, tendon of biceps brachii, right testis
NR5A1	77	tissue_specific	yes	right adrenal gland cortex, right adrenal gland, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SOX9	4,935
SRY	2,835
NR5A1	2,146
SOX3	47

Intra-cohort edges

A	B	Sources
NR5A1	SOX9	biogrid_interaction, string_interaction
NR5A1	SRY	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SRY	Q05066	10
NR5A1	Q13285	6
SOX9	P48436	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SOX3	P41225	58.40

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 4 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
Transcriptional regulation of testis differentiation	3	535.3×	2e-07	SOX9, SRY, NR5A1
Deactivation of the beta-catenin transactivating complex	3	174.8×	3e-06	SOX3, SOX9, SRY
TCF dependent signaling in response to WNT	3	88.3×	2e-05	SOX3, SOX9, SRY
Signaling by WNT	3	84.0×	2e-05	SOX3, SOX9, SRY
Developmental Biology	3	10.8×	0.006	SOX9, SRY, NR5A1
Signal Transduction	3	7.6×	0.013	SOX3, SOX9, SRY
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	150.3×	0.021	SOX9
Transcriptional regulation of pluripotent stem cells	1	135.9×	0.021	NR5A1
SUMOylation of intracellular receptors	1	84.0×	0.027	NR5A1
Developmental Lineage of Pancreatic Acinar Cells	1	75.1×	0.027	SOX9
Transcriptional regulation by RUNX2	1	63.4×	0.027	SOX9
Developmental Lineage of Pancreatic Ductal Cells	1	57.1×	0.027	SOX9
Developmental Cell Lineages	1	56.0×	0.027	SOX9
RNA Polymerase II Transcription	2	11.3×	0.027	SOX9, NR5A1
Gene expression (Transcription)	2	8.9×	0.027	SOX9, NR5A1
Nuclear Receptor transcription pathway	1	50.1×	0.028	NR5A1
SUMO E3 ligases SUMOylate target proteins	1	44.6×	0.028	NR5A1
Transcriptional and post-translational regulation of MITF-M expression and activity	1	44.6×	0.028	SOX9
SUMOylation	1	40.8×	0.028	NR5A1
Generic Transcription Pathway	2	7.5×	0.028	SOX9, NR5A1
MITF-M-regulated melanocyte development	1	28.6×	0.038	SOX9
Post-translational protein modification	1	4.8×	0.201	NR5A1
Metabolism of proteins	1	3.1×	0.286	NR5A1

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
positive regulation of male gonad development	3	1263.9×	9e-08	SOX9, SRY, NR5A1
sex determination	2	842.6×	1e-04	SOX3, NR5A1
Sertoli cell differentiation	2	766.0×	1e-04	SOX9, NR5A1
male sex determination	2	702.2×	1e-04	SRY, NR5A1
positive regulation of transcription by RNA polymerase II	4	14.9×	6e-04	SOX3, SOX9, SRY, NR5A1
positive regulation of gene expression	3	29.1×	0.002	SOX9, SRY, NR5A1
negative regulation of immune system process	1	2106.5×	0.005	SOX9
primary sex determination	1	2106.5×	0.005	NR5A1
epithelial cell proliferation involved in prostatic bud elongation	1	2106.5×	0.005	SOX9
regulation of cell proliferation involved in tissue homeostasis	1	2106.5×	0.005	SOX9
regulation of branching involved in lung morphogenesis	1	2106.5×	0.005	SOX9
cell proliferation involved in heart morphogenesis	1	2106.5×	0.005	SOX9
regulation of epithelial cell proliferation involved in lung morphogenesis	1	2106.5×	0.005	SOX9
heart valve formation	1	1404.3×	0.005	SOX9
neural crest cell fate specification	1	1404.3×	0.005	SOX9
male germ-line sex determination	1	1404.3×	0.005	SOX9
intrahepatic bile duct development	1	1404.3×	0.005	SOX9
bronchus cartilage development	1	1404.3×	0.005	SOX9
lung smooth muscle development	1	1404.3×	0.005	SOX9
ureter urothelium development	1	1404.3×	0.005	SOX9
ureter smooth muscle cell differentiation	1	1404.3×	0.005	SOX9
response to gonadotropin-releasing hormone	1	1404.3×	0.005	NR5A1
negative regulation of beta-catenin-TCF complex assembly	1	1404.3×	0.005	SOX9
male gonad development	2	78.0×	0.005	SOX9, NR5A1
glial cell fate specification	1	1053.2×	0.005	SOX9
cellular response to heparin	1	1053.2×	0.005	SOX9
renal vesicle induction	1	1053.2×	0.005	SOX9
positive regulation of kidney development	1	1053.2×	0.005	SOX9
negative regulation of female gonad development	1	1053.2×	0.005	NR5A1
chondrocyte hypertrophy	1	842.6×	0.005	SOX9

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SOX3	0	0
SOX9	0	0
SRY	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
SOX9	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	NR5A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	SOX3, SOX9, SRY

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SOX3	0	—
SOX9	3	—
SRY	0	—
NR5A1	88	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.