Craniosynostosis

Summary

Craniosynostosis (MONDO:0015469) is a disease (an umbrella term covering 29 Mondo subtypes) with 61 cohort genes and 17 clinical trials. The dominant Reactome pathway is GLI proteins bind promoters of Hh responsive genes to promote transcription (3 cohort genes). Top therapeutic interventions include sodium chloride, aminocaproic acid, and tranexamic acid.

At a glance

• Prevalence: 1-5 / 10 000 (France) [Orphanet-validated]
• Umbrella term: 29 Mondo subtypes
• Cohort genes: 61
• ClinVar variants: 311
• Clinical trials: 17

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-5 / 10 000	47.6	France	Validated
Prevalence at birth	1-5 / 10 000	49.4	Australia	Validated
Prevalence at birth	1-5 / 10 000	43	United States	Validated
Prevalence at birth	1-5 / 10 000	24.3	Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	craniosynostosis
Mondo ID	MONDO:0015469
MeSH	D003398
OMIM	123100
Orphanet	1531
DOID	DOID:2340
ICD-10-CM	Q75.0
ICD-11	458033798
NCIT	C84655
UMLS	C0010278
MedGen	1163
GARD	0006209
MedDRA	10048907, 10049889
Is cancer (heuristic)	no

Also known as: craniosynostosis syndrome · CSO · premature closure of cranial sutures

Data availability: 311 ClinVar variants · 7 GenCC gene-disease records · 1 cell line.

Disease family

An umbrella term covering 29 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › dysostosis › synostosis › craniosynostosis

Related subtypes (10): Banki syndrome, humeroradial synostosis, calcaneonavicular coalition, tibio-fibular synostosis, multiple synostoses syndrome, humero-radio-ulnar synostosis, congenital radioulnar synostosis, humero-ulnar synostosis, coronal synostosis, syndactyly and jejunal atresia, non-syndromic pansynostosis

Subtypes (29): craniosynostosis, Adelaide type, craniosynostosis with ectopia lentis, craniosynostosis syndrome, autosomal recessive, craniosynostosis with ocular abnormalities and hallucal defects, isolated craniosynostosis, syndromic craniosynostosis, craniosynostosis Fontaine type, craniosynostosis Maroteaux Fonfria type, craniosynostosis alopecia brain defect, craniosynostosis arthrogryposis cleft palate, craniosynostosis autosomal dominant, craniosynostosis cleft lip palate arthrogryposis, craniosynostosis contractures cleft, craniosynostosis exostoses nevus epibulbar dermoid, craniosynostosis intellectual disability heart defects, Hordnes Engebretsen Knudtson syndrome, Iida Kannari syndrome, mehta lewis patton syndrome, non-syndromic unicoronal craniosynostosis, non-syndromic unilambdoid craniosynostosis, non-syndromic unifrontosphenoidal craniosynostosis, non-syndromic unisquamosal craniosynostosis, non-syndromic multisutural craniosynostosis, non-syndromic non-specific multisutural craniosynostosis, non-syndromic bilambdoid craniosynostosis, non-syndromic unicoronal and sagittal craniosynostosis, non-syndromic metopic and sagittal craniosynostosis, non-syndromic bicoronal and metopic craniosynostosis, non-syndromic bicoronal and sagittal craniosynostosis

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

311 retrieved; paginated sample, class counts are floors:

128 uncertain significance, 65 conflicting classifications of pathogenicity, 48 benign/likely benign, 30 benign, 16 pathogenic, 16 likely pathogenic, 6 likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
267821	46;XX;t(3;12)(q13.2;q14)dn		Pathogenic	criteria provided, single submitter
13263	NM_000141.5(FGFR2):c.1025G>A (p.Cys342Tyr)	FGFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13268	NM_000141.5(FGFR2):c.1032G>A (p.Ala344=)	FGFR2	Pathogenic	criteria provided, multiple submitters, no conflicts
16329	NM_000142.5(FGFR3):c.1172C>A (p.Ala391Glu)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16340	NM_000142.5(FGFR3):c.749C>G (p.Pro250Arg)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1177290	NM_000168.6(GLI3):c.368-459_473+494del	GLI3	Pathogenic	criteria provided, single submitter
2429382	NM_001142784.3(IL11RA):c.919T>C (p.Trp307Arg)	IL11RA	Pathogenic	no assertion criteria provided
280246	NM_006766.5(KAT6A):c.3661G>T (p.Glu1221Ter)	KAT6A	Pathogenic	criteria provided, multiple submitters, no conflicts
1065630	NM_000528.4(MAN2B1):c.215_216del (p.His72fs)	MAN2B1	Pathogenic	criteria provided, single submitter
4531312	NM_022716.4(PRRX1):c.370C>T (p.Arg124Ter)	PRRX1	Pathogenic	criteria provided, single submitter
4075258	NM_003036.4(SKI):c.59C>G (p.Thr20Arg)	SKI	Pathogenic	criteria provided, single submitter
1344679	NM_003108.4(SOX11):c.191G>A (p.Arg64His)	SOX11	Pathogenic	criteria provided, single submitter
974904	NM_001367873.1(SOX6):c.242C>G (p.Ser81Ter)	SOX6	Pathogenic	criteria provided, single submitter
1344584	NM_207037.2(TCF12):c.1643_1647del (p.Glu548fs)	TCF12	Pathogenic	criteria provided, single submitter
1172629	NM_001378418.1(TCF20):c.1166_1167del (p.Leu389fs)	TCF20	Pathogenic	criteria provided, single submitter
402116	NM_021224.6(ZNF462):c.3787C>T (p.Arg1263Ter)	ZNF462	Pathogenic	no assertion criteria provided
402117	NM_021224.6(ZNF462):c.4263del (p.Glu1422fs)	ZNF462	Pathogenic	no assertion criteria provided
402118	NM_021224.6(ZNF462):c.2979_2980delinsA (p.Val994fs)	ZNF462	Pathogenic	criteria provided, single submitter
1679340	NM_014255.7(CNPY2):c.46_50del (p.Gly16fs)	CNPY2	Likely pathogenic	criteria provided, single submitter
1344681	NM_001903.5(CTNNA1):c.2572_2586dup (p.Ser858_Lys862dup)	CTNNA1	Likely pathogenic	no assertion criteria provided
1344680	NM_001374353.1(GLI2):c.1600G>A (p.Ala534Thr)	GLI2	Likely pathogenic	criteria provided, single submitter
1344686	NM_001448.3(GPC4):c.455del (p.Val152fs)	GPC4	Likely pathogenic	no assertion criteria provided
523381	NM_000834.5(GRIN2B):c.2216T>G (p.Met739Arg)	GRIN2B	Likely pathogenic	criteria provided, single submitter
1164007	NM_001271938.2(MEGF8):c.7970_7972del (p.Ser2657del)	MEGF8	Likely pathogenic	criteria provided, single submitter
373987	NM_003995.4(NPR2):c.2162_2172del (p.Ser721fs)	NPR2	Likely pathogenic	no assertion criteria provided
373988	NM_003995.4(NPR2):c.779A>T (p.Glu260Val)	NPR2	Likely pathogenic	no assertion criteria provided
4072149	NM_002816.5(PSMD12):c.1284G>A (p.Trp428Ter)	PSMD12	Likely pathogenic	criteria provided, single submitter
691564	NM_207037.2(TCF12):c.1769del (p.Asp589_Leu590insTer)	TCF12	Likely pathogenic	criteria provided, single submitter
691565	NM_207037.2(TCF12):c.1606del (p.Thr536fs)	TCF12	Likely pathogenic	criteria provided, single submitter
1344682	NM_003221.4(TFAP2B):c.3G>A (p.Met1Ile)	TFAP2B	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 29 · Orphanet: 165 · 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
PRRX1	Moderate	Autosomal dominant	craniosynostosis	8
RARA	Moderate	Autosomal dominant	craniosynostosis	3
SPRY1	Moderate	Autosomal recessive	craniosynostosis
AXIN2	Limited	Autosomal dominant	craniosynostosis	7
DHRS3	Limited	Autosomal recessive	craniosynostosis
EFNA4	Limited	Autosomal dominant	craniosynostosis
FGF10	Limited	Autosomal dominant	craniosynostosis	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AXIN2	Orphanet:401911	AXIN2-related polyposis
PRRX1	Orphanet:990	Agnathia-holoprosencephaly-situs inversus syndrome
FGF10	Orphanet:2363	Lacrimoauriculodentodigital syndrome
FGF10	Orphanet:86815	Aplasia of lacrimal and salivary glands
RARA	Orphanet:520	Acute promyelocytic leukemia
RUNX2	Orphanet:1452	Cleidocranial dysplasia
RUNX2	Orphanet:2504	Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome
SKI	Orphanet:1606	1p36 deletion syndrome
SKI	Orphanet:2462	Shprintzen-Goldberg syndrome
SOX11	Orphanet:1465	Coffin-Siris syndrome
CDKL5	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CDKL5	Orphanet:3095	Atypical Rett syndrome
CDKL5	Orphanet:505652	CDKL5-deficiency disorder
CDKL5	Orphanet:697160	Infantile epileptic spasms syndrome
TCF12	Orphanet:209916	Extraskeletal myxoid chondrosarcoma
TCF12	Orphanet:35099	Non-syndromic bicoronal craniosynostosis
TCF20	Orphanet:528084	Non-specific syndromic intellectual disability
TFAP2B	Orphanet:46627	Char syndrome
TFAP2B	Orphanet:466729	Familial patent arterial duct
TGFBR1	Orphanet:284973	Marfan syndrome type 2
TGFBR1	Orphanet:60030	Loeys-Dietz syndrome
TGFBR1	Orphanet:65748	Multiple self-healing squamous epithelioma
TGFBR1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
TRPS1	Orphanet:502	Trichorhinophalangeal syndrome type 2
TRPS1	Orphanet:77258	Trichorhinophalangeal syndrome type 1
KAT6A	Orphanet:370026	Acute myeloid leukemia with t(8;16)(p11;p13) translocation
KAT6A	Orphanet:457193	KAT6-related intellectual disability-craniofacial anomalies-cardiac defects syndrome
COG5	Orphanet:263487	COG5-CDG
ADGRV1	Orphanet:231178	Usher syndrome type 2
ADGRV1	Orphanet:36387	Genetic epilepsy with febrile seizure plus
WDR19	Orphanet:1515	Cranioectodermal dysplasia
WDR19	Orphanet:3156	Senior-Loken syndrome
WDR19	Orphanet:474	Jeune syndrome
WDR19	Orphanet:93592	Juvenile nephronophthisis
CORIN	Orphanet:275555	Preeclampsia
ADAMTSL4	Orphanet:1885	Isolated ectopia lentis
CYP26B1	Orphanet:293925	Lethal occipital encephalocele-skeletal dysplasia syndrome
ZNF462	Orphanet:502430	Weiss-Kruszka Syndrome
MED13L	Orphanet:216718	Isolated congenitally uncorrected transposition of the great arteries
MED13L	Orphanet:369891	Developmental delay-facial dysmorphism syndrome due to MED13L deficiency
ALG6	Orphanet:79320	ALG6-CDG
CSF1R	Orphanet:313808	Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
CSF1R	Orphanet:556985	Early-onset calcifying leukoencephalopathy-skeletal dysplasia
KANSL1	Orphanet:363958	17q21.31 microdeletion syndrome
KANSL1	Orphanet:363965	Koolen-De Vries syndrome due to a point mutation
NPRL2	Orphanet:98820	Familial focal epilepsy with variable foci
CTNNA1	Orphanet:26106	Hereditary diffuse gastric cancer
CTNNA1	Orphanet:99001	Butterfly-shaped pigment dystrophy
CPLANE1	Orphanet:2754	Orofaciodigital syndrome type 6
CPLANE1	Orphanet:475	Isolated Joubert syndrome

Cohort genes → proteins

61 cohort genes, 61 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	61

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DHRS3	HGNC:17693	ENSG00000162496	O75911	Short-chain dehydrogenase/reductase 3	gencc,clinvar
AXIN2	HGNC:904	ENSG00000168646	Q9Y2T1	Axin-2	gencc,clinvar
PRRX1	HGNC:9142	ENSG00000116132	P54821	Paired mesoderm homeobox protein 1	gencc,clinvar
SPRY1	HGNC:11269	ENSG00000164056	O43609	Protein sprouty homolog 1	gencc
EFNA4	HGNC:3224	ENSG00000243364	P52798	Ephrin-A4	gencc
FGF10	HGNC:3666	ENSG00000070193	O15520	Fibroblast growth factor 10	gencc
RARA	HGNC:9864	ENSG00000131759	P10276	Retinoic acid receptor alpha	gencc
RUNX2	HGNC:10472	ENSG00000124813	Q13950	Runt-related transcription factor 2	clinvar
SKI	HGNC:10896	ENSG00000157933	P12755	Ski oncogene	clinvar
SOX11	HGNC:11191	ENSG00000176887	P35716	Transcription factor SOX-11	clinvar
CDKL5	HGNC:11411	ENSG00000008086	O76039	Cyclin-dependent kinase-like 5	clinvar
TCF12	HGNC:11623	ENSG00000140262	Q99081	Transcription factor 12	clinvar
TCF20	HGNC:11631	ENSG00000100207	Q9UGU0	Transcription factor 20	clinvar
TFAP2B	HGNC:11743	ENSG00000008196	Q92481	Transcription factor AP-2-beta	clinvar
TGFBR1	HGNC:11772	ENSG00000106799	P36897	TGF-beta receptor type-1	clinvar
TRPS1	HGNC:12340	ENSG00000104447	Q9UHF7	Zinc finger transcription factor Trps1	clinvar
KAT6A	HGNC:13013	ENSG00000083168	Q92794	Histone acetyltransferase KAT6A	clinvar
CNPY2	HGNC:13529	ENSG00000257727	Q9Y2B0	Protein canopy homolog 2	clinvar
COG5	HGNC:14857	ENSG00000164597	Q9UP83	Conserved oligomeric Golgi complex subunit 5	clinvar
SOX6	HGNC:16421	ENSG00000110693	P35712	Transcription factor SOX-6	clinvar
CLASP1	HGNC:17088	ENSG00000074054	Q7Z460	CLIP-associating protein 1	clinvar
HAPLN2	HGNC:17410	ENSG00000132702	Q9GZV7	Hyaluronan and proteoglycan link protein 2	clinvar
ADGRV1	HGNC:17416	ENSG00000164199	Q8WXG9	Adhesion G-protein coupled receptor V1	clinvar
WDR19	HGNC:18340	ENSG00000157796	Q8NEZ3	WD repeat-containing protein 19	clinvar
CORIN	HGNC:19012	ENSG00000145244	Q9Y5Q5	Atrial natriuretic peptide-converting enzyme	clinvar
ADAMTSL4	HGNC:19706	ENSG00000143382	Q6UY14	ADAMTS-like protein 4	clinvar
CYP26B1	HGNC:20581	ENSG00000003137	Q9NR63	Cytochrome P450 26B1	clinvar
ZNF462	HGNC:21684	ENSG00000148143	Q96JM2	Zinc finger protein 462	clinvar
MED13L	HGNC:22962	ENSG00000123066	Q71F56	Mediator of RNA polymerase II transcription subunit 13-like	clinvar
ALG6	HGNC:23157	ENSG00000088035	Q9Y672	Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase	clinvar
CSF1R	HGNC:2433	ENSG00000182578	P07333	Macrophage colony-stimulating factor 1 receptor	clinvar
KANSL1	HGNC:24565	ENSG00000120071	Q7Z3B3	KAT8 regulatory NSL complex subunit 1	clinvar
NPRL2	HGNC:24969	ENSG00000114388	Q8WTW4	GATOR1 complex protein NPRL2	clinvar
CTNNA1	HGNC:2509	ENSG00000044115	P35221	Catenin alpha-1	clinvar
CPLANE1	HGNC:25801	ENSG00000197603	Q9H799	Ciliogenesis and planar polarity effector 1	clinvar
SPECC1L	HGNC:29022	ENSG00000100014	Q69YQ0	Cytospin-A	clinvar
DNMT3A	HGNC:2978	ENSG00000119772	Q9Y6K1	DNA (cytosine-5)-methyltransferase 3A	clinvar
MEGF8	HGNC:3233	ENSG00000105429	Q7Z7M0	Multiple epidermal growth factor-like domains protein 8	clinvar
ERF	HGNC:3444	ENSG00000105722	P50548	ETS domain-containing transcription factor ERF	clinvar
ETF1	HGNC:3477	ENSG00000120705	P62495	Eukaryotic peptide chain release factor subunit 1	clinvar
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	clinvar
FBN2	HGNC:3604	ENSG00000138829	P35556	Fibrillin-2	clinvar
FGFR1	HGNC:3688	ENSG00000077782	P11362	Fibroblast growth factor receptor 1	clinvar
FGFR2	HGNC:3689	ENSG00000066468	P21802	Fibroblast growth factor receptor 2	clinvar
FGFR3	HGNC:3690	ENSG00000068078	P22607	Fibroblast growth factor receptor 3	clinvar
GLI2	HGNC:4318	ENSG00000074047	P10070	Zinc finger protein GLI2	clinvar
GLI3	HGNC:4319	ENSG00000106571	P10071	Transcriptional activator GLI3	clinvar
GPC4	HGNC:4452	ENSG00000076716	O75487	Glypican-4	clinvar
GRIN2B	HGNC:4586	ENSG00000273079	Q13224	Glutamate receptor ionotropic, NMDA 2B	clinvar
IGF1R	HGNC:5465	ENSG00000140443	P08069	Insulin-like growth factor 1 receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DHRS3	Short-chain dehydrogenase/reductase 3	Catalyzes the reduction of all-trans-retinal to all-trans-retinol in the presence of NADPH.
AXIN2	Axin-2	Inhibitor of the Wnt signaling pathway.
PRRX1	Paired mesoderm homeobox protein 1	Master transcription factor of stromal fibroblasts for myofibroblastic lineage progression.
SPRY1	Protein sprouty homolog 1	Inhibits fibroblast growth factor (FGF)-induced retinal lens fiber differentiation, probably by inhibiting FGF-mediated phosphorylation of ERK1/2.
EFNA4	Ephrin-A4	Cell surface GPI-bound ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development.
FGF10	Fibroblast growth factor 10	Plays an important role in the regulation of embryonic development, cell proliferation and cell differentiation.
RARA	Retinoic acid receptor alpha	Receptor for retinoic acid.
RUNX2	Runt-related transcription factor 2	Transcription factor involved in osteoblastic differentiation and skeletal morphogenesis.
SKI	Ski oncogene	May play a role in terminal differentiation of skeletal muscle cells but not in the determination of cells to the myogenic lineage.
SOX11	Transcription factor SOX-11	Transcription factor that acts as a transcriptional activator.
CDKL5	Cyclin-dependent kinase-like 5	Mediates phosphorylation of MECP2.
TCF12	Transcription factor 12	Transcriptional regulator.
TCF20	Transcription factor 20	Transcriptional activator that binds to the regulatory region of MMP3 and thereby controls stromelysin expression.
TFAP2B	Transcription factor AP-2-beta	Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes.
TGFBR1	TGF-beta receptor type-1	Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3.
TRPS1	Zinc finger transcription factor Trps1	Transcriptional repressor.
KAT6A	Histone acetyltransferase KAT6A	Histone acetyltransferase that acetylates lysine residues in histone H3 and histone H4 (in vitro).
CNPY2	Protein canopy homolog 2	Positive regulator of neurite outgrowth by stabilizing myosin regulatory light chain (MRLC).
COG5	Conserved oligomeric Golgi complex subunit 5	Required for normal Golgi function.
SOX6	Transcription factor SOX-6	Transcription factor that plays a key role in several developmental processes, including neurogenesis, chondrocytes differentiation and cartilage formation.
CLASP1	CLIP-associating protein 1	Microtubule plus-end tracking protein that promotes the stabilization of dynamic microtubules.
HAPLN2	Hyaluronan and proteoglycan link protein 2	Mediates a firm binding of versican V2 to hyaluronic acid.
ADGRV1	Adhesion G-protein coupled receptor V1	G-protein coupled receptor which has an essential role in the development of hearing and vision.
WDR19	WD repeat-containing protein 19	As component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), it is involved in cilia function and/or assembly.
CORIN	Atrial natriuretic peptide-converting enzyme	Serine-type endopeptidase involved in atrial natriuretic peptide (NPPA) and brain natriuretic peptide (NPPB) processing.
ADAMTSL4	ADAMTS-like protein 4	Positive regulation of apoptosis.
CYP26B1	Cytochrome P450 26B1	A cytochrome P450 monooxygenase involved in the metabolism of retinoates (RAs), the active metabolites of vitamin A, and critical signaling molecules in animals.
ZNF462	Zinc finger protein 462	Zinc finger nuclear factor involved in transcription by regulating chromatin structure and organization.
MED13L	Mediator of RNA polymerase II transcription subunit 13-like	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
ALG6	Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase	Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
CSF1R	Macrophage colony-stimulating factor 1 receptor	Tyrosine-protein kinase that acts as a cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes…
KANSL1	KAT8 regulatory NSL complex subunit 1	Non-catalytic component of the NSL histone acetyltransferase complex, a multiprotein complex that mediates histone H4 acetylation at ‘Lys-5’- and ‘Lys-8’ (H4K5ac and H4K8ac) at transcription start sites and promotes transcription initiatio…
NPRL2	GATOR1 complex protein NPRL2	Catalytic component of the GATOR1 complex, a multiprotein complex that functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
CTNNA1	Catenin alpha-1	Associates with the cytoplasmic domain of a variety of cadherins.
CPLANE1	Ciliogenesis and planar polarity effector 1	Involved in ciliogenesis.
SPECC1L	Cytospin-A	Involved in cytokinesis and spindle organization.
DNMT3A	DNA (cytosine-5)-methyltransferase 3A	Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development.
MEGF8	Multiple epidermal growth factor-like domains protein 8	Acts as a negative regulator of hedgehog signaling.
ERF	ETS domain-containing transcription factor ERF	Potent transcriptional repressor that binds to the H1 element of the Ets2 promoter.
ETF1	Eukaryotic peptide chain release factor subunit 1	Component of the eRF1-eRF3-GTP ternary complex, a ternary complex that mediates translation termination in response to the termination codons.
FBN1	Fibrillin-1	Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues.
FBN2	Fibrillin-2	Fibrillins are structural components of 10-12 nm extracellular calcium-binding microfibrils, which occur either in association with elastin or in elastin-free bundles.
FGFR1	Fibroblast growth factor receptor 1	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration.
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…
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.
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.
GPC4	Glypican-4	Cell surface proteoglycan that bears heparan sulfate.
GRIN2B	Glutamate receptor ionotropic, NMDA 2B	Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+).
IGF1R	Insulin-like growth factor 1 receptor	Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1).

Protein-family classification

Druggable: 18 · Difficult: 16 · Unknown: 27 · Druggable fraction: 0.3

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
Kinase	8	3.6×	0.015
Transcription factor	14	1.9×	0.064
Nuclear receptor	1	6.3×	0.489
Complement	1	4.4×	0.510
Antibody/Immunoglobulin	2	1.0×	0.974
Other/Unknown	27	0.8×	0.974
Enzyme (other)	4	0.8×	0.974
Protease	1	0.6×	0.974
Scaffold/PPI	2	0.6×	0.974
GPCR	1	0.4×	0.974

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DHRS3	Enzyme (other)	yes	1.1.1.300	SDR_fam, NAD(P)-bd_dom_sf, KR_dom
AXIN2	Other/Unknown	no		DIX, Axin_b-cat-bd, RGS
PRRX1	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
SPRY1	Other/Unknown	no		Sprouty, Sprouty_domain
EFNA4	Other/Unknown	no		Ephrin_RBD, Cupredoxin, Ephrin_CS
FGF10	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
RARA	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
RUNX2	Transcription factor	no		AML1_Runt, p53-like_TF_DNA-bd_sf, p53/RUNT-type_TF_DNA-bd_sf
SKI	Other/Unknown	no		SKI/SNO/DAC, DNA-bd_dom_put_sf, SAND-like_dom_sf
SOX11	Transcription factor	no		HMG_box_dom, SOX-12/11/4, HMG_box_dom_sf
CDKL5	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
TCF12	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, NeuroDiff_E-box_TFs
TCF20	Transcription factor	no		Znf_PHD, Znf_RING/FYVE/PHD, EPHD
TFAP2B	Transcription factor	no		TF_AP2, TF_AP2_beta, TF_AP2_C
TGFBR1	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
TRPS1	Transcription factor	no		Znf_GATA, Znf_C2H2_type, Znf_NHR/GATA
KAT6A	Transcription factor	no	2.3.1.48	Znf_PHD, HAT_MYST-type, Histone_H1/H5_H15
CNPY2	Other/Unknown	no		SaposinB_dom, DUF3456, CNPY
COG5	Other/Unknown	no		Cog5, COG5_helical, COG5_N
SOX6	Transcription factor	no		HMG_box_dom, HMG_box_dom_sf, SOX/SOX-like_TF
CLASP1	Other/Unknown	no		ARM-like, ARM-type_fold, HEAT_type_2
HAPLN2	Antibody/Immunoglobulin	yes		Link_dom, Ig_sub, Ig-like_dom
ADGRV1	GPCR	yes		GPCR_2_secretin-like, Calx_beta, EPTP
WDR19	Transcription factor	no		WD40_rpt, TPR-like_helical_dom_sf, WD40/YVTN_repeat-like_dom_sf
CORIN	Protease	yes		SRCR, Trypsin_dom, LDrepeatLR_classA_rpt
ADAMTSL4	Other/Unknown	no		TSP1_rpt, ADAMTS_spacer1, PLAC
CYP26B1	Other/Unknown	no		Cyt_P450, Cyt_P450_E_grp-IV, Cyt_P450_CS
ZNF462	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Zinc_finger/UBP_domain
MED13L	Other/Unknown	no		Med13_C, Mediator_Med13_N, MID_MedPIWI
ALG6	Enzyme (other)	yes	2.4.1.267	Glyco_trans_ALG6/ALG8
CSF1R	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
KANSL1	Other/Unknown	no		NSL1, PEHE_dom
NPRL2	Other/Unknown	no		NPR2-like
CTNNA1	Other/Unknown	no		Vinculin_CS, Alpha_catenin, Vinculin/catenin
CPLANE1	Scaffold/PPI	no		CPLANE1, WD40_repeat_dom_sf
SPECC1L	Other/Unknown	no		CH_dom, CH_dom_sf, F-actin_Monoox_Mical
DNMT3A	Complement	yes	2.1.1.37	PWWP_dom, C5_MeTfrase, C5_DNA_meth_AS
MEGF8	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, CUB_dom
ERF	Other/Unknown	no		Ets_dom, WH-like_DNA-bd_sf, WH_DNA-bd_sf
ETF1	Other/Unknown	no		Peptide_chain-rel_eRF1/aRF1, eRF1_Pelota-like_N, eRF1_2
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
FBN2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
FGFR1	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
FGFR2	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
FGFR3	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
GLI2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
GLI3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
GPC4	Other/Unknown	no		Glypican, Glypican_CS
GRIN2B	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
IGF1R	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom

Expression context

Cohort genes with no expression data: 0.

58 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)	61
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	9
cortical plate	6
ventricular zone	6
buccal mucosa cell	5
tibia	5
ganglionic eminence	5
granulocyte	4
upper arm skin	3
tendon	3
primordial germ cell in gonad	3
monocyte	3
cerebellar hemisphere	3
right hemisphere of cerebellum	3
corpus callosum	3
right uterine tube	3
colonic epithelium	3
upper leg skin	3
olfactory bulb	2
oviduct epithelium	2
endocervix	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DHRS3	283	ubiquitous	marker	olfactory bulb, right lobe of liver, tibial nerve
AXIN2	221	ubiquitous	marker	oviduct epithelium, upper arm skin, body of uterus
PRRX1	266	ubiquitous	marker	calcaneal tendon, tendon, urethra
SPRY1	272	ubiquitous	marker	pericardium, omental fat pad, peritoneum
EFNA4	197	ubiquitous	marker	primordial germ cell in gonad, skin of leg, skin of abdomen
FGF10	169	broad	marker	buccal mucosa cell, synovial joint, endocervix
RARA	276	ubiquitous	marker	mammary duct, monocyte, granulocyte
RUNX2	241	ubiquitous	marker	tibia, mucosa of paranasal sinus, trabecular bone tissue
SKI	268	ubiquitous	marker	nipple, right hemisphere of cerebellum, cerebellar hemisphere
SOX11	93	broad	marker	ganglionic eminence, cortical plate, embryo
CDKL5	257	ubiquitous	marker	frontal pole, Brodmann (1909) area 23, cortical plate
TCF12	295	ubiquitous	marker	periodontal ligament, ventricular zone, ganglionic eminence
TCF20	134	ubiquitous	yes	cortical plate, ganglionic eminence, tonsil
TFAP2B	128	broad	marker	corpus epididymis, cauda epididymis, oocyte
TGFBR1	269	ubiquitous	marker	saphenous vein, tibia, visceral pleura
TRPS1	284	ubiquitous	marker	mammary duct, epithelium of mammary gland, calcaneal tendon
KAT6A	299	ubiquitous	marker	nipple, medial globus pallidus, globus pallidus
CNPY2	290	ubiquitous	marker	adenohypophysis, stromal cell of endometrium, pituitary gland
COG5	142	ubiquitous	marker	corpus callosum, calcaneal tendon, tonsil
SOX6	235	ubiquitous	marker	epithelial cell of pancreas, tibia, kidney epithelium
CLASP1	286	ubiquitous	marker	cortical plate, calcaneal tendon, dorsal motor nucleus of vagus nerve
HAPLN2	174	tissue_specific	marker	C1 segment of cervical spinal cord, spinal cord, putamen
ADGRV1	196	broad	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
WDR19	269	ubiquitous	marker	right uterine tube, bronchial epithelial cell, adenohypophysis
CORIN	176	tissue_specific	marker	cardiac muscle of right atrium, heart right ventricle, myocardium
ADAMTSL4	216	ubiquitous	marker	decidua, mucosa of stomach, lower esophagus mucosa
CYP26B1	239	broad	marker	pons, upper arm skin, cerebellar vermis
ZNF462	258	ubiquitous	marker	buccal mucosa cell, oviduct epithelium, corpus callosum
MED13L	297	ubiquitous	marker	calcaneal tendon, colonic epithelium, tendon
ALG6	268	ubiquitous	yes	secondary oocyte, primordial germ cell in gonad, upper leg skin

Protein interactions among cohort

Intra-cohort edges: 25.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IGF1R	6,823
FGFR1	5,693
TGFBR1	4,828
DNMT3A	4,771
FGFR3	4,510
CSF1R	4,392
FGF10	4,233
RUNX2	4,101
RARA	3,885
PSMD12	3,726

Intra-cohort edges

A	B	Sources
ADAMTSL4	FBN1	string_interaction
ADAMTSL4	FBN2	string_interaction
ALG6	FGFR3	intact
CNPY2	GPC4	string_interaction
CORIN	NPR2	string_interaction
CYP26B1	DHRS3	string_interaction
CYP26B1	RARA	string_interaction
DNMT3A	PRRX1	biogrid_interaction
FBN1	FBN2	intact, string_interaction
FBN1	TGFBR1	string_interaction
FBN2	TGFBR1	string_interaction
FGF10	FGFR1	string_interaction
FGF10	FGFR2	biogrid_interaction, intact
FGF10	FGFR3	string_interaction
FGFR1	FGFR2	intact
GLI2	GLI3	intact
GLI2	PTCH1	string_interaction
GLI2	RUNX2	string_interaction
GLI3	PTCH1	string_interaction
PTCH1	SPECC1L	string_interaction
RUNX2	SMAD6	intact
RUNX2	TRPS1	string_interaction
SMAD6	TGFBR1	string_interaction
SOX6	TRPS1	biogrid_interaction
SPECC1L	TCF12	string_interaction

Structural data

PDB: 35 · AlphaFold-only: 26 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDE4D	Q08499	122
PSMD12	O00232	118
FGFR1	P11362	83
FGFR2	P21802	63
IGF1R	P08069	46
TGFBR1	P36897	44
DNMT3A	Q9Y6K1	43
GRIN2B	Q13224	36
ETF1	P62495	33
CSF1R	P07333	26
KAT6A	Q92794	21
KIF1A	Q12756	21
PTCH1	Q13635	16
FGFR3	P22607	15
RARA	P10276	14
FBN1	P35555	11
NPRL2	Q8WTW4	10
CTNNA1	P35221	10
MEGF8	Q7Z7M0	5
IL11RA	Q14626	5
RUNX2	Q13950	4
SKI	P12755	4
SOX11	P35716	4
WDR19	Q8NEZ3	4
CDKL5	O76039	3
CLASP1	Q7Z460	3
FGF10	O15520	2
TCF12	Q99081	2
KANSL1	Q7Z3B3	2
ERF	P50548	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DHRS3	O75911	94.16
ALG6	Q9Y672	93.08
MAN2B1	O00754	91.78
CYP26B1	Q9NR63	90.99
HAPLN2	Q9GZV7	89.57
CNPY2	Q9Y2B0	84.95
COG5	Q9UP83	84.37
NPR2	P20594	84.00
EFNA4	P52798	83.78
GPC4	O75487	83.68
KIF5C	O60282	78.70
SMAD6	O43541	72.34
CORIN	Q9Y5Q5	70.20
SPECC1L	Q69YQ0	67.07
PRRX1	P54821	66.38
MSX1	P28360	66.06
ADAMTSL4	Q6UY14	65.18
SPRY1	O43609	61.99
MED13L	Q71F56	56.79
SOX6	P35712	56.48
TRPS1	Q9UHF7	49.12
GLI2	P10070	42.68
TCF20	Q9UGU0	39.03
ADGRV1	Q8WXG9
CPLANE1	Q9H799
FBN2	P35556

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 325. Enrichment computed across 61 evidence-associated genes (50 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 50 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
GLI proteins bind promoters of Hh responsive genes to promote transcription	3	97.9×	9e-04	GLI2, GLI3, PTCH1
PI3K Cascade	4	21.8×	0.005	FGF10, FGFR1, FGFR2, FGFR3
RUNX2 regulates chondrocyte maturation	2	91.4×	0.015	RUNX2, GLI2
Hedgehog ‘off’ state	4	14.3×	0.015	WDR19, GLI2, GLI3, PTCH1
Hedgehog ‘on’ state	4	12.7×	0.017	GLI2, GLI3, PSMD12, PTCH1
FGFR1b ligand binding and activation	2	50.8×	0.031	FGF10, FGFR1
Constitutive Signaling by Aberrant PI3K in Cancer	4	10.2×	0.031	FGF10, FGFR1, FGFR2, FGFR3
FGFR2b ligand binding and activation	2	45.7×	0.034	FGF10, FGFR2
RAF/MAP kinase cascade	5	6.1×	0.047	FGF10, FGFR1, FGFR2, FGFR3, GRIN2B
RUNX2 regulates bone development	2	32.6×	0.051	RUNX2, SMAD6
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	4	7.7×	0.051	FGF10, FGFR1, FGFR2, FGFR3
Signaling by FGFR2 amplification mutants	1	228.4×	0.054	FGFR2
t(4;14) translocations of FGFR3	1	228.4×	0.054	FGFR3
Defective ALG6 causes CDG-1c	1	228.4×	0.054	ALG6
Defective CYP26B1 causes RHFCA	1	228.4×	0.054	CYP26B1
Signaling by FGFR2 fusions	1	228.4×	0.054	FGFR2
Signaling by FGFR3 fusions in cancer	1	228.4×	0.054	FGFR3
Activated point mutants of FGFR2	2	26.9×	0.054	FGF10, FGFR2
Physiological factors	2	26.9×	0.054	CORIN, NPR2
Phospholipase C-mediated cascade: FGFR1	2	26.9×	0.054	FGF10, FGFR1
Phospholipase C-mediated cascade; FGFR2	2	25.4×	0.054	FGF10, FGFR2
Specification of the neural plate border	2	25.4×	0.054	TFAP2B, MSX1
Downstream signaling of activated FGFR1	2	21.8×	0.054	FGF10, FGFR1
PI-3K cascade:FGFR1	2	20.8×	0.054	FGF10, FGFR1
SHC-mediated cascade:FGFR1	2	19.9×	0.054	FGF10, FGFR1
PI-3K cascade:FGFR2	2	19.9×	0.054	FGF10, FGFR2
Respiratory syncytial virus (RSV) attachment and entry	2	19.9×	0.054	GPC4, IGF1R
RA biosynthesis pathway	2	19.0×	0.054	DHRS3, CYP26B1
SHC-mediated cascade:FGFR2	2	19.0×	0.054	FGF10, FGFR2
FRS-mediated FGFR1 signaling	2	18.3×	0.054	FGF10, FGFR1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 61 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic limb morphogenesis	8	52.6×	2e-09	PRRX1, SKI, WDR19, CYP26B1, MEGF8, FBN2, FGFR1, PTCH1
bone morphogenesis	6	59.2×	3e-07	DHRS3, SKI, CYP26B1, FGFR2, FGFR3, MSX1
stem cell proliferation	7	35.8×	3e-07	AXIN2, PRRX1, RUNX2, FGF10, FGFR1, GLI3, PTCH1
odontogenesis of dentin-containing tooth	7	34.5×	3e-07	RUNX2, CTNNA1, FGF10, GLI2, GLI3, LRP4, MSX1
embryonic cranial skeleton morphogenesis	5	47.6×	9e-06	PRRX1, RUNX2, TGFBR1, WDR19, FGFR2
chondrocyte differentiation	6	29.6×	9e-06	RUNX2, SOX6, FGFR1, FGFR3, GLI3, NPR2
positive regulation of stem cell proliferation	5	43.2×	1e-05	PRRX1, RUNX2, SOX11, FGF10, FGFR1
roof of mouth development	6	24.4×	2e-05	DHRS3, PRRX1, SKI, TGFBR1, GLI3, MSX1
ureteric bud development	5	37.3×	2e-05	SPRY1, FGFR1, FGFR2, SMAD6, RARA
limb morphogenesis	4	69.1×	2e-05	MEGF8, GLI3, NPR2, PTCH1
positive regulation of phospholipase activity	3	165.8×	3e-05	FGFR1, FGFR2, FGFR3
embryonic digestive tract morphogenesis	4	61.4×	3e-05	SOX11, FGF10, FGFR2, GLI3
skeletal system development	7	14.4×	4e-05	TGFBR1, TRPS1, HAPLN2, FBN1, FGFR1, FGFR3, GLI2
smoothened signaling pathway	6	17.8×	7e-05	PRRX1, RUNX2, CTNNA1, MEGF8, GLI2, GLI3
bud elongation involved in lung branching	3	118.4×	9e-05	SPRY1, FGF10, FGFR2
proximal/distal pattern formation	4	42.5×	1e-04	CYP26B1, GLI2, GLI3, LRP4
kidney development	6	13.8×	2e-04	SOX11, TFAP2B, TGFBR1, CYP26B1, GLI2, LRP4
metanephros development	4	33.5×	3e-04	SPRY1, FBN1, FGF10, GLI3
negative regulation of smoothened signaling pathway	4	29.9×	4e-04	RUNX2, MEGF8, GLI3, PTCH1
mammary gland bud formation	2	276.3×	5e-04	FGF10, FGFR2
branch elongation involved in salivary gland morphogenesis	2	276.3×	5e-04	FGF10, FGFR2
mesenchymal cell differentiation involved in lung development	2	276.3×	5e-04	FGF10, FGFR2
fibroblast growth factor receptor apoptotic signaling pathway	2	276.3×	5e-04	FGF10, FGFR3
positive regulation of cell population proliferation	10	5.5×	5e-04	TFAP2B, TGFBR1, CSF1R, FGF10, FGFR1, FGFR2, FGFR3, IGF1R (+2 more)
organ induction	3	59.2×	5e-04	SPRY1, FGF10, FGFR1
embryonic camera-type eye development	3	59.2×	5e-04	WDR19, FGF10, RARA
mesenchymal cell proliferation	3	55.2×	7e-04	PRRX1, FGFR1, MSX1
in utero embryonic development	7	8.3×	7e-04	TGFBR1, WDR19, FGFR1, FGFR2, GLI3, MSX1, PTCH1
response to vitamin A	3	51.8×	7e-04	CYP26B1, DNMT3A, RARA
smooth muscle tissue development	3	51.8×	7e-04	TFAP2B, NPR2, PTCH1

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

1 drug in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Sodium Chloride	Phase 2

Drug target analysis

Approved (phase 4): 12 · Phase ≥3: 12 · Phased (≥1): 14 · Undrugged: 47

Druggability breadth: 30 of 61 evidence-associated genes (49%) 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
RARA	BEXAROTENE
CDKL5	FEDRATINIB
TGFBR1	MOMELOTINIB
CYP26B1	BEXAROTENE
CSF1R	PONATINIB
FGFR1	PONATINIB
FGFR2	PONATINIB
FGFR3	PONATINIB
GRIN2B	HALOPERIDOL
IGF1R	FEDRATINIB
PDE4D	INAMRINONE
PSMD12	BORTEZOMIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDE4D	269	4
FGFR1	93	4
CSF1R	79	4
FGFR3	64	4
FGFR2	59	4
GRIN2B	35	4
TGFBR1	28	4
IGF1R	27	4
CDKL5	14	4
RARA	11	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEXAROTENE	4	CYP26B1, RARA
ADAPALENE	4	RARA
TAZAROTENE	4	RARA
TAMIBAROTENE	4	RARA
TRIFAROTENE	4	RARA
TRETINOIN	4	RARA
ALITRETINOIN	4	RARA
FEDRATINIB	4	CDKL5, CSF1R, FGFR1, FGFR2, FGFR3, IGF1R
CAPMATINIB	4	CDKL5
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1
NINTEDANIB	4	CSF1R, FGFR1, FGFR2, FGFR3, IGF1R, TGFBR1
DASATINIB	4	CSF1R, FGFR1, FGFR2, FGFR3, PDE4D, TGFBR1
CRIZOTINIB	4	CSF1R, FGFR3, IGF1R, PDE4D, TGFBR1
KETOCONAZOLE	4	CYP26B1
PONATINIB	4	CSF1R, FGFR1, FGFR2, FGFR3, PDE4D
AXITINIB	4	CSF1R, FGFR1, FGFR2, FGFR3
SORAFENIB	4	CSF1R, FGFR1, FGFR2, FGFR3
DASATINIB ANHYDROUS	4	CSF1R
SUNITINIB MALATE	4	CSF1R
NERATINIB	4	CSF1R, PDE4D
IBRUTINIB	4	CSF1R, FGFR2
ENTRECTINIB	4	CSF1R, FGFR1, FGFR3, IGF1R
PACRITINIB	4	CSF1R
VANDETANIB	4	CSF1R, FGFR1, FGFR2, FGFR3
NILOTINIB	4	CSF1R, PDE4D
BOSUTINIB	4	CSF1R
FILGOTINIB	4	CSF1R
BRIGATINIB	4	CSF1R, FGFR1, FGFR2, FGFR3, IGF1R
PEXIDARTINIB	4	CSF1R

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 15.

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

Symbol	Assays	Type breakdown
FGFR1	1,465	Binding:1428, Functional:24, ADMET:13
IGF1R	1,091	Binding:1037, Functional:53, ADMET:1
FGFR3	975	Binding:948, Functional:18, ADMET:9
FGFR2	966	Binding:940, Functional:22, ADMET:4
CSF1R	897	Binding:879, Functional:17, ADMET:1
PDE4D	863	Binding:805, Functional:33, ADMET:23, Toxicity:2
TGFBR1	541	Binding:516, Functional:13, ADMET:12
GRIN2B	471	Binding:429, Functional:36, ADMET:5, Toxicity:1
RARA	368	Binding:279, Functional:85, ADMET:4
DNMT3A	120	Binding:118, ADMET:1, Functional:1
CDKL5	74	Binding:74
MAN2B1	53	Binding:52, ADMET:1
KAT6A	42	Binding:39, Functional:3
PSMD12	27	Binding:27
AXIN2	14	Binding:14
PRRX1	11	Binding:11
NPR2	11	Binding:11
CLASP1	10	Binding:10
CYP26B1	6	Binding:6
SPECC1L	6	Binding:6
GLI2	6	Binding:6
PTCH1	4	Binding:4
KIF5C	3	Binding:3
CTNNA1	2	Binding:2
IL11RA	2	Binding:2
KIF1A	2	Binding:2
TCF12	1	Binding:1
CNPY2	1	Binding:1
COG5	1	Binding:1
ETF1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DHRS3	1.1.1.300	NADP-retinol dehydrogenase
CDKL5	2.7.11.22	cyclin-dependent kinase
TGFBR1	2.7.10.2, 2.7.11.30	non-specific protein-tyrosine kinase, receptor protein serine/threonine kinase
KAT6A	2.3.1.48	histone acetyltransferase
ALG6	2.4.1.267	dolichyl-P-Glc:Man9GlcNAc2-PP-dolichol alpha-1,3-glucosyltransferase
CSF1R	2.7.10.1	receptor protein-tyrosine kinase
DNMT3A	2.1.1.37	DNA (cytosine-5-)-methyltransferase
FGFR1	2.7.10.1	receptor protein-tyrosine kinase
FGFR2	2.7.10.1	receptor protein-tyrosine kinase
FGFR3	2.7.10.1	receptor protein-tyrosine kinase
IGF1R	2.7.10.1	receptor protein-tyrosine kinase
MAN2B1	3.2.1.24	alpha-mannosidase
NPR2	4.6.1.2	guanylate cyclase
PDE4D	3.1.4.53	3’,5’-cyclic-AMP phosphodiesterase
KIF1A	5.6.1.3	plus-end-directed kinesin ATPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RARA	368
TGFBR1	541
CSF1R	897
DNMT3A	120
FGFR1	1,465
FGFR2	966
FGFR3	975
GRIN2B	471
IGF1R	1,091
PDE4D	863

Pharmacogenomics

Cohort genes with a PharmGKB record: 61; 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)
BEXAROTENE	4	CYP26B1, RARA
ADAPALENE	4	RARA
TAZAROTENE	4	RARA
TAMIBAROTENE	4	RARA
TRIFAROTENE	4	RARA
TRETINOIN	4	RARA
ALITRETINOIN	4	RARA
FEDRATINIB	4	CDKL5, CSF1R, FGFR1, FGFR2, FGFR3, IGF1R
CAPMATINIB	4	CDKL5
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1
NINTEDANIB	4	CSF1R, FGFR1, FGFR2, FGFR3, IGF1R, TGFBR1
DASATINIB	4	CSF1R, FGFR1, FGFR2, FGFR3, PDE4D, TGFBR1
CRIZOTINIB	4	CSF1R, FGFR3, IGF1R, PDE4D, TGFBR1
KETOCONAZOLE	4	CYP26B1
PONATINIB	4	CSF1R, FGFR1, FGFR2, FGFR3, PDE4D
AXITINIB	4	CSF1R, FGFR1, FGFR2, FGFR3
SORAFENIB	4	CSF1R, FGFR1, FGFR2, FGFR3
DASATINIB ANHYDROUS	4	CSF1R
SUNITINIB MALATE	4	CSF1R
NERATINIB	4	CSF1R, PDE4D
IBRUTINIB	4	CSF1R, FGFR2
ENTRECTINIB	4	CSF1R, FGFR1, FGFR3, IGF1R
PACRITINIB	4	CSF1R
VANDETANIB	4	CSF1R, FGFR1, FGFR2, FGFR3
NILOTINIB	4	CSF1R, PDE4D
BOSUTINIB	4	CSF1R
FILGOTINIB	4	CSF1R
BRIGATINIB	4	CSF1R, FGFR1, FGFR2, FGFR3, IGF1R
PEXIDARTINIB	4	CSF1R

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	12	RARA, CDKL5, TGFBR1, CYP26B1, CSF1R, FGFR1, FGFR2, FGFR3, GRIN2B, IGF1R (+2 more)
B	Phased (≥1) drug, not yet approved	2	SPECC1L, MAN2B1
C	Druggable family + PDB, no drug	2	DNMT3A, IL11RA
D	Druggable family + AlphaFold only, no drug	6	DHRS3, HAPLN2, ADGRV1, CORIN, ALG6, NPR2
E	Difficult family or no structure, no drug	39	AXIN2, PRRX1, SPRY1, EFNA4, FGF10, RUNX2, SKI, SOX11, TCF12, TCF20 (+29 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DHRS3	0	CYP26B1
FGF10	0	FGFR1
SMAD6	0	TGFBR1
DNMT3A	120	—
AXIN2	14	—
PRRX1	11	—
SPRY1	0	—
EFNA4	0	—
RUNX2	0	—
SKI	0	—
SOX11	0	—
TCF12	1	—
TCF20	0	—
TFAP2B	0	—
TRPS1	0	—
KAT6A	42	—
CNPY2	1	—
COG5	1	—
SOX6	0	—
CLASP1	10	—
HAPLN2	0	—
ADGRV1	0	—
WDR19	0	—
CORIN	0	—
ADAMTSL4	0	—
ZNF462	0	—
MED13L	0	—
ALG6	0	—
KANSL1	0	—
NPRL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 17.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	13
PHASE4	2
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT02229968	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of Amicar for Children Having Craniofacial Surgery
NCT00912119	PHASE1	COMPLETED	Amicar Pharmacokinetics of Children Having Craniofacial Surgery
NCT03025763	Not specified	ACTIVE_NOT_RECRUITING	Network Of Clinical Research Studies On Craniosynostosis, Skull Malformations With Premature Fusion Of Skull Bones
NCT05911139	Not specified	ENROLLING_BY_INVITATION	Influence of General Anesthesia on the Dynamic Changes in Brain Damage Markers During and After Craniosynostosis Operations in Infancy
NCT06928727	Not specified	RECRUITING	Ocular Characteristics in Patients With Craniosynostosis
NCT00077831	Not specified	COMPLETED	Child and Infant Learning Project
NCT00106977	Not specified	COMPLETED	Clinical Study of Muenke Syndrome (FGFR3-Related Craniosynostosis)
NCT00367796	Not specified	COMPLETED	Genetic Analysis of Craniosynostosis, Philadelphia Type
NCT00769847	Not specified	WITHDRAWN	Endoscopic Treatment for Isolated, Single Suture Craniosynostosis
NCT00773643	Not specified	COMPLETED	Osteogenic Profiling of Tissue From Children With Craniosynostosis
NCT01898650	Not specified	COMPLETED	MRI for Non-invasive Evaluation of Brain Stress
NCT02287805	Not specified	COMPLETED	Qualitative and Quantitative Study Which Aims to Determine the Specifics of the Announcement for the Diagnosis of Patients With Craniosynostosis and Their Parents to Better Support Them in Their Care
NCT02561728	Not specified	WITHDRAWN	Hanger Helmet Study
NCT03231085	Not specified	COMPLETED	Comparison of the Rate of Preoperative Haemoglobin After Administration of Epoetin Alpha Associated With an Oral Medical Supplementation Versus Intravenous Before Surgery of Craniosynostosis at the Child
NCT04704284	Not specified	COMPLETED	Comparing MRI to CT on Pediatric Craniosynostosis.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SODIUM CHLORIDE	4	2
AMINOCAPROIC ACID	4	1
TRANEXAMIC ACID	4	1