46 XY differences of sex development

Summary

46 XY differences of sex development (MONDO:0020040) is a disease (an umbrella term covering 24 Mondo subtypes) caused by DMRT1 (GenCC Strong), with 15 cohort genes and 2 clinical trials. The dominant Reactome pathway is Transcriptional regulation of testis differentiation (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Denmark) [Orphanet-validated]
• Causal gene: DMRT1 (GenCC Strong)
• Umbrella term: 24 Mondo subtypes
• Cohort genes: 15
• ClinVar variants: 162
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.06	Denmark	Validated
Prevalence at birth	1-9 / 100 000	6.4	Denmark	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	46 XY differences of sex development
Mondo ID	MONDO:0020040
MeSH	D058490
Orphanet	98085
NCIT	C127171
SNOMED CT	8234004
UMLS	C2751824
MedGen	414114
GARD	0008538
Is cancer (heuristic)	no

Also known as: 46 XY differences of sex development · 46, XY disorder of sexual development · 46, XY DSD · 46, XY female · 46,XY disorder of sex development · 46,XY disorders of Sex development · 46,XY DSD · XY female

Data availability: 162 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 24 Mondo subtypes.

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

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

Subtypes (24): 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, 46,XY ovotesticular disorder of sex development, 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

162 retrieved; paginated sample, class counts are floors:

51 uncertain significance, 30 pathogenic, 24 likely benign, 20 benign, 15 likely pathogenic, 11 conflicting classifications of pathogenicity, 9 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068954	NM_004959.5(NR5A1):c.232_244del (p.Met78fs)	NR5A1	Pathogenic	criteria provided, single submitter
1075535	NM_004959.5(NR5A1):c.75C>G (p.Tyr25Ter)	NR5A1	Pathogenic	criteria provided, single submitter
1075935	NM_004959.5(NR5A1):c.572del (p.Arg191fs)	NR5A1	Pathogenic	criteria provided, single submitter
1256011	NM_004959.5(NR5A1):c.250C>T (p.Arg84Cys)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1354651	NM_004959.5(NR5A1):c.231del (p.Met78fs)	NR5A1	Pathogenic	criteria provided, single submitter
1412226	NM_004959.5(NR5A1):c.895C>T (p.Gln299Ter)	NR5A1	Pathogenic	criteria provided, single submitter
1442980	NM_004959.5(NR5A1):c.86C>T (p.Thr29Met)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454827	NM_004959.5(NR5A1):c.984del (p.Gln329fs)	NR5A1	Pathogenic	criteria provided, single submitter
1687572	NM_004959.5(NR5A1):c.259C>T (p.Arg87Cys)	NR5A1	Pathogenic	criteria provided, multiple submitters, no conflicts
2000749	NM_004959.5(NR5A1):c.1221C>A (p.Cys407Ter)	NR5A1	Pathogenic	criteria provided, single submitter
2019693	NM_004959.5(NR5A1):c.591C>G (p.Tyr197Ter)	NR5A1	Pathogenic	criteria provided, single submitter
2087543	NM_004959.5(NR5A1):c.1065_1138+158del	NR5A1	Pathogenic	criteria provided, single submitter
2092105	NM_004959.5(NR5A1):c.1106_1109del (p.Val369fs)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2136807	NM_004959.5(NR5A1):c.205C>G (p.Arg69Gly)	NR5A1	Pathogenic	criteria provided, single submitter
2921914	NM_004959.5(NR5A1):c.601del (p.Tyr201fs)	NR5A1	Pathogenic	criteria provided, single submitter
2938097	NM_004959.5(NR5A1):c.64G>A (p.Gly22Ser)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2941241	NM_004959.5(NR5A1):c.236G>C (p.Arg79Pro)	NR5A1	Pathogenic	criteria provided, single submitter
2944523	NM_004959.5(NR5A1):c.245-2A>G	NR5A1	Pathogenic	criteria provided, single submitter
2947882	NM_004959.5(NR5A1):c.991-18C>A	NR5A1	Pathogenic	criteria provided, single submitter
3245234	NC_000009.11:g.(?127245037)(127267690_?)del	NR5A1	Pathogenic	criteria provided, single submitter
3245235	NC_000009.11:g.(?127262349)(127267690_?)del	NR5A1	Pathogenic	criteria provided, single submitter
3245237	NC_000009.11:g.(?127262449)(127265674_?)del	NR5A1	Pathogenic	criteria provided, single submitter
3596432	NM_004959.5(NR5A1):c.247G>A (p.Val83Met)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372437	NM_004959.5(NR5A1):c.937C>T (p.Arg313Cys)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3755587	NM_004959.5(NR5A1):c.785_791del (p.Phe262fs)	NR5A1	Pathogenic	criteria provided, single submitter
3757286	NM_004959.5(NR5A1):c.105del (p.Phe36fs)	NR5A1	Pathogenic	criteria provided, single submitter
3757330	NM_004959.5(NR5A1):c.795del (p.Cys266fs)	NR5A1	Pathogenic	criteria provided, single submitter
3759840	NM_004959.5(NR5A1):c.1223_1224dup (p.Tyr409fs)	NR5A1	Pathogenic	criteria provided, single submitter
449434	NM_004959.5(NR5A1):c.938G>A (p.Arg313His)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4783699	NM_004959.5(NR5A1):c.319C>T (p.Gln107Ter)	NR5A1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 48 · 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
DMRT1	Strong	Autosomal dominant	46,XY disorder of sex development	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DMRT1	Orphanet:242	46,XY complete gonadal dysgenesis
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
SRCAP	Orphanet:2044	Floating-Harbor syndrome
SRCAP	Orphanet:528084	Non-specific syndromic intellectual disability
PORCN	Orphanet:2092	Focal dermal hypoplasia
PORCN	Orphanet:98938	Colobomatous microphthalmia
CHD7	Orphanet:138	CHARGE syndrome
CHD7	Orphanet:39041	Omenn syndrome
CHD7	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
CHD7	Orphanet:478	Kallmann syndrome
FGFR3	Orphanet:15	Achondroplasia
FGFR3	Orphanet:1860	Thanatophoric dysplasia type 1
FGFR3	Orphanet:2363	Lacrimoauriculodentodigital syndrome
FGFR3	Orphanet:251576	Gliosarcoma
FGFR3	Orphanet:251579	Giant cell glioblastoma
FGFR3	Orphanet:35099	Non-syndromic bicoronal craniosynostosis
FGFR3	Orphanet:429	Hypochondroplasia
FGFR3	Orphanet:53271	Muenke syndrome
FGFR3	Orphanet:794	Saethre-Chotzen syndrome
FGFR3	Orphanet:85164	Camptodactyly-tall stature-scoliosis-hearing loss syndrome
FGFR3	Orphanet:85165	Severe achondroplasia-developmental delay-acanthosis nigricans syndrome
FGFR3	Orphanet:93262	Crouzon syndrome-acanthosis nigricans syndrome
FGFR3	Orphanet:93274	Thanatophoric dysplasia type 2
INSR	Orphanet:2297	Insulin-resistance syndrome type A
INSR	Orphanet:263458	Hyperinsulinism due to INSR deficiency
INSR	Orphanet:508	Donohue syndrome
INSR	Orphanet:769	Rabson-Mendenhall syndrome
LHCGR	Orphanet:3000	Familial peripheral male-limited precocious puberty
LHCGR	Orphanet:96265	Leydig cell hypoplasia due to complete LH resistance
LHCGR	Orphanet:96266	Leydig cell hypoplasia due to partial LH resistance
NR2F2	Orphanet:99067	Complete atrioventricular septal defect with ventricular hypoplasia
NR2F2	Orphanet:99068	Complete atrioventricular septal defect-tetralogy of Fallot
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
PKD1	Orphanet:730	Autosomal dominant polycystic kidney disease
PKD1	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
POR	Orphanet:63269	Antley-Bixler syndrome with genital anomaly and disorder of steroidogenesis
POR	Orphanet:95699	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency
PRKD1	Orphanet:276145	Malignant epithelial tumor of salivary glands
PRKD1	Orphanet:708019	Congenital heart defect-ectodermal dysplasia- brachydactyly-telangiectasia syndrome

Cohort genes → proteins

15 cohort genes, 15 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	15

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DMRT1	HGNC:2934	ENSG00000137090	Q9Y5R6	Doublesex- and mab-3-related transcription factor 1	gencc
SOX8	HGNC:11203	ENSG00000005513	P57073	Transcription factor SOX-8	clinvar
SRY	HGNC:11311	ENSG00000184895	Q05066	Sex-determining region Y protein	clinvar
SRCAP	HGNC:16974	ENSG00000080603	Q6ZRS2	Chromatin remodeling protein SRCAP	clinvar
ADAMTS16	HGNC:17108	ENSG00000145536	Q8TE57	A disintegrin and metalloproteinase with thrombospondin motifs 16	clinvar
PORCN	HGNC:17652	ENSG00000102312	Q9H237	Protein-serine O-palmitoleoyltransferase porcupine	clinvar
CHD7	HGNC:20626	ENSG00000171316	Q9P2D1	ATP-dependent chromatin remodeler CHD7	clinvar
FGFR3	HGNC:3690	ENSG00000068078	P22607	Fibroblast growth factor receptor 3	clinvar
INSR	HGNC:6091	ENSG00000171105	P06213	Insulin receptor	clinvar
LHCGR	HGNC:6585	ENSG00000138039	P22888	Lutropin-choriogonadotropic hormone receptor	clinvar
NR2F2	HGNC:7976	ENSG00000185551	P24468	COUP transcription factor 2	clinvar
NR5A1	HGNC:7983	ENSG00000136931	Q13285	Steroidogenic factor 1	clinvar
PKD1	HGNC:9008	ENSG00000008710	P98161	Polycystin-1	clinvar
POR	HGNC:9208	ENSG00000127948	P16435	NADPH–cytochrome P450 reductase	clinvar
PRKD1	HGNC:9407	ENSG00000184304	Q15139	Serine/threonine-protein kinase D1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DMRT1	Doublesex- and mab-3-related transcription factor 1	Transcription factor that plays a key role in male sex determination and differentiation by controlling testis development and male germ cell proliferation.
SOX8	Transcription factor SOX-8	Transcription factor that may play a role in central nervous system, limb and facial development.
SRY	Sex-determining region Y protein	Transcriptional regulator that controls a genetic switch in male development.
SRCAP	Chromatin remodeling protein SRCAP	Acts both as a chromatin remodeler and transcription coregulator.
PORCN	Protein-serine O-palmitoleoyltransferase porcupine	Protein-serine O-palmitoleoyltransferase that acts as a key regulator of the Wnt signaling pathway by mediating the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1(9Z)), to Wnt proteins.
CHD7	ATP-dependent chromatin remodeler CHD7	ATP-dependent chromatin-remodeling factor, slides nucleosomes along DNA; nucleosome sliding requires ATP.
FGFR3	Fibroblast growth factor receptor 3	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 and apoptosis.
INSR	Insulin receptor	Receptor tyrosine kinase which mediates the pleiotropic actions of insulin.
LHCGR	Lutropin-choriogonadotropic hormone receptor	Receptor for lutropin-choriogonadotropic hormone.
NR2F2	COUP transcription factor 2	Ligand-activated transcription factor.
NR5A1	Steroidogenic factor 1	Transcriptional activator.
PKD1	Polycystin-1	Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B.
POR	NADPH–cytochrome P450 reductase	This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes.
PRKD1	Serine/threonine-protein kinase D1	Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and tr…

Protein-family classification

Druggable: 10 · Difficult: 2 · Unknown: 3 · 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.

Family	Genes	Fold	FDR
Nuclear receptor	2	51.5×	0.005
Kinase	3	5.5×	0.062
Protease	1	2.4×	0.630
Antibody/Immunoglobulin	1	1.9×	0.630
Enzyme (other)	2	1.6×	0.630
GPCR	1	1.6×	0.630
Transcription factor	2	1.1×	0.638
Other/Unknown	3	0.4×	0.999

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DMRT1	Other/Unknown	no		DM_DNA-bd, DMRT1-like, DMRT
SOX8	Transcription factor	no		HMG_box_dom, Sox_N, HMG_box_dom_sf
SRY	Transcription factor	no		HMG_box_dom, SRY, HMG_box_dom_sf
SRCAP	Other/Unknown	no		SNF2_N, Helicase_C-like, Helicase_ATP-bd
ADAMTS16	Protease	yes		TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N
PORCN	Enzyme (other)	yes	2.3.1.250	MBOAT_fam, LPLAT_7/PORCN-like
CHD7	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
FGFR3	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
INSR	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
LHCGR	GPCR	yes		GPCR_Rhodpsn, Gphrmn_rcpt_fam, LSH_rcpt
NR2F2	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
NR5A1	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
PKD1	Antibody/Immunoglobulin	yes		GPS, LRRNT, PC1
POR	Enzyme (other)	yes	1.6.2.4	Flavdoxin-like, OxRdtase_FAD/NAD-bd, Flavoprot_Pyr_Nucl_cyt_Rdtase
PRKD1	Kinase	yes	2.7.11.13	Prot_kinase_dom, PH_domain, PKC_DAG/PE

Expression context

Cohort genes with no expression data: 0.

12 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)	15
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	3
sural nerve	3
right adrenal gland	3
male germ line stem cell (sensu Vertebrata) in testis	2
primordial germ cell in gonad	2
tendon of biceps brachii	2
right adrenal gland cortex	2
inferior vagus X ganglion	1
lateral globus pallidus	1
subthalamic nucleus	1
right testis	1
granulocyte	1
stromal cell of endometrium	1
left ovary	1
lower esophagus mucosa	1
cerebellar vermis	1
secondary oocyte	1
skin of hip	1
upper arm skin	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DMRT1	23	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell
SOX8	194	broad	marker	inferior vagus X ganglion, lateral globus pallidus, subthalamic nucleus
SRY	66	tissue_specific	yes	primordial germ cell in gonad, tendon of biceps brachii, right testis
SRCAP	167	ubiquitous	yes	sural nerve, stromal cell of endometrium, granulocyte
ADAMTS16	135	broad	marker	buccal mucosa cell, tendon of biceps brachii, left ovary
PORCN	184	ubiquitous	marker	lower esophagus mucosa, right adrenal gland cortex, right adrenal gland
CHD7	269	ubiquitous	marker	secondary oocyte, cerebellar vermis, sural nerve
FGFR3	262	broad	marker	upper leg skin, skin of hip, upper arm skin
INSR	296	ubiquitous	marker	buccal mucosa cell, palpebral conjunctiva, visceral pleura
LHCGR	123	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, sural nerve, lower esophagus muscularis layer
NR2F2	289	ubiquitous	marker	urethra, cardia of stomach, dorsal root ganglion
NR5A1	77	tissue_specific	yes	right adrenal gland cortex, right adrenal gland, left adrenal gland
PKD1	290		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
POR	266	ubiquitous	marker	adrenal tissue, right lobe of liver, right adrenal gland
PRKD1	239	ubiquitous	marker	ventricular zone, seminal vesicle, thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHD7	4,819
FGFR3	4,510
INSR	4,446
SRCAP	2,987
SRY	2,835
NR2F2	2,741
POR	2,263
SOX8	2,209
NR5A1	2,146
PRKD1	2,131

Intra-cohort edges

A	B	Sources
DMRT1	NR5A1	string_interaction
DMRT1	SOX8	string_interaction
DMRT1	SRY	string_interaction
NR5A1	SRY	string_interaction
PKD1	PRKD1	string_interaction

Structural data

PDB: 12 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INSR	P06213	88
FGFR3	P22607	15
PKD1	P98161	13
SRY	Q05066	10
SRCAP	Q6ZRS2	10
POR	P16435	9
PORCN	Q9H237	7
NR5A1	Q13285	6
LHCGR	P22888	4
CHD7	Q9P2D1	3
DMRT1	Q9Y5R6	1
NR2F2	P24468	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADAMTS16	Q8TE57	72.07
PRKD1	Q15139	68.99
SOX8	P57073	59.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 68. Enrichment computed across 15 evidence-associated genes (13 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 13 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	164.7×	4e-05	SRY, DMRT1, NR5A1
t(4;14) translocations of FGFR3	1	878.5×	0.026	FGFR3
Signaling by FGFR3 fusions in cancer	1	878.5×	0.026	FGFR3
LGK974 inhibits PORCN	1	439.2×	0.039	PORCN
IRS activation	1	175.7×	0.076	INSR
FGFR3b ligand binding and activation	1	125.5×	0.076	FGFR3
Signal attenuation	1	79.9×	0.076	INSR
Signaling by activated point mutants of FGFR3	1	73.2×	0.076	FGFR3
Hormone ligand-binding receptors	1	73.2×	0.076	LHCGR
FGFR3c ligand binding and activation	1	67.6×	0.076	FGFR3
Phospholipase C-mediated cascade; FGFR3	1	67.6×	0.076	FGFR3
Signaling by Insulin receptor	1	67.6×	0.076	INSR
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	2	14.9×	0.076	FGFR3, INSR
PIP3 activates AKT signaling	2	10.3×	0.076	FGFR3, INSR
Cytochrome P450 - arranged by substrate type	1	54.9×	0.080	POR
Insulin receptor signalling cascade	1	51.7×	0.080	INSR
PI-3K cascade:FGFR3	1	48.8×	0.080	FGFR3
SHC-mediated cascade:FGFR3	1	46.2×	0.080	FGFR3
Transcriptional regulation of pluripotent stem cells	1	41.8×	0.080	NR5A1
FRS-mediated FGFR3 signaling	1	41.8×	0.080	FGFR3
VxPx cargo-targeting to cilium	1	39.9×	0.080	PKD1
Signaling by FGFR3 in disease	1	38.2×	0.080	FGFR3
Negative regulation of FGFR3 signaling	1	33.8×	0.086	FGFR3
WNT ligand biogenesis and trafficking	1	32.5×	0.086	PORCN
Insulin receptor recycling	1	29.3×	0.091	INSR
SUMOylation of intracellular receptors	1	25.8×	0.099	NR5A1
Defective B3GALTL causes PpS	1	23.7×	0.103	ADAMTS16
O-glycosylation of TSR domain-containing proteins	1	23.1×	0.103	ADAMTS16
Sphingolipid de novo biosynthesis	1	22.0×	0.103	PRKD1
Negative regulation of the PI3K/AKT network	1	21.4×	0.103	INSR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
male sex determination	4	374.5×	6e-08	SRY, DMRT1, INSR, NR5A1
positive regulation of male gonad development	3	337.0×	9e-06	SRY, DMRT1, NR5A1
positive regulation of transcription by RNA polymerase II	9	8.9×	9e-06	SOX8, SRY, SRCAP, CHD7, DMRT1, NR2F2, NR5A1, PKD1 (+1 more)
male gonad development	4	41.6×	2e-04	SOX8, INSR, LHCGR, NR5A1
genitalia development	2	224.7×	0.002	CHD7, PKD1
Sertoli cell differentiation	2	204.3×	0.002	DMRT1, NR5A1
placenta blood vessel development	2	187.2×	0.002	NR2F2, PKD1
Sertoli cell development	2	149.8×	0.003	SOX8, DMRT1
sex differentiation	2	112.3×	0.005	SRY, DMRT1
female gonad development	2	107.0×	0.005	NR2F2, NR5A1
adrenal gland development	2	89.9×	0.006	INSR, NR5A1
positive regulation of mitotic nuclear division	2	72.5×	0.008	DMRT1, INSR
positive regulation of gene expression	4	10.3×	0.011	SOX8, SRY, NR5A1, PRKD1
right ventricular compact myocardium morphogenesis	1	1123.5×	0.011	CHD7
radial pattern formation	1	1123.5×	0.011	NR2F2
nitrate catabolic process	1	1123.5×	0.011	POR
negative regulation of developmental growth	1	1123.5×	0.011	FGFR3
positive regulation of growth plate cartilage chondrocyte proliferation	1	1123.5×	0.011	POR
metanephric distal tubule morphogenesis	1	1123.5×	0.011	PKD1
regulation of steroid hormone biosynthetic process	1	1123.5×	0.011	LHCGR
positive regulation of steroid hormone biosynthetic process	1	1123.5×	0.011	POR
hormone-mediated signaling pathway	2	53.5×	0.011	LHCGR, NR5A1
heart morphogenesis	2	49.9×	0.011	CHD7, INSR
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	3	15.7×	0.011	FGFR3, INSR, PRKD1
primary sex determination	1	561.7×	0.012	NR5A1
positive regulation of gliogenesis	1	561.7×	0.012	SOX8
regulation of skeletal muscle contraction by modulation of calcium ion sensitivity of myofibril	1	561.7×	0.012	PRKD1
ovulation cycle process	1	561.7×	0.012	LHCGR
luteinizing hormone signaling pathway	1	561.7×	0.012	LHCGR
protein palmitoleylation	1	561.7×	0.012	PORCN

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 4 · Phased (≥1): 6 · Undrugged: 9

Druggability breadth: 9 of 15 evidence-associated genes (60%) 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
FGFR3	PONATINIB
INSR	FEDRATINIB
PRKD1	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR3	64	4
INSR	36	4
PRKD1	26	4
NR2F2	3	3
PORCN	2	2
POR	1	2
DMRT1	0	0
SOX8	0	0
SRY	0	0
SRCAP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	FGFR3
PEMIGATINIB	4	FGFR3
NINTEDANIB	4	FGFR3, INSR, PRKD1
FEDRATINIB	4	FGFR3, INSR
LENVATINIB	4	FGFR3
AXITINIB	4	FGFR3
SORAFENIB	4	FGFR3, INSR
INFIGRATINIB PHOSPHATE	4	FGFR3, INSR
INFIGRATINIB	4	FGFR3, INSR
ENTRECTINIB	4	FGFR3, INSR
CERITINIB	4	FGFR3, INSR
VANDETANIB	4	FGFR3
NINTEDANIB ESYLATE	4	FGFR3
BRIGATINIB	4	FGFR3, INSR, PRKD1
ERDAFITINIB	4	FGFR3
FUTIBATINIB	4	FGFR3
PAZOPANIB	4	FGFR3
SUNITINIB	4	FGFR3, INSR, PRKD1
DASATINIB	4	FGFR3
CRIZOTINIB	4	FGFR3, INSR, PRKD1
MIDOSTAURIN	4	FGFR3, PRKD1
NERATINIB	4	INSR, PRKD1
OSIMERTINIB	4	INSR
LAPATINIB	4	INSR
INGENOL MEBUTATE	4	PRKD1
TAMOXIFEN	4	PRKD1
GEFITINIB	4	PRKD1
LINIFANIB	3	FGFR3, INSR
SEMAXANIB	3	FGFR3
BRIVANIB	3	FGFR3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
FGFR3	975	Binding:948, Functional:18, ADMET:9
INSR	954	Binding:900, Functional:49, ADMET:4, Toxicity:1
PRKD1	660	Binding:650, Functional:10
NR5A1	88	Binding:84, Functional:4
LHCGR	54	Binding:35, Functional:18, ADMET:1
PORCN	31	Binding:31
PKD1	27	Binding:27
POR	21	ADMET:14, Binding:7
NR2F2	2	Binding:1, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PORCN	2.3.1.250	[Wnt protein] O-palmitoleoyl transferase
FGFR3	2.7.10.1	receptor protein-tyrosine kinase
INSR	2.7.10.1	receptor protein-tyrosine kinase
POR	1.6.2.4	NADPH-hemoprotein reductase
PRKD1	2.7.11.13	protein kinase C

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
FGFR3	975
INSR	954
PRKD1	660

Pharmacogenomics

Cohort genes with a PharmGKB record: 15; 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)
PONATINIB	4	FGFR3
PEMIGATINIB	4	FGFR3
NINTEDANIB	4	FGFR3, INSR, PRKD1
FEDRATINIB	4	FGFR3, INSR
LENVATINIB	4	FGFR3
AXITINIB	4	FGFR3
SORAFENIB	4	FGFR3, INSR
INFIGRATINIB PHOSPHATE	4	FGFR3, INSR
INFIGRATINIB	4	FGFR3, INSR
ENTRECTINIB	4	FGFR3, INSR
CERITINIB	4	FGFR3, INSR
VANDETANIB	4	FGFR3
NINTEDANIB ESYLATE	4	FGFR3
BRIGATINIB	4	FGFR3, INSR, PRKD1
ERDAFITINIB	4	FGFR3
FUTIBATINIB	4	FGFR3
PAZOPANIB	4	FGFR3
SUNITINIB	4	FGFR3, INSR, PRKD1
DASATINIB	4	FGFR3
CRIZOTINIB	4	FGFR3, INSR, PRKD1
MIDOSTAURIN	4	FGFR3, PRKD1
NERATINIB	4	INSR, PRKD1
OSIMERTINIB	4	INSR
LAPATINIB	4	INSR
INGENOL MEBUTATE	4	PRKD1
TAMOXIFEN	4	PRKD1
GEFITINIB	4	PRKD1
LINIFANIB	3	FGFR3, INSR
SEMAXANIB	3	FGFR3
BRIVANIB	3	FGFR3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	FGFR3, INSR, PRKD1
B	Phased (≥1) drug, not yet approved	3	PORCN, NR2F2, POR
C	Druggable family + PDB, no drug	3	LHCGR, NR5A1, PKD1
D	Druggable family + AlphaFold only, no drug	1	ADAMTS16
E	Difficult family or no structure, no drug	5	DMRT1, SOX8, SRY, SRCAP, CHD7

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PKD1	27	PRKD1
DMRT1	0	—
SOX8	0	—
SRY	0	—
SRCAP	0	—
ADAMTS16	0	—
CHD7	0	—
LHCGR	54	—
NR5A1	88	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT06723938	Not specified	RECRUITING	Phenotypic and Genotypic Characterisation of a Large, Multicentre Italian Cohort of 46, XY DSD Patients