46,XY ovotesticular disorder of sex development

Summary

46,XY ovotesticular disorder of sex development (MONDO:0017968) is a disease with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 19

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1.3	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0000048	Bifid scrotum	Very frequent (80-99%)
HP:0000051	Perineal hypospadias	Very frequent (80-99%)
HP:0000054	Micropenis	Very frequent (80-99%)
HP:0000056	Abnormality of the clitoris	Very frequent (80-99%)
HP:0000058	Abnormality of the labia	Very frequent (80-99%)
HP:0000062	Ambiguous genitalia	Very frequent (80-99%)
HP:0000063	Fused labia minora	Very frequent (80-99%)
HP:0001197	Abnormality of prenatal development or birth	Very frequent (80-99%)
HP:0010459	True hermaphroditism	Very frequent (80-99%)
HP:0010460	Abnormality of the female genitalia	Very frequent (80-99%)
HP:0010461	Abnormality of the male genitalia	Very frequent (80-99%)
HP:0012244	Abnormal sex determination	Very frequent (80-99%)
HP:0012861	Ovotestis	Very frequent (80-99%)
HP:0100779	Urogenital sinus anomaly	Very frequent (80-99%)
HP:0000041	Chordee	Frequent (30-79%)
HP:0000150	Gonadoblastoma	Frequent (30-79%)
HP:0030258	Hyperpigmented genitalia	Frequent (30-79%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000039	Epispadias	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	46,XY ovotesticular disorder of sex development
Mondo ID	MONDO:0017968
Orphanet	325345
SNOMED CT	763683004
UMLS	C2697358
MedGen	394582
GARD	0021469
Is cancer (heuristic)	no

Also known as: 46,XY ovotesticular DSD

Data availability: 1 ClinVar variant.

Disease family

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

Related subtypes (23): Frasier syndrome, WAGR syndrome, Denys-Drash syndrome, familial adrenal hypoplasia with absent pituitary luteinizing hormone, PAGOD syndrome, XY type gonadal dysgenesis-associated anomalies syndrome, 46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency, 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency, X-linked myotubular myopathy-abnormal genitalia syndrome, alpha thalassemia-X-linked intellectual disability syndrome, chondrodysplasia-pseudohermaphroditism syndrome, disorder of sex development-intellectual disability syndrome, 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome, sudden infant death-dysgenesis of the testes syndrome, Meacham syndrome, Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, distal monosomy 9p, dysmorphism-short stature-deafness-disorder of sex development syndrome, 46,XY partial gonadal dysgenesis, testicular agenesis, penile agenesis, androgen insensitivity syndrome, male pseudohermaphroditism due to defective lh molecule

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
11613	NM_005491.5(MAMLD1):c.2176C>T (p.Arg726Ter)	MAMLD1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAMLD1	Orphanet:456328	X-linked myotubular myopathy-abnormal genitalia syndrome
MAMLD1	Orphanet:95706	Non-syndromic posterior hypospadias

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
MAMLD1	HGNC:2568	ENSG00000013619	Q13495	Mastermind-like domain-containing protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAMLD1	Mastermind-like domain-containing protein 1	Transactivates the HES3 promoter independently of NOTCH proteins.

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)
MAMLD1	Other/Unknown	no		MAMLD1

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
male germ line stem cell (sensu Vertebrata) in testis	1
right ovary	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAMLD1	197	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, right ovary, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAMLD1	1,220

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAMLD1	Q13495	44.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
NOTCH2 intracellular domain regulates transcription	1	951.7×	0.005	MAMLD1
RUNX3 regulates NOTCH signaling	1	815.7×	0.005	MAMLD1
Regulation of beta-cell development	1	713.8×	0.005	MAMLD1
Signaling by NOTCH2	1	713.8×	0.005	MAMLD1
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	713.8×	0.005	MAMLD1
NOTCH4 Intracellular Domain Regulates Transcription	1	571.0×	0.005	MAMLD1
Signaling by NOTCH3	1	519.1×	0.005	MAMLD1
Signaling by NOTCH4	1	496.5×	0.005	MAMLD1
NOTCH3 Intracellular Domain Regulates Transcription	1	439.2×	0.005	MAMLD1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	407.9×	0.005	MAMLD1
Signaling by NOTCH1 in Cancer	1	407.9×	0.005	MAMLD1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	407.9×	0.005	MAMLD1
Notch-HLH transcription pathway	1	407.9×	0.005	MAMLD1
Formation of paraxial mesoderm	1	407.9×	0.005	MAMLD1
Pre-NOTCH Expression and Processing	1	368.4×	0.005	MAMLD1
Signaling by NOTCH1	1	356.9×	0.005	MAMLD1
Transcriptional regulation by RUNX3	1	271.9×	0.007	MAMLD1
Gastrulation	1	259.6×	0.007	MAMLD1
NOTCH1 Intracellular Domain Regulates Transcription	1	237.9×	0.007	MAMLD1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	196.9×	0.007	MAMLD1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	196.9×	0.007	MAMLD1
Signaling by NOTCH	1	175.7×	0.008	MAMLD1
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	146.4×	0.009	MAMLD1
Pre-NOTCH Transcription and Translation	1	122.8×	0.011	MAMLD1
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.022	MAMLD1
RNA Polymerase II Transcription	1	22.5×	0.053	MAMLD1
Gene expression (Transcription)	1	17.8×	0.064	MAMLD1
Generic Transcription Pathway	1	15.1×	0.073	MAMLD1
Developmental Biology	1	14.5×	0.074	MAMLD1
Disease	1	13.1×	0.079	MAMLD1

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
spermatid differentiation	1	1685.2×	0.002	MAMLD1
male gonad development	1	156.0×	0.010	MAMLD1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	MAMLD1

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
MAMLD1	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	MAMLD1

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)
MAMLD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.