Disorder of sexual differentiation

Summary

Disorder of sexual differentiation (MONDO:0002145) is a disease (an umbrella term covering 8 Mondo subtypes) with 33 cohort genes and 12 clinical trials. The dominant Reactome pathway is Transcriptional regulation of testis differentiation (3 cohort genes). Top therapeutic interventions include hydrocortisone.

At a glance

• Umbrella term: 8 Mondo subtypes
• Cohort genes: 33
• ClinVar variants: 45
• Clinical trials: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	disorder of sexual differentiation
Mondo ID	MONDO:0002145
MeSH	D012734
Orphanet	90771
DOID	DOID:1923
NCIT	C103186
SNOMED CT	39179006
UMLS	C2930619
MedGen	415936
MedDRA	10070597
Is cancer (heuristic)	no

Also known as: CARD · conditions affecting reproductive development · differences of sex development · disorder of sex development · disorder of sex differentiation · disorder of sexual differentiation · disorders of sex development · disorders of sex development (DSD) · DSD · intersex · intersex conditions · sex differentiation disorder · sexual differentiation disorder

Data availability: 45 ClinVar variants · 3 GenCC gene-disease records · 6 cell lines.

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › disorder of sexual differentiation

Related subtypes (5): precocious puberty, hypogonadism, testicular disorder, ovarian disorder, gonadoblastoma

Subtypes (8): gynecomastia disorder, true hermaphroditism, 46,XX ovotesticular disorder of sex development, 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

ClinVar germline variants

45 retrieved; paginated sample, class counts are floors:

26 uncertain significance, 9 pathogenic, 5 conflicting classifications of pathogenicity, 3 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
9813	NM_000044.6(AR):c.1789G>A (p.Ala597Thr)	AR	Pathogenic	criteria provided, multiple submitters, no conflicts
1202591	NM_001127222.2(CACNA1A):c.655A>G (p.Ile219Val)	CACNA1A	Pathogenic	no assertion criteria provided
1202595	NM_000197.2(HSD17B3):c.679A>G (p.Thr227Ala)	HSD17B3	Pathogenic	no assertion criteria provided
14392	NM_000233.4(LHCGR):c.1660C>T (p.Arg554Ter)	LHCGR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
929443	NM_001127392.3(MYRF):c.2572+1G>A	MYRF	Pathogenic	criteria provided, single submitter
1202586	NM_004959.5(NR5A1):c.244+1G>T	NR5A1	Pathogenic	criteria provided, single submitter
1202587	NM_004959.5(NR5A1):c.218G>A (p.Cys73Tyr)	NR5A1	Pathogenic	no assertion criteria provided
1202588	NM_004959.5(NR5A1):c.104G>A (p.Gly35Asp)	NR5A1	Pathogenic	no assertion criteria provided
1202604	NM_004959.5(NR5A1):c.1223A>C (p.His408Pro)	NR5A1	Pathogenic	no assertion criteria provided
935575	NM_004959.5(NR5A1):c.219C>G (p.Cys73Trp)	NR5A1	Pathogenic	criteria provided, single submitter
631595	NM_003193.5(TBCE):c.100+1G>A	TBCE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3767296	NM_000044.6(AR):c.2246C>T (p.Ala749Val)	AR	Likely pathogenic	criteria provided, single submitter
1342170	NM_000197.2(HSD17B3):c.3G>A (p.Met1Ile)	HSD17B3	Likely pathogenic	no assertion criteria provided
1202589	NM_001127392.3(MYRF):c.313A>G (p.Asn105Asp)	MYRF	Likely pathogenic	no assertion criteria provided
194727	NM_001110556.2(FLNA):c.2449C>T (p.Pro817Ser)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
476699	NM_024426.6(WT1):c.314C>G (p.Ala105Gly)	LOC107982234	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
419489	NM_000233.4(LHCGR):c.383+2T>C	STON1-GTF2A1L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1202606	NM_003244.4(TGIF1):c.16+1719dup	TGIF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
981464	NM_024426.6(WT1):c.1437A>G (p.Thr479=)	WT1	Conflicting classifications of pathogenicity	no assertion criteria provided
1205840	NM_005189.3(CBX2):c.404G>A (p.Arg135Gln)	CBX2	Uncertain significance	no assertion criteria provided
996035	NM_005189.3(CBX2):c.117-3C>T	CBX2	Uncertain significance	no assertion criteria provided
1202603	NM_173648.4(CCDC141):c.1979G>A (p.Arg660Gln)	CCDC141	Uncertain significance	no assertion criteria provided
1202599	NM_021044.4(DHH):c.913G>A (p.Gly305Arg)	DHH	Uncertain significance	no assertion criteria provided
2191482	NM_032656.4(DHX37):c.2498G>A (p.Arg833Gln)	DHX37	Uncertain significance	criteria provided, multiple submitters, no conflicts
1202602	NM_000141.5(FGFR2):c.1132A>G (p.Ile378Val)	FGFR2	Uncertain significance	no assertion criteria provided
1199404	NM_198391.3(FLRT3):c.182C>G (p.Thr61Arg)	FLRT3	Uncertain significance	no assertion criteria provided
1199394	NM_001349338.3(FOXP1):c.181-18031T>C	FOXP1	Uncertain significance	no assertion criteria provided
1202593	NM_000823.4(GHRHR):c.812+4A>C	GHRHR	Uncertain significance	no assertion criteria provided
1202605	NM_001374353.1(GLI2):c.1238C>G (p.Ala413Gly)	GLI2	Uncertain significance	criteria provided, single submitter
800795	NM_000168.6(GLI3):c.1527G>C (p.Glu509Asp)	GLI3	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 107 · 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
IGSF10	Moderate	Autosomal dominant	disorder of sexual differentiation	2
RXFP2	Limited	Autosomal recessive	disorder of sexual differentiation	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOX4	Orphanet:1465	Coffin-Siris syndrome
TBCE	Orphanet:2323	Sanjad-Sakati syndrome
TBCE	Orphanet:496756	Early-onset progressive encephalopathy-spastic ataxia-distal spinal muscular atrophy syndrome
TBCE	Orphanet:93324	Autosomal recessive Kenny-Caffey syndrome
TGIF1	Orphanet:220386	Semilobar holoprosencephaly
TGIF1	Orphanet:280195	Septopreoptic holoprosencephaly
TGIF1	Orphanet:280200	Microform holoprosencephaly
TGIF1	Orphanet:93924	Lobar holoprosencephaly
TGIF1	Orphanet:93925	Alobar holoprosencephaly
TGIF1	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
MYRF	Orphanet:647811	Cardiac-urogenital syndrome
WT1	Orphanet:220	Denys-Drash syndrome
WT1	Orphanet:242	46,XY complete gonadal dysgenesis
WT1	Orphanet:251510	46,XY partial gonadal dysgenesis
WT1	Orphanet:3097	Meacham syndrome
WT1	Orphanet:347	Frasier syndrome
WT1	Orphanet:654	Nephroblastoma
WT1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
WT1	Orphanet:83469	Desmoplastic small round cell tumor
WT1	Orphanet:893	WAGR syndrome
WWOX	Orphanet:251510	46,XY partial gonadal dysgenesis
WWOX	Orphanet:284282	Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to WWOX deficiency
WWOX	Orphanet:708171	Facial dysmorphism-corpus callosum hypoplasia-infantile epileptic encephalopathy
WWOX	Orphanet:99977	Squamous cell carcinoma of the esophagus
CACNA1A	Orphanet:2131	Alternating hemiplegia of childhood
CACNA1A	Orphanet:2382	Lennox-Gastaut syndrome
CACNA1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA1A	Orphanet:569	Familial or sporadic hemiplegic migraine
CACNA1A	Orphanet:71518	Benign paroxysmal torticollis of infancy
CACNA1A	Orphanet:97	Familial paroxysmal ataxia
CACNA1A	Orphanet:98758	Spinocerebellar ataxia type 6
CBX2	Orphanet:242	46,XY complete gonadal dysgenesis
SPRY4	Orphanet:363494	Non-seminomatous germ cell tumor of testis
SPRY4	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
SPRY4	Orphanet:478	Kallmann syndrome
DHX37	Orphanet:242	46,XY complete gonadal dysgenesis
DHX37	Orphanet:251510	46,XY partial gonadal dysgenesis
DHX37	Orphanet:983	Testicular regression syndrome
PROK2	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
PROK2	Orphanet:478	Kallmann syndrome
MAMLD1	Orphanet:456328	X-linked myotubular myopathy-abnormal genitalia syndrome
MAMLD1	Orphanet:95706	Non-syndromic posterior hypospadias
CCDC141	Orphanet:478	Kallmann syndrome
DHH	Orphanet:168563	46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome
DHH	Orphanet:242	46,XY complete gonadal dysgenesis
FGFR2	Orphanet:1540	Jackson-Weiss syndrome
FGFR2	Orphanet:1555	Cutis gyrata-acanthosis nigricans-craniosynostosis syndrome
FGFR2	Orphanet:168624	Familial scaphocephaly syndrome, McGillivray type
FGFR2	Orphanet:207	Crouzon syndrome
FGFR2	Orphanet:2363	Lacrimoauriculodentodigital syndrome

Cohort genes → proteins

33 cohort genes, 32 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	33

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RXFP2	HGNC:17318	ENSG00000133105	Q8WXD0	Relaxin receptor 2	gencc,clinvar
IGSF10	HGNC:26384	ENSG00000152580	Q6WRI0	Immunoglobulin superfamily member 10	gencc
SOX4	HGNC:11200	ENSG00000124766	Q06945	Transcription factor SOX-4	clinvar
TBCE	HGNC:11582	ENSG00000284770	Q15813	Tubulin-specific chaperone E	clinvar
TGIF1	HGNC:11776	ENSG00000177426	Q15583	Homeobox protein TGIF1	clinvar
MYRF	HGNC:1181	ENSG00000124920	Q9Y2G1	Myelin regulatory factor	clinvar
WT1	HGNC:12796	ENSG00000184937	P19544	Wilms tumor protein	clinvar
WWOX	HGNC:12799	ENSG00000186153	Q9NZC7	WW domain-containing oxidoreductase	clinvar
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	clinvar
CBX2	HGNC:1552	ENSG00000173894	Q14781	Chromobox protein homolog 2	clinvar
SPRY4	HGNC:15533	ENSG00000187678	Q9C004	Protein sprouty homolog 4	clinvar
DHX37	HGNC:17210	ENSG00000150990	Q8IY37	Probable ATP-dependent RNA helicase DHX37	clinvar
PROK2	HGNC:18455	ENSG00000163421	Q9HC23	Prokineticin-2	clinvar
GPRC6A	HGNC:18510	ENSG00000173612	Q5T6X5	G-protein coupled receptor family C group 6 member A	clinvar
MAMLD1	HGNC:2568	ENSG00000013619	Q13495	Mastermind-like domain-containing protein 1	clinvar
CCDC141	HGNC:26821	ENSG00000163492	Q6ZP82	Coiled-coil domain-containing protein 141	clinvar
DHH	HGNC:2865	ENSG00000139549	O43323	Desert hedgehog protein	clinvar
STON1-GTF2A1L	HGNC:30651	ENSG00000068781		STON1-GTF2A1L readthrough	clinvar
FGFR2	HGNC:3689	ENSG00000066468	P21802	Fibroblast growth factor receptor 2	clinvar
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	clinvar
FLRT3	HGNC:3762	ENSG00000125848	Q9NZU0	Leucine-rich repeat transmembrane protein FLRT3	clinvar
FOXP1	HGNC:3823	ENSG00000114861	Q9H334	Forkhead box protein P1	clinvar
GHRHR	HGNC:4266	ENSG00000106128	Q02643	Growth hormone-releasing hormone receptor	clinvar
GLI2	HGNC:4318	ENSG00000074047	P10070	Zinc finger protein GLI2	clinvar
GLI3	HGNC:4319	ENSG00000106571	P10071	Transcriptional activator GLI3	clinvar
HSD17B3	HGNC:5212	ENSG00000130948	P37058	17-beta-hydroxysteroid dehydrogenase type 3	clinvar
KISS1	HGNC:6341	ENSG00000170498	Q15726	Metastasis-suppressor KiSS-1	clinvar
AR	HGNC:644	ENSG00000169083	P10275	Androgen receptor	clinvar
AREG	HGNC:651	ENSG00000109321	P15514	Amphiregulin	clinvar
LHCGR	HGNC:6585	ENSG00000138039	P22888	Lutropin-choriogonadotropic hormone receptor	clinvar
NR5A1	HGNC:7983	ENSG00000136931	Q13285	Steroidogenic factor 1	clinvar
PLXNA3	HGNC:9101	ENSG00000130827	P51805	Plexin-A3	clinvar
PROP1	HGNC:9455	ENSG00000175325	O75360	Homeobox protein prophet of Pit-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RXFP2	Relaxin receptor 2	Receptor for relaxin.
IGSF10	Immunoglobulin superfamily member 10	Involved in the control of early migration of neurons expressing gonadotropin-releasing hormone (GNRH neurons).
SOX4	Transcription factor SOX-4	Transcriptional activator that binds with high affinity to the T-cell enhancer motif 5’-AACAAAG-3’ motif.
TBCE	Tubulin-specific chaperone E	Tubulin-folding protein; involved in the second step of the tubulin folding pathway and in the regulation of tubulin heterodimer dissociation.
TGIF1	Homeobox protein TGIF1	Binds to a retinoid X receptor (RXR) responsive element from the cellular retinol-binding protein II promoter (CRBPII-RXRE).
MYRF	Myelin regulatory factor	Constitutes a precursor of the transcription factor.
WT1	Wilms tumor protein	Transcription factor that plays an important role in cellular development and cell survival.
WWOX	WW domain-containing oxidoreductase	Putative oxidoreductase.
CACNA1A	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
CBX2	Chromobox protein homolog 2	Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development.
SPRY4	Protein sprouty homolog 4	Suppresses the insulin receptor and EGFR-transduced MAPK signaling pathway, but does not inhibit MAPK activation by a constitutively active mutant Ras.
DHX37	Probable ATP-dependent RNA helicase DHX37	ATP-binding RNA helicase that plays a role in maturation of the small ribosomal subunit in ribosome biogenesis.
PROK2	Prokineticin-2	May function as an output molecule from the suprachiasmatic nucleus (SCN) that transmits behavioral circadian rhythm.
GPRC6A	G-protein coupled receptor family C group 6 member A	Receptor activated by multiple ligands, including osteocalcin (BGLAP), basic amino acids, and various cations.
MAMLD1	Mastermind-like domain-containing protein 1	Transactivates the HES3 promoter independently of NOTCH proteins.
CCDC141	Coiled-coil domain-containing protein 141	Plays a critical role in cortical radial and GnRH neurons migration during brain development.
DHH	Desert hedgehog protein	The C-terminal part of the desert hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity.
FGFR2	Fibroblast growth factor receptor 2	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosis, and in the regulation of embryonic de…
FLNA	Filamin-A	Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins.
FLRT3	Leucine-rich repeat transmembrane protein FLRT3	Functions in cell-cell adhesion, cell migration and axon guidance, exerting an attractive or repulsive role depending on its interaction partners.
FOXP1	Forkhead box protein P1	Transcriptional repressor.
GHRHR	Growth hormone-releasing hormone receptor	Receptor for GRF, coupled to G proteins which activate adenylyl cyclase.
GLI2	Zinc finger protein GLI2	Functions as a transcription regulator in the hedgehog (Hh) pathway.
GLI3	Transcriptional activator GLI3	Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development.
HSD17B3	17-beta-hydroxysteroid dehydrogenase type 3	Catalyzes the conversion of 17-oxosteroids to 17beta-hydroxysteroids.
KISS1	Metastasis-suppressor KiSS-1	Kisspeptins are ligands for the G-protein coupled receptor KISS1R/GPR54.
AR	Androgen receptor	Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues.
AREG	Amphiregulin	Ligand of the EGF receptor/EGFR.
LHCGR	Lutropin-choriogonadotropic hormone receptor	Receptor for lutropin-choriogonadotropic hormone.
NR5A1	Steroidogenic factor 1	Transcriptional activator.
PLXNA3	Plexin-A3	Coreceptor for SEMA3A and SEMA3F.
PROP1	Homeobox protein prophet of Pit-1	Possibly involved in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes.

Protein-family classification

Druggable: 14 · Difficult: 9 · Unknown: 10 · Druggable fraction: 0.42

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	2	23.4×	0.022
Antibody/Immunoglobulin	5	4.4×	0.022
GPCR	4	2.9×	0.107
Transcription factor	8	2.0×	0.107
Ion channel	1	3.4×	0.463
Kinase	1	0.8×	0.999
Other/Unknown	10	0.5×	0.999
Scaffold/PPI	1	0.5×	0.999
Enzyme (other)	1	0.4×	0.999

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RXFP2	GPCR	yes		GPCR_Rhodpsn, Leu-rich_rpt, LDrepeatLR_classA_rpt
IGSF10	Antibody/Immunoglobulin	yes		LRRNT, Cys-rich_flank_reg_C, Leu-rich_rpt
SOX4	Transcription factor	no		HMG_box_dom, SOX-12/11/4, HMG_box_dom_sf
TBCE	Other/Unknown	no		Ubiquitin-like_dom, CAP-Gly_domain, Ubiquitin-like_domsf
TGIF1	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
MYRF	Transcription factor	no		p53-like_TF_DNA-bd_sf, NDT80_DNA-bd_dom, MYRF_C2
WT1	Transcription factor	no		Wilms_tumour_N, Znf_C2H2_type, Znf_C2H2_sf
WWOX	Scaffold/PPI	no		WW_dom, SDR_fam, WW_dom_sf
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
CBX2	Other/Unknown	no		Chromo/chromo_shadow_dom, Chromo-like_dom_sf, Chromodomain_CS
SPRY4	Other/Unknown	no		Sprouty, Sprouty_domain
DHX37	Other/Unknown	no		Helicase_C-like, Helicase-assoc_dom, DEAD/DEAH_box_helicase_dom
PROK2	Other/Unknown	no		Prokineticin, Prokineticin_domain
GPRC6A	GPCR	yes		GPCR_3_Ca_sens_rcpt-rel, GPCR_3, ANF_lig-bd_rcpt
MAMLD1	Other/Unknown	no		MAMLD1
CCDC141	Antibody/Immunoglobulin	yes		Spectrin_repeat, Ig_sub2, Ig_sub
DHH	Other/Unknown	no		Hedgehog_signalling_dom, Hedgehog, Hedgehog_Hint
STON1-GTF2A1L	Other/Unknown	no
FGFR2	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
FLRT3	Antibody/Immunoglobulin	yes		LRRNT, Cys-rich_flank_reg_C, Leu-rich_rpt
FOXP1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_2, FOXP-CC
GHRHR	GPCR	yes		GPCR_2_secretin-like, GPCR_2_extracellular_dom, GPCR_2_GHRH_rcpt
GLI2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
GLI3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
HSD17B3	Enzyme (other)	yes	1.1.1.51	SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf
KISS1	Other/Unknown	no		Metastasis-suppressor_KiSS-1
AR	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Andrgn_rcpt, Znf_hrmn_rcpt
AREG	Other/Unknown	no		EGF
LHCGR	GPCR	yes		GPCR_Rhodpsn, Gphrmn_rcpt_fam, LSH_rcpt
NR5A1	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
PLXNA3	Antibody/Immunoglobulin	yes		Semap_dom, Plexin_repeat, IPT_dom
PROP1	Transcription factor	no		HTH_motif, HD, Homeodomain-like_sf

Expression context

Cohort genes with no expression data: 0.

25 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
moderate (6-20)	1
broad (>20)	31
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	4
ventricular zone	4
right testis	3
adenohypophysis	3
cortical plate	2
stromal cell of endometrium	2
C1 segment of cervical spinal cord	2
germinal epithelium of ovary	2
right hemisphere of cerebellum	2
oocyte	2
primordial germ cell in gonad	2
right lung	2
pancreatic ductal cell	2
tendon of biceps brachii	2
adrenal tissue	2
left testis	2
lower esophagus muscularis layer	2
pituitary gland	2
buccal mucosa cell	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RXFP2	61	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell, monocyte
IGSF10	219	broad	marker	cardiac muscle of right atrium, left ovary, kidney epithelium
SOX4	295	ubiquitous	marker	cortical plate, ganglionic eminence, embryo
TBCE	134	ubiquitous	yes	ventricular zone, hindlimb stylopod muscle, cortical plate
TGIF1	267	ubiquitous	marker	stromal cell of endometrium, gall bladder, ventricular zone
MYRF	223	ubiquitous	marker	middle frontal gyrus, C1 segment of cervical spinal cord, inferior vagus X ganglion
WT1	168	broad	marker	germinal epithelium of ovary, renal glomerulus, metanephric glomerulus
WWOX	286	ubiquitous	marker	parotid gland, cervix squamous epithelium, cranial nerve II
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
CBX2	178	ubiquitous	marker	secondary oocyte, oocyte, primordial germ cell in gonad
SPRY4	219	ubiquitous	marker	left coronary artery, right lung, ascending aorta
DHX37	236	ubiquitous	yes	pancreatic ductal cell, tendon of biceps brachii, medial globus pallidus
PROK2	159	broad	marker	blood, bone marrow, trabecular bone tissue
GPRC6A	20		marker	male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue, primordial germ cell in gonad
MAMLD1	197	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, right ovary, right testis
CCDC141	149	broad	marker	heart left ventricle, adrenal tissue, right atrium auricular region
DHH	123	tissue_specific	yes	tibial nerve, right testis, left testis
STON1-GTF2A1L	127	tissue_specific	yes	muscle layer of sigmoid colon, lower esophagus muscularis layer, lower esophagus
FGFR2	272	broad	marker	C1 segment of cervical spinal cord, spinal cord, corpus callosum
FLNA	285	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
FLRT3	248	ubiquitous	marker	endothelial cell, lower lobe of lung, pericardium
FOXP1	256	ubiquitous	marker	pancreatic ductal cell, oviduct epithelium, cardia of stomach
GHRHR	154	broad	marker	pituitary gland, adenohypophysis, oocyte
GLI2	211	ubiquitous	marker	tibia, germinal epithelium of ovary, ventricular zone
GLI3	263	ubiquitous	marker	ventricular zone, olfactory bulb, tendon of biceps brachii
HSD17B3	129	tissue_specific	yes	right testis, left testis, testis
KISS1	105	tissue_specific	marker	placenta, right lobe of liver, epithelium of bronchus
AR	250	ubiquitous	marker	seminal vesicle, urethra, nipple
AREG	216	ubiquitous	marker	mucosa of urinary bladder, endometrium epithelium, right lung
LHCGR	123	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, sural nerve, lower esophagus muscularis layer

Protein interactions among cohort

Intra-cohort edges: 19.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AR	7,400
WWOX	5,892
FLNA	5,321
WT1	3,938
DHX37	3,123
GLI2	3,112
FOXP1	2,939
SOX4	2,846
GLI3	2,825
AREG	2,745

Intra-cohort edges

A	B	Sources
AR	GLI2	biogrid_interaction
AR	GLI3	biogrid_interaction
AR	MAMLD1	string_interaction
AR	TGIF1	string_interaction
AREG	LHCGR	string_interaction
CCDC141	IGSF10	string_interaction
DHH	GLI2	string_interaction
DHH	GLI3	string_interaction
DHH	NR5A1	string_interaction
FLRT3	SPRY4	string_interaction
GHRHR	PROP1	string_interaction
GLI2	GLI3	intact
HSD17B3	LHCGR	string_interaction
HSD17B3	MAMLD1	string_interaction
HSD17B3	NR5A1	string_interaction
KISS1	PROK2	string_interaction
MAMLD1	NR5A1	string_interaction
NR5A1	RXFP2	string_interaction
NR5A1	WT1	string_interaction

Structural data

PDB: 22 · AlphaFold-only: 10 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AR	P10275	95
FGFR2	P21802	63
WT1	P19544	28
FLNA	P21333	26
TBCE	Q15813	6
NR5A1	Q13285	6
DHH	O43323	5
CACNA1A	O00555	4
LHCGR	P22888	4
TGIF1	Q15583	3
CBX2	Q14781	3
FLRT3	Q9NZU0	3
MYRF	Q9Y2G1	2
GHRHR	Q02643	2
KISS1	Q15726	2
RXFP2	Q8WXD0	1
WWOX	Q9NZC7	1
SPRY4	Q9C004	1
DHX37	Q8IY37	1
FOXP1	Q9H334	1
GLI3	P10071	1
AREG	P15514	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HSD17B3	P37058	93.59
PLXNA3	P51805	84.77
GPRC6A	Q5T6X5	84.32
CCDC141	Q6ZP82	72.36
PROP1	O75360	70.74
PROK2	Q9HC23	69.22
IGSF10	Q6WRI0	58.70
SOX4	Q06945	55.71
MAMLD1	Q13495	44.08
GLI2	P10070	42.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 173. Enrichment computed across 33 evidence-associated genes (27 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 27 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	79.3×	0.001	WT1, DHH, NR5A1
GLI proteins bind promoters of Hh responsive genes to promote transcription	2	120.8×	0.010	GLI2, GLI3
SUMO E3 ligases SUMOylate target proteins	3	19.8×	0.022	CBX2, AR, NR5A1
SUMOylation	3	18.1×	0.022	CBX2, AR, NR5A1
Hedgehog ‘on’ state	3	17.6×	0.022	DHH, GLI2, GLI3
Signal Transduction	9	3.4×	0.022	RXFP2, SOX4, TGIF1, CBX2, MAMLD1, KISS1, AR, AREG (+1 more)
Transcriptional regulation of pluripotent stem cells	2	40.3×	0.027	FOXP1, NR5A1
RUNX2 regulates osteoblast differentiation	2	33.8×	0.034	GLI3, AR
Signaling by FGFR2 amplification mutants	1	423.0×	0.041	FGFR2
Signaling by FGFR2 fusions	1	423.0×	0.041	FGFR2
SUMOylation of intracellular receptors	2	24.9×	0.045	AR, NR5A1
Class A/1 (Rhodopsin-like receptors)	3	8.2×	0.070	RXFP2, KISS1, LHCGR
Peptide ligand-binding receptors	3	8.2×	0.070	RXFP2, PROK2, KISS1
G alpha (s) signalling events	3	8.1×	0.070	RXFP2, GHRHR, LHCGR
RNA Polymerase II Transcription	5	4.2×	0.070	TGIF1, CBX2, MAMLD1, AR, NR5A1
Nuclear Receptor transcription pathway	2	14.8×	0.080	AR, NR5A1
PIP3 activates AKT signaling	3	7.4×	0.080	CBX2, FGFR2, AREG
GPCR ligand binding	3	7.1×	0.080	RXFP2, KISS1, LHCGR
Signaling by Overexpressed Wild-Type EGFR in Cancer	1	105.7×	0.086	AREG
Hedgehog ‘off’ state	2	13.2×	0.086	GLI2, GLI3
HHAT G278V doesn’t palmitoylate Hh-Np	1	84.6×	0.089	DHH
RUNX2 regulates chondrocyte maturation	1	84.6×	0.089	GLI2
G alpha (q) signalling events	3	6.4×	0.089	PROK2, GPRC6A, KISS1
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	2	10.8×	0.104	CBX2, MAMLD1
Gene expression (Transcription)	5	3.3×	0.109	TGIF1, CBX2, MAMLD1, AR, NR5A1
Release of Hh-Np from the secreting cell	1	52.9×	0.109	DHH
Ligand-receptor interactions	1	52.9×	0.109	DHH
Relaxin receptors	1	47.0×	0.109	RXFP2
Inhibition of Signaling by Overexpressed EGFR	1	47.0×	0.109	AREG
OAS antiviral response	1	47.0×	0.109	FLNA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 32 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
male gonad development	6	29.3×	2e-05	RXFP2, WT1, MAMLD1, AR, LHCGR, NR5A1
positive regulation of male gonad development	3	158.0×	2e-04	WT1, DHX37, NR5A1
Leydig cell differentiation	3	112.8×	4e-04	DHH, AR, NR5A1
male genitalia development	3	83.2×	8e-04	WT1, HSD17B3, LHCGR
developmental growth	3	68.7×	0.001	TBCE, GLI2, GLI3
hindgut morphogenesis	2	263.3×	0.002	GLI2, GLI3
negative regulation of female gonad development	2	263.3×	0.002	WT1, NR5A1
cellular response to gonadotropin stimulus	2	175.5×	0.003	WT1, LHCGR
heart development	5	12.3×	0.003	SOX4, WT1, FLRT3, GLI2, GLI3
hormone-mediated signaling pathway	3	37.6×	0.003	RXFP2, LHCGR, NR5A1
pyramidal neuron development	2	131.7×	0.005	FGFR2, PLXNA3
tissue development	2	117.0×	0.005	WT1, NR5A1
osteoblast differentiation	4	15.2×	0.005	WWOX, DHH, GLI2, GLI3
sex determination	2	105.3×	0.006	WT1, NR5A1
adenylate cyclase-activating G protein-coupled receptor signaling pathway	4	14.1×	0.006	RXFP2, GPRC6A, GHRHR, LHCGR
regulation of steroid biosynthetic process	2	95.8×	0.006	DHH, NR5A1
male sex determination	2	87.8×	0.007	DHH, NR5A1
negative regulation of apoptotic process	6	6.5×	0.008	RXFP2, WT1, PROK2, FLNA, GLI3, PROP1
positive regulation of insulin-like growth factor receptor signaling pathway	2	75.2×	0.008	GHRHR, AR
negative regulation of transcription by RNA polymerase II	8	4.4×	0.008	SOX4, TGIF1, WT1, CBX2, FGFR2, GLI2, GLI3, AR
axon guidance	4	11.3×	0.010	FLRT3, GLI2, GLI3, PLXNA3
embryonic digestive tract development	2	62.0×	0.010	GLI2, GLI3
mammary gland alveolus development	2	62.0×	0.010	AR, AREG
embryonic digestive tract morphogenesis	2	58.5×	0.011	FGFR2, GLI3
glial cell proliferation	2	55.4×	0.011	SOX4, AREG
hormone metabolic process	2	55.4×	0.011	GHRHR, NR5A1
lung development	3	18.6×	0.011	FGFR2, GLI2, GLI3
smoothened signaling pathway	3	17.0×	0.013	DHH, GLI2, GLI3
camera-type eye morphogenesis	2	47.9×	0.014	SOX4, GLI3
seminiferous tubule development	2	47.9×	0.014	AR, LHCGR

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Testosterone	Phase 3 (in late-stage trials)

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 5 · Phased (≥1): 6 · Undrugged: 27

Druggability breadth: 14 of 33 evidence-associated genes (42%) 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.

Symbol	Example approved molecule
CACNA1A	NIMODIPINE
FGFR2	PONATINIB
GHRHR	DOCETAXEL
AR	PROGESTERONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AR	116	4
FGFR2	59	4
CACNA1A	2	4
HSD17B3	2	3
FLNA	1	2
GHRHR	1	4
RXFP2	0	0
IGSF10	0	0
SOX4	0	0
TBCE	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIMODIPINE	4	CACNA1A
TACRINE	4	CACNA1A
PONATINIB	4	FGFR2
PEMIGATINIB	4	FGFR2
NINTEDANIB	4	FGFR2
FEDRATINIB	4	FGFR2
LENVATINIB	4	FGFR2
AXITINIB	4	FGFR2
SORAFENIB	4	FGFR2
INFIGRATINIB PHOSPHATE	4	FGFR2
INFIGRATINIB	4	FGFR2
IBRUTINIB	4	FGFR2
CERITINIB	4	FGFR2
VANDETANIB	4	FGFR2
NINTEDANIB ESYLATE	4	FGFR2
BRIGATINIB	4	FGFR2
ERDAFITINIB	4	FGFR2
FUTIBATINIB	4	FGFR2
PAZOPANIB	4	FGFR2
SUNITINIB	4	FGFR2
DASATINIB	4	FGFR2
ERLOTINIB	4	FGFR2
MIDOSTAURIN	4	FGFR2
DOCETAXEL	4	GHRHR
PROGESTERONE	4	AR
ENZALUTAMIDE	4	AR
HYDROCORTISONE ACETATE	4	AR
EPLERENONE	4	AR
CHLORMADINONE ACETATE	4	AR
ARIPIPRAZOLE	4	AR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
AR	2,100	Binding:1727, Functional:339, ADMET:33, Unclassified:1
FGFR2	966	Binding:940, Functional:22, ADMET:4
NR5A1	88	Binding:84, Functional:4
HSD17B3	64	Binding:62, ADMET:2
LHCGR	54	Binding:35, Functional:18, ADMET:1
CACNA1A	19	Binding:18, Functional:1
CBX2	12	Binding:11, Functional:1
FLNA	7	Binding:7
GLI2	6	Binding:6
RXFP2	5	Functional:3, Binding:2
GHRHR	3	Binding:3
GPRC6A	2	Binding:2
AREG	1	Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FGFR2	2.7.10.1	receptor protein-tyrosine kinase
HSD17B3	1.1.1.51, 1.1.1.64	3(or 17)beta-hydroxysteroid dehydrogenase, testosterone 17beta-dehydrogenase (NADP+)

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
FGFR2	966
AR	2,100

Pharmacogenomics

Cohort genes with a PharmGKB record: 33; 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.

Compound	Max phase	Cohort target (bioactivity)
NIMODIPINE	4	CACNA1A
TACRINE	4	CACNA1A
PONATINIB	4	FGFR2
PEMIGATINIB	4	FGFR2
NINTEDANIB	4	FGFR2
FEDRATINIB	4	FGFR2
LENVATINIB	4	FGFR2
AXITINIB	4	FGFR2
SORAFENIB	4	FGFR2
INFIGRATINIB PHOSPHATE	4	FGFR2
INFIGRATINIB	4	FGFR2
IBRUTINIB	4	FGFR2
CERITINIB	4	FGFR2
VANDETANIB	4	FGFR2
NINTEDANIB ESYLATE	4	FGFR2
BRIGATINIB	4	FGFR2
ERDAFITINIB	4	FGFR2
FUTIBATINIB	4	FGFR2
PAZOPANIB	4	FGFR2
SUNITINIB	4	FGFR2
DASATINIB	4	FGFR2
ERLOTINIB	4	FGFR2
MIDOSTAURIN	4	FGFR2
DOCETAXEL	4	GHRHR
PROGESTERONE	4	AR
ENZALUTAMIDE	4	AR
HYDROCORTISONE ACETATE	4	AR
EPLERENONE	4	AR
CHLORMADINONE ACETATE	4	AR
ARIPIPRAZOLE	4	AR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	CACNA1A, FGFR2, GHRHR, AR
B	Phased (≥1) drug, not yet approved	2	FLNA, HSD17B3
C	Druggable family + PDB, no drug	4	RXFP2, FLRT3, LHCGR, NR5A1
D	Druggable family + AlphaFold only, no drug	4	IGSF10, GPRC6A, CCDC141, PLXNA3
E	Difficult family or no structure, no drug	19	SOX4, TBCE, TGIF1, MYRF, WT1, WWOX, CBX2, SPRY4, DHX37, PROK2 (+9 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MAMLD1	0	AR
PROP1	0	GHRHR
RXFP2	5	—
IGSF10	0	—
SOX4	0	—
TBCE	0	—
TGIF1	0	—
MYRF	0	—
WT1	0	—
WWOX	0	—
CBX2	12	—
SPRY4	0	—
DHX37	0	—
PROK2	0	—
GPRC6A	2	—
CCDC141	0	—
DHH	0	—
STON1-GTF2A1L	0	—
FLRT3	0	—
FOXP1	0	—
GLI2	6	—
GLI3	0	—
KISS1	0	—
AREG	1	—
LHCGR	54	—
NR5A1	88	—
PLXNA3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	11
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03718234	PHASE1	COMPLETED	Subcutaneous Hydrocortisone Children With Congenital Adrenal Hyperplasia
NCT03102554	Not specified	ENROLLING_BY_INVITATION	Genetics of Differences of Sex Development and Hypospadias
NCT03283852	Not specified	RECRUITING	Identifying New Genetic Causes to Development Disorders
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04717349	Not specified	RECRUITING	Data Collection Study of Pediatric and Adolescent Gynecology Conditions
NCT05058781	Not specified	RECRUITING	Minipuberty in Infants Born With Potential Hypogonadism Hypogonadotrope
NCT06692049	Not specified	RECRUITING	Gonadal Tissue Cryopreservation for Fertility Preservation in Children with a Disorder of Sex Development
NCT06989593	Not specified	RECRUITING	Breaking Silence Through Story: A Narrative Medicine Intervention for Parents of Children With Urogenital Conditions
NCT00485186	Not specified	WITHDRAWN	Gene Polymorphisms Influencing Steroid Synthesis and Action
NCT01875640	Not specified	COMPLETED	Decision Support for Parents Receiving Information About Child’s Rare Disease
NCT02784184	Not specified	UNKNOWN	COPENHAGEN Minipuberty Study
NCT04195490	Not specified	UNKNOWN	Evaluation of Outcomes of Feminizing Genitoplasty in Children With Disorders of Sex Development

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
HYDROCORTISONE	4	1