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Atlas / Disease / 46,XX disorder of sex development

46,XX disorder of sex development

disease
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Also known as 46,XX differences of Sex development46,XX disorders of Sex development46,XX DSDfemale pseudohermaphroditism

Summary

46,XX disorder of sex development (MONDO:0017576) is a disease (an umbrella term covering 6 Mondo subtypes) with 3 cohort genes.

At a glance

  • Umbrella term: 6 Mondo subtypes
  • Cohort genes: 3
  • ClinVar variants: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

FieldValue
Canonical name46,XX disorder of sex development
Mondo IDMONDO:0017576
MeSHD058489
Orphanet2982
NCITC127169
SNOMED CT8800006
UMLSC2936403
MedGen424728
GARD0018783
Is cancer (heuristic)no

Also known as: 46,XX differences of Sex development · 46,XX disorders of Sex development · 46,XX DSD · female pseudohermaphroditism

Data availability: 1 ClinVar variant · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 6 Mondo subtypes.

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

Related subtypes (7): gynecomastia disorder, true hermaphroditism, 46,XX ovotesticular 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

Subtypes (6): 46,XX disorder of sex development-skeletal anomalies syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, 46,XX disorder of sex development-anorectal anomalies syndrome, Michels Caskey syndrome, 46,XX testicular disorder of sex development, 46,XX true hermaphroditism, SRY-positive

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 uncertain significance

ClinVarVariant (HGVS)GeneClassificationReview
2429362NM_006293.4(TYRO3):c.666_667insCACTGCCTGCAGCCCCCTTCAACATCACC (p.Ala223fs)TYRO3Uncertain significanceno assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 7 · 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.

GeneClassificationInheritanceDiseaseRecords
DMRT1StrongAutosomal dominant46,XY disorder of sex development4
NR5A1ModerateAutosomal recessive46,XX disorder of sex development12

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
DMRT1Orphanet:24246,XY complete gonadal dysgenesis
NR5A1Orphanet:213846,XX ovotesticular difference of sex development
NR5A1Orphanet:24246,XY complete gonadal dysgenesis
NR5A1Orphanet:24346,XX gonadal dysgenesis
NR5A1Orphanet:25151046,XY partial gonadal dysgenesis
NR5A1Orphanet:39346,XX testicular difference of sex development
NR5A1Orphanet:399805Male infertility with azoospermia or oligozoospermia due to single gene mutation

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

SubsetGenes
multi_evidence3

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
DMRT1HGNC:2934ENSG00000137090Q9Y5R6Doublesex- and mab-3-related transcription factor 1gencc
NR5A1HGNC:7983ENSG00000136931Q13285Steroidogenic factor 1gencc
TYRO3HGNC:12446ENSG00000092445Q06418Tyrosine-protein kinase receptor TYRO3clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
DMRT1Doublesex- and mab-3-related transcription factor 1Transcription factor that plays a key role in male sex determination and differentiation by controlling testis development and male germ cell proliferation.
NR5A1Steroidogenic factor 1Transcriptional activator.
TYRO3Tyrosine-protein kinase receptor TYRO3Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including TULP1 or GAS6.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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.

FamilyGenesFoldFDR
Nuclear receptor1128.6×0.023
Kinase19.2×0.157
Other/Unknown10.6×0.914

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
DMRT1Other/UnknownnoDM_DNA-bd, DMRT1-like, DMRT
NR5A1Nuclear receptoryesNucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
TYRO3Kinaseyes2.7.10.1Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2

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)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)3
unknown0

Top tissues across cohort

TissueCohort genes
buccal mucosa cell1
male germ line stem cell (sensu Vertebrata) in testis1
primordial germ cell in gonad1
left adrenal gland1
right adrenal gland1
right adrenal gland cortex1
Brodmann (1909) area 101
frontal pole1
paraflocculus1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
DMRT123tissue_specificmarkerprimordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell
NR5A177tissue_specificyesright adrenal gland cortex, right adrenal gland, left adrenal gland
TYRO3252ubiquitousmarkerfrontal pole, Brodmann (1909) area 10, paraflocculus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

SymbolInteractor count
TYRO32,285
NR5A12,146
DMRT11,513

Intra-cohort edges

ABSources
DMRT1NR5A1string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
NR5A1Q132856
DMRT1Q9Y5R61
TYRO3Q064181

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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.

PathwayCohort genesFoldFDRSample cohort genes
Transcriptional regulation of testis differentiation2475.8×7e-05DMRT1, NR5A1
Transcriptional regulation of pluripotent stem cells1181.3×0.034NR5A1
SUMOylation of intracellular receptors1112.0×0.034NR5A1
Dengue Virus Attachment and Entry186.5×0.034TYRO3
Nuclear Receptor transcription pathway166.8×0.034NR5A1
SUMO E3 ligases SUMOylate target proteins159.5×0.034NR5A1
SUMOylation154.4×0.034NR5A1
RNA Polymerase II Transcription17.5×0.207NR5A1
Post-translational protein modification16.4×0.207NR5A1
Gene expression (Transcription)16.0×0.207NR5A1
Generic Transcription Pathway15.0×0.210NR5A1
Developmental Biology14.8×0.210NR5A1
Metabolism of proteins14.1×0.223NR5A1

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 termCohort genesFoldFDRSample cohort genes
positive regulation of male gonad development21123.5×3e-05DMRT1, NR5A1
Sertoli cell differentiation21021.3×3e-05DMRT1, NR5A1
male sex determination2936.2×3e-05DMRT1, NR5A1
primary sex determination12808.7×0.003NR5A1
positive regulation of meiosis I12808.7×0.003DMRT1
regulation of nodal signaling pathway12808.7×0.003DMRT1
male germ cell proliferation11872.4×0.003DMRT1
forebrain cell migration11872.4×0.003TYRO3
negative regulation of lymphocyte activation11872.4×0.003TYRO3
response to gonadotropin-releasing hormone11872.4×0.003NR5A1
male sex differentiation11404.3×0.004DMRT1
negative regulation of female gonad development11404.3×0.004NR5A1
meiosis I1802.5×0.005DMRT1
ovulation cycle1802.5×0.005TYRO3
positive regulation of viral life cycle1802.5×0.005TYRO3
negative regulation of meiotic nuclear division1702.2×0.005DMRT1
luteinization1624.1×0.005NR5A1
primordial germ cell migration1624.1×0.005DMRT1
tissue development1624.1×0.005NR5A1
sex determination1561.7×0.005NR5A1
secretion by cell1561.7×0.005TYRO3
regulation of steroid biosynthetic process1510.7×0.005NR5A1
vagina development1510.7×0.005TYRO3
calcineurin-mediated signaling1510.7×0.005NR5A1
spermatogenesis223.4×0.006TYRO3, DMRT1
Leydig cell differentiation1401.2×0.006NR5A1
maintenance of protein location in nucleus1374.5×0.006NR5A1
Sertoli cell development1374.5×0.006DMRT1
oocyte development1312.1×0.007DMRT1
natural killer cell differentiation1295.6×0.007TYRO3

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

SymbolExample approved molecule
TYRO3CABOZANTINIB

Top cohort targets by molecule count

SymbolMoleculesMax phase
TYRO3304
DMRT100
NR5A100

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
CABOZANTINIB4TYRO3
VANDETANIB4TYRO3
BOSUTINIB4TYRO3
NINTEDANIB4TYRO3
SUNITINIB4TYRO3
ERLOTINIB4TYRO3
CRIZOTINIB4TYRO3
MIDOSTAURIN4TYRO3
CANERTINIB3TYRO3
ITACITINIB3TYRO3
CEDIRANIB3TYRO3
POVORCITINIB3TYRO3
DOVITINIB3TYRO3
LESTAURTINIB3TYRO3
DORAMAPIMOD2TYRO3
FORETINIB2TYRO3
SU-0148132TYRO3
REBASTINIB2TYRO3
ADAVOSERTIB2TYRO3
ILORASERTIB2TYRO3
BEMCENTINIB2TYRO3
BMS-7776072TYRO3
R-4062TYRO3
TOZASERTIB2TYRO3
PELITINIB2TYRO3
MLN-80541TYRO3
SNS-3141TYRO3
PD-01662851TYRO3
AST-4871TYRO3
PF-072658071TYRO3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

SymbolAssaysType breakdown
TYRO3380Binding:376, Functional:3, Toxicity:1
NR5A188Binding:84, Functional:4

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
TYRO32.7.10.1receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

SymbolChEMBL assays
TYRO3380

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

30 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.

CompoundMax phaseCohort target (bioactivity)
CABOZANTINIB4TYRO3
VANDETANIB4TYRO3
BOSUTINIB4TYRO3
NINTEDANIB4TYRO3
SUNITINIB4TYRO3
ERLOTINIB4TYRO3
CRIZOTINIB4TYRO3
MIDOSTAURIN4TYRO3
CANERTINIB3TYRO3
ITACITINIB3TYRO3
CEDIRANIB3TYRO3
POVORCITINIB3TYRO3
DOVITINIB3TYRO3
LESTAURTINIB3TYRO3
DORAMAPIMOD2TYRO3
FORETINIB2TYRO3
SU-0148132TYRO3
REBASTINIB2TYRO3
ADAVOSERTIB2TYRO3
ILORASERTIB2TYRO3
BEMCENTINIB2TYRO3
BMS-7776072TYRO3
R-4062TYRO3
TOZASERTIB2TYRO3
PELITINIB2TYRO3
MLN-80541TYRO3
SNS-3141TYRO3
PD-01662851TYRO3
AST-4871TYRO3
PF-072658071TYRO3

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

TierDefinitionGenesSymbols
AApproved (phase 4 drug)1TYRO3
BPhased (≥1) drug, not yet approved0
CDruggable family + PDB, no drug1NR5A1
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug1DMRT1

Undrugged target profiles

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

SymbolChEMBL assaysDrugged partners (top 3)
DMRT10—
NR5A188—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
v1.1.2
BioBTree
v2.0.2

Sources 70

This page pulls from 70 datasets indexed by BioBTree:

alphafoldantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticscellosauruschembl_activitychembl_assaychembl_documentchembl_moleculechembl_targetcivic_evidenceclingen_dosageclinical_trialsclinvarctd_gene_interactiondepmapdiamond_similarityefoensemblentrezesm2_similarityfantom5_genefantom5_promotergardgenccgenerifgogtopdbgtopdb_interactiongwasgwas_studyhgncintactinterpromedgenmeshmimmondomondochildmondoparentncitorphanetpatentpatent_compoundpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assayreactomerefseqrhearnacentralsctidscxa_expressionscxa_gene_experimentsignorstring_interactiontranscriptufeatureumlsuniprot