Saethre-Chotzen syndrome

Summary

Saethre-Chotzen syndrome (MONDO:0007042) is a disease caused by variants in TWIST1 and FGFR2, with 5 cohort genes and 7 clinical trials. Top therapeutic interventions include hydrochlorothiazide.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal genes: TWIST1 (GenCC Definitive), FGFR2 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 368
• Phenotypes (HPO): 61
• Clinical trials: 7

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Validated
Prevalence at birth	1-9 / 100 000	3	Europe	Validated
Prevalence at birth	1-9 / 100 000	1	Australia	Validated

Signs & symptoms

Clinical features (HPO)

61 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000324	Facial asymmetry	Very frequent (80-99%)
HP:0000348	High forehead	Very frequent (80-99%)
HP:0000929	Abnormal skull morphology	Very frequent (80-99%)
HP:0001363	Craniosynostosis	Very frequent (80-99%)
HP:0004209	Clinodactyly of the 5th finger	Very frequent (80-99%)
HP:0004440	Coronal craniosynostosis	Very frequent (80-99%)
HP:0006101	Finger syndactyly	Very frequent (80-99%)
HP:0000377	Abnormal pinna morphology	Frequent (30-79%)
HP:0000189	Narrow palate	Frequent (30-79%)
HP:0000248	Brachycephaly	Frequent (30-79%)
HP:0000270	Delayed cranial suture closure	Frequent (30-79%)
HP:0000294	Low anterior hairline	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000426	Prominent nasal bridge	Frequent (30-79%)
HP:0000444	Convex nasal ridge	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000643	Blepharospasm	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0001357	Plagiocephaly	Frequent (30-79%)
HP:0003307	Hyperlordosis	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0007598	Bilateral single transverse palmar creases	Frequent (30-79%)
HP:0007678	Lacrimal duct stenosis	Frequent (30-79%)
HP:0008551	Microtia	Frequent (30-79%)
HP:0009738	Abnormality of the antihelix	Frequent (30-79%)
HP:0009899	Prominent crus of helix	Frequent (30-79%)
HP:0010807	Open bite	Frequent (30-79%)
HP:0011386	Narrow internal auditory canal	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000193	Bifid uvula	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000327	Hypoplasia of the maxilla	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000405	Conductive hearing impairment	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000601	Hypotelorism	Occasional (5-29%)
HP:0000646	Amblyopia	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0001199	Triphalangeal thumb	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001627	Abnormal heart morphology	Occasional (5-29%)
HP:0001822	Hallux valgus	Occasional (5-29%)
HP:0001837	Broad toe	Occasional (5-29%)
HP:0002076	Migraine	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002342	Intellectual disability, moderate	Occasional (5-29%)
HP:0002516	Increased intracranial pressure	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Saethre-Chotzen syndrome
Mondo ID	MONDO:0007042
OMIM	101400
Orphanet	794
DOID	DOID:14768
ICD-11	2109857109
NCIT	C75034
SNOMED CT	83015004
UMLS	C0175699
MedGen	64221
GARD	0007598
NORD	1686
Is cancer (heuristic)	no

Also known as: acrocephalo-syndactyly, type 3 · acrocephalosyndactyly type 3 · ACS3 · blepharophimosis, epicanthus inversus, and ptosis 3 · blepharophimosis, epicanthus inversus, and ptosis 3, formerly · blepharophimosis,epicanthus inversus, and ptosis 3 (formerly) · Saethre Chotzen Syndrome · Saethre-Chotzen syndrome · Saethre-Chotzen syndrome with or without eyelid anomalies · SCS · type III Acrocephalosyndactyly

Data availability: 368 ClinVar variants · 8 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic craniosynostosis › acrocephalosyndactyly › Saethre-Chotzen syndrome

Related subtypes (3): acrocephalopolysyndactyly, Apert syndrome, Jackson-Weiss syndrome

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

368 retrieved; paginated sample, class counts are floors:

156 uncertain significance, 64 pathogenic, 47 conflicting classifications of pathogenicity, 32 benign/likely benign, 24 likely benign, 16 likely pathogenic, 16 pathogenic/likely pathogenic, 13 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
981203	GRCh37/hg19 7p21.2-21.1(chr7:14470668-20385165)x1	AGMO	Pathogenic	no assertion criteria provided
2664505	GRCh37/hg19 7p21.1(chr7:19066802-19662813)x1	FERD3L	Pathogenic	no assertion criteria provided
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
13272	NM_000141.5(FGFR2):c.755C>G (p.Ser252Trp)	FGFR2	Pathogenic	criteria provided, multiple submitters, no conflicts
13273	NM_000141.5(FGFR2):c.758C>G (p.Pro253Arg)	FGFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13277	NM_000141.5(FGFR2):c.1124A>G (p.Tyr375Cys)	FGFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13285	NM_000141.5(FGFR2):c.804_809del (p.Val269_Val270del)	FGFR2	Pathogenic	no assertion criteria provided
13289	NM_000141.5(FGFR2):c.943G>T (p.Ala315Ser)	FGFR2	Pathogenic	criteria provided, multiple submitters, no conflicts
13293	NM_000141.5(FGFR2):c.870G>T (p.Trp290Cys)	FGFR2	Pathogenic	criteria provided, multiple submitters, no conflicts
374817	NM_000141.5(FGFR2):c.1013G>A (p.Gly338Glu)	FGFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374823	NM_000141.5(FGFR2):c.1694A>G (p.Glu565Gly)	FGFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449024	NM_000141.5(FGFR2):c.314A>G (p.Tyr105Cys)	FGFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
478046	NM_000141.5(FGFR2):c.1150G>A (p.Gly384Arg)	FGFR2	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
1075291	NM_000474.4(TWIST1):c.587G>A (p.Trp196Ter)	LOC129998021	Pathogenic	criteria provided, single submitter
1164065	NM_000474.4(TWIST1):c.437_448del (p.Ile146_Leu149del)	LOC129998021	Pathogenic	no assertion criteria provided
1455499	NM_000474.4(TWIST1):c.467T>G (p.Ile156Ser)	LOC129998021	Pathogenic	criteria provided, single submitter
2070030	NM_000474.4(TWIST1):c.465C>G (p.Tyr155Ter)	LOC129998021	Pathogenic	criteria provided, multiple submitters, no conflicts
2504943	NM_000474.4(TWIST1):c.399_423dup (p.Lys142fs)	LOC129998021	Pathogenic	criteria provided, multiple submitters, no conflicts
3235827	NM_000474.4(TWIST1):c.481C>T (p.Gln161Ter)	LOC129998021	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3760234	NM_000474.4(TWIST1):c.480C>A (p.Tyr160Ter)	LOC129998021	Pathogenic	criteria provided, single submitter
458685	NC_000007.14:g.(?19116693)(19117341_?)del	LOC129998021	Pathogenic	criteria provided, single submitter
4783655	NM_000474.4(TWIST1):c.480C>G (p.Tyr160Ter)	LOC129998021	Pathogenic	criteria provided, single submitter
572211	NM_000474.4(TWIST1):c.475C>T (p.Leu159Phe)	LOC129998021	Pathogenic	criteria provided, single submitter
694504	NM_000474.4(TWIST1):c.400_420dup (p.Ser140_Asp141insIleIleProThrLeuProSer)	LOC129998021	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7980	NM_000474.4(TWIST1):c.541G>T (p.Glu181Ter)	LOC129998021	Pathogenic	no assertion criteria provided
7982	NM_000474.4(TWIST1):c.466A>G (p.Ile156Val)	LOC129998021	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
835124	NM_000474.4(TWIST1):c.446T>G (p.Leu149Arg)	LOC129998021	Pathogenic	criteria provided, single submitter
970861	NM_000474.4(TWIST1):c.433A>G (p.Lys145Glu)	LOC129998021	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 55 · Orphanet: 28 · 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
TWIST1	Definitive	Autosomal dominant	Saethre-Chotzen syndrome	17
FGFR2	Strong	Autosomal dominant	Saethre-Chotzen syndrome	38

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TWIST1	Orphanet:35093	Non-syndromic sagittal craniosynostosis
TWIST1	Orphanet:35099	Non-syndromic bicoronal craniosynostosis
TWIST1	Orphanet:794	Saethre-Chotzen syndrome
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
FGFR2	Orphanet:313855	FGFR2-related bent bone dysplasia
FGFR2	Orphanet:596008	Antley-Bixler syndrome without genital anomaly or disorder of steroidogenesis
FGFR2	Orphanet:794	Saethre-Chotzen syndrome
FGFR2	Orphanet:87	Apert syndrome
FGFR2	Orphanet:93258	Pfeiffer syndrome type 1
FGFR2	Orphanet:93259	Pfeiffer syndrome type 2
FGFR2	Orphanet:93260	Pfeiffer syndrome type 3
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

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TWIST1	HGNC:12428	ENSG00000122691	Q15672	Twist-related protein 1	gencc,clinvar
FGFR2	HGNC:3689	ENSG00000066468	P21802	Fibroblast growth factor receptor 2	gencc,clinvar
FERD3L	HGNC:16660	ENSG00000146618	Q96RJ6	Fer3-like protein	clinvar
AGMO	HGNC:33784	ENSG00000187546	Q6ZNB7	Alkylglycerol monooxygenase	clinvar
FGFR3	HGNC:3690	ENSG00000068078	P22607	Fibroblast growth factor receptor 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TWIST1	Twist-related protein 1	Acts as a transcriptional regulator.
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…
FERD3L	Fer3-like protein	Transcription factor that binds to the E-box and functions as inhibitor of transcription.
AGMO	Alkylglycerol monooxygenase	Glyceryl-ether monooxygenase that cleaves the O-alkyl bond of ether lipids.
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.

Protein-family classification

Druggable: 3 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.6

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	2	11.1×	0.036
Transcription factor	2	3.3×	0.171
Enzyme (other)	1	2.4×	0.353

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TWIST1	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, TWIST1_bHLH
FGFR2	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
FERD3L	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, E-box_TF_Regulators
AGMO	Enzyme (other)	yes	1.14.16.5	Fatty_acid_hydroxylase, Sterol_desaturase/TMEM195, AGMP_C
FGFR3	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of paranasal sinus	1
oocyte	1
periodontal ligament	1
C1 segment of cervical spinal cord	1
corpus callosum	1
spinal cord	1
bone marrow cell	1
cortical plate	1
sural nerve	1
liver	1
male germ line stem cell (sensu Vertebrata) in testis	1
right lobe of liver	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
TWIST1	233	ubiquitous	marker	periodontal ligament, mucosa of paranasal sinus, oocyte
FGFR2	272	broad	marker	C1 segment of cervical spinal cord, spinal cord, corpus callosum
FERD3L	33	tissue_specific	yes	sural nerve, cortical plate, bone marrow cell
AGMO	118	broad	marker	liver, right lobe of liver, male germ line stem cell (sensu Vertebrata) in testis
FGFR3	262	broad	marker	upper leg skin, skin of hip, upper arm skin

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGFR3	4,510
TWIST1	3,507
FERD3L	660
AGMO	654
FGFR2	449

Intra-cohort edges

A	B	Sources
FGFR3	TWIST1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGFR2	P21802	63
FGFR3	P22607	15
TWIST1	Q15672	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AGMO	Q6ZNB7	93.90
FERD3L	Q96RJ6	71.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 38. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by FGFR2 amplification mutants	1	2855.0×	0.002	FGFR2
t(4;14) translocations of FGFR3	1	2855.0×	0.002	FGFR3
Signaling by FGFR2 fusions	1	2855.0×	0.002	FGFR2
Signaling by FGFR3 fusions in cancer	1	2855.0×	0.002	FGFR3
PI3K Cascade	2	135.9×	0.002	FGFR2, FGFR3
Constitutive Signaling by Aberrant PI3K in Cancer	2	63.4×	0.002	FGFR2, FGFR3
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	2	48.4×	0.003	FGFR2, FGFR3
PIP3 activates AKT signaling	2	33.4×	0.006	FGFR2, FGFR3
RAF/MAP kinase cascade	2	30.5×	0.007	FGFR2, FGFR3
FGFR3b ligand binding and activation	1	407.9×	0.009	FGFR3
FGFR2b ligand binding and activation	1	285.5×	0.011	FGFR2
Signaling by activated point mutants of FGFR3	1	237.9×	0.011	FGFR3
FGFR3c ligand binding and activation	1	219.6×	0.011	FGFR3
FGFR2c ligand binding and activation	1	219.6×	0.011	FGFR2
Phospholipase C-mediated cascade; FGFR3	1	219.6×	0.011	FGFR3
Activated point mutants of FGFR2	1	167.9×	0.011	FGFR2
Triglyceride biosynthesis	1	167.9×	0.011	AGMO
Triglyceride metabolism	1	167.9×	0.011	AGMO
Phospholipase C-mediated cascade; FGFR2	1	158.6×	0.011	FGFR2
PI-3K cascade:FGFR3	1	158.6×	0.011	FGFR3
SHC-mediated cascade:FGFR3	1	150.3×	0.011	FGFR3
Signaling by FGFR2 IIIa TM	1	150.3×	0.011	FGFR2
FRS-mediated FGFR3 signaling	1	135.9×	0.012	FGFR3
PI-3K cascade:FGFR2	1	124.1×	0.012	FGFR2
Signaling by FGFR3 in disease	1	124.1×	0.012	FGFR3
SHC-mediated cascade:FGFR2	1	119.0×	0.012	FGFR2
FRS-mediated FGFR2 signaling	1	109.8×	0.012	FGFR2
Negative regulation of FGFR3 signaling	1	109.8×	0.012	FGFR3
FGFR2 alternative splicing	1	105.7×	0.012	FGFR2
Negative regulation of FGFR2 signaling	1	92.1×	0.014	FGFR2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of phospholipase activity	2	1348.2×	1e-04	FGFR2, FGFR3
endochondral bone growth	2	674.1×	3e-04	FGFR2, FGFR3
developmental process	2	269.6×	9e-04	TWIST1, FERD3L
bone morphogenesis	2	240.7×	9e-04	FGFR2, FGFR3
embryonic cranial skeleton morphogenesis	2	232.4×	9e-04	TWIST1, FGFR2
fibroblast growth factor receptor signaling pathway	2	114.2×	0.003	FGFR2, FGFR3
bone mineralization	2	108.7×	0.003	FGFR2, FGFR3
fibroblast growth factor receptor signaling pathway involved in negative regulation of apoptotic process in bone marrow cell	1	3370.4×	0.003	FGFR2
fibroblast growth factor receptor signaling pathway involved in hemopoiesis	1	3370.4×	0.003	FGFR2
fibroblast growth factor receptor signaling pathway involved in positive regulation of cell proliferation in bone marrow	1	3370.4×	0.003	FGFR2
negative regulation of developmental growth	1	3370.4×	0.003	FGFR3
lateral sprouting from an epithelium	1	3370.4×	0.003	FGFR2
cell proliferation involved in heart valve development	1	3370.4×	0.003	TWIST1
positive regulation of endocardial cushion to mesenchymal transition involved in heart valve formation	1	3370.4×	0.003	TWIST1
obsolete membrane lipid metabolic process	1	1685.2×	0.004	AGMO
orbitofrontal cortex development	1	1685.2×	0.004	FGFR2
prostate gland morphogenesis	1	1685.2×	0.004	FGFR2
squamous basal epithelial stem cell differentiation involved in prostate gland acinus development	1	1685.2×	0.004	FGFR2
mammary gland bud formation	1	1685.2×	0.004	FGFR2
branch elongation involved in salivary gland morphogenesis	1	1685.2×	0.004	FGFR2
embryonic camera-type eye formation	1	1685.2×	0.004	TWIST1
mesenchymal cell differentiation involved in lung development	1	1685.2×	0.004	FGFR2
fibroblast growth factor receptor apoptotic signaling pathway	1	1685.2×	0.004	FGFR3
cellular response to hypoxia	2	48.5×	0.004	TWIST1, FGFR2
regulation of osteoblast proliferation	1	1123.5×	0.005	FGFR2
fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development	1	1123.5×	0.005	FGFR2
prostate epithelial cord elongation	1	1123.5×	0.005	FGFR2
bone maturation	1	1123.5×	0.005	FGFR3
regulation of dopaminergic neuron differentiation	1	1123.5×	0.005	FERD3L
negative regulation of double-strand break repair	1	1123.5×	0.005	TWIST1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
FGFR2	PONATINIB
FGFR3	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR3	64	4
FGFR2	59	4
TWIST1	0	0
FERD3L	0	0
AGMO	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	FGFR2, FGFR3
PEMIGATINIB	4	FGFR2, FGFR3
NINTEDANIB	4	FGFR2, FGFR3
FEDRATINIB	4	FGFR2, FGFR3
LENVATINIB	4	FGFR2, FGFR3
AXITINIB	4	FGFR2, FGFR3
SORAFENIB	4	FGFR2, FGFR3
INFIGRATINIB PHOSPHATE	4	FGFR2, FGFR3
INFIGRATINIB	4	FGFR2, FGFR3
IBRUTINIB	4	FGFR2
CERITINIB	4	FGFR2, FGFR3
VANDETANIB	4	FGFR2, FGFR3
NINTEDANIB ESYLATE	4	FGFR2, FGFR3
BRIGATINIB	4	FGFR2, FGFR3
ERDAFITINIB	4	FGFR2, FGFR3
FUTIBATINIB	4	FGFR2, FGFR3
PAZOPANIB	4	FGFR2, FGFR3
SUNITINIB	4	FGFR2, FGFR3
DASATINIB	4	FGFR2, FGFR3
ERLOTINIB	4	FGFR2
MIDOSTAURIN	4	FGFR2, FGFR3
ENTRECTINIB	4	FGFR3
CRIZOTINIB	4	FGFR3
LINIFANIB	3	FGFR2, FGFR3
SEMAXANIB	3	FGFR2, FGFR3
BRIVANIB	3	FGFR2, FGFR3
CEDIRANIB	3	FGFR2, FGFR3
DOVITINIB	3	FGFR2, FGFR3
LESTAURTINIB	3	FGFR2, FGFR3
ALISERTIB	3	FGFR3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
FGFR3	975	Binding:948, Functional:18, ADMET:9
FGFR2	966	Binding:940, Functional:22, ADMET:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FGFR2	2.7.10.1	receptor protein-tyrosine kinase
AGMO	1.14.16.5	alkylglycerol monooxygenase
FGFR3	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
FGFR2	966
FGFR3	975

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	FGFR2, FGFR3
PEMIGATINIB	4	FGFR2, FGFR3
NINTEDANIB	4	FGFR2, FGFR3
FEDRATINIB	4	FGFR2, FGFR3
LENVATINIB	4	FGFR2, FGFR3
AXITINIB	4	FGFR2, FGFR3
SORAFENIB	4	FGFR2, FGFR3
INFIGRATINIB PHOSPHATE	4	FGFR2, FGFR3
INFIGRATINIB	4	FGFR2, FGFR3
IBRUTINIB	4	FGFR2
CERITINIB	4	FGFR2, FGFR3
VANDETANIB	4	FGFR2, FGFR3
NINTEDANIB ESYLATE	4	FGFR2, FGFR3
BRIGATINIB	4	FGFR2, FGFR3
ERDAFITINIB	4	FGFR2, FGFR3
FUTIBATINIB	4	FGFR2, FGFR3
PAZOPANIB	4	FGFR2, FGFR3
SUNITINIB	4	FGFR2, FGFR3
DASATINIB	4	FGFR2, FGFR3
ERLOTINIB	4	FGFR2
MIDOSTAURIN	4	FGFR2, FGFR3
ENTRECTINIB	4	FGFR3
CRIZOTINIB	4	FGFR3
LINIFANIB	3	FGFR2, FGFR3
SEMAXANIB	3	FGFR2, FGFR3
BRIVANIB	3	FGFR2, FGFR3
CEDIRANIB	3	FGFR2, FGFR3
DOVITINIB	3	FGFR2, FGFR3
LESTAURTINIB	3	FGFR2, FGFR3
ALISERTIB	3	FGFR3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	FGFR2, FGFR3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	AGMO
E	Difficult family or no structure, no drug	2	TWIST1, FERD3L

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TWIST1	0	—
FERD3L	0	—
AGMO	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04676399	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Improving Pain Management Via Spinal Cord Stimulation and Blood Pressure Reduction
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04548375	Not specified	RECRUITING	Multicenter Outcome Registry of AnaLgesic Effect of SCS(MORALES) Registry Protocol
NCT07535372	Not specified	NOT_YET_RECRUITING	ASO Treatment for Syndromic Craniosynostoses
NCT03670147	Not specified	TERMINATED	Paresthesia Free Spinal Cord Stimulation (PF-SCS)
NCT05466110	Not specified	UNKNOWN	Spinal Cord Stimulation Versus Instrumentation for FBSS
NCT05540756	Not specified	WITHDRAWN	Study on the Use of Intraoperative Neurophysiological Monitoring in Spinal Cord Stimulator Trials

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
HYDROCHLOROTHIAZIDE	4	1
CHEMBL354261	0	1