Larsen syndrome

Summary

Larsen syndrome (MONDO:0007875) is a disease caused by variants in FLNB and GZF1, with 4 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal genes: FLNB (GenCC Strong), GZF1 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 95
• Phenotypes (HPO): 27
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.4	Europe	Validated
Point prevalence	1-9 / 1 000 000		France	Validated
Prevalence at birth	1-9 / 1 000 000	0.65	France	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0000272	Malar flattening	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001799	Short nail	Very frequent (80-99%)
HP:0005008	Large joint dislocations	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0009836	Broad distal phalanx of finger	Very frequent (80-99%)
HP:0009882	Short distal phalanx of finger	Very frequent (80-99%)
HP:0011220	Prominent forehead	Very frequent (80-99%)
HP:0011304	Broad thumb	Very frequent (80-99%)
HP:0012368	Flat face	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0004232	Accessory carpal bones	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000405	Conductive hearing impairment	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001363	Craniosynostosis	Occasional (5-29%)
HP:0001626	Abnormality of the cardiovascular system	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003319	Abnormality of the cervical spine	Occasional (5-29%)
HP:0003422	Vertebral segmentation defect	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0005930	Abnormality of epiphysis morphology	Occasional (5-29%)
HP:0006101	Finger syndactyly	Occasional (5-29%)
HP:0008755	Laryngotracheomalacia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Larsen syndrome
Mondo ID	MONDO:0007875
MeSH	C580241
OMIM	150250
Orphanet	503
DOID	DOID:14764
ICD-11	607849551
SNOMED CT	63387002
UMLS	C0175778
MedGen	104500
GARD	0006860
NORD	1349
Is cancer (heuristic)	no

Also known as: autosomal dominant Larsen syndrome · Larsen syndrome · LRS

Data availability: 95 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › Larsen syndrome

Related subtypes (51): disorder of sexual differentiation, hereditary neurocutaneous angioma, nevoid basal cell carcinoma syndrome, angioosteohypertrophic syndrome, schwannomatosis, linear nevus sebaceous syndrome, lethal Larsen-like syndrome, pseudodiastrophic dysplasia, focal dermal hypoplasia, microtia, neurofibromatosis-Noonan syndrome, Becker nevus syndrome, Legius syndrome, bone fragility with contractures, arterial rupture, and deafness, blindness - scoliosis - arachnodactyly syndrome, cutis laxa - Marfanoid syndrome, Maffucci syndrome, hydrops fetalis, ankyloblepharon filiforme-imperforate anus syndrome, developmental anomaly of metabolic origin, progeroid syndrome, facial cleft, Desbuquois dysplasia, cysts and fistulae of the face and oral cavity, macroglossia, middle ear anomaly, cleft palate, cutis laxa, infectious embryofetopathy, toxic or drug-related embryofetopathy, hemihyperplasia-multiple lipomatosis syndrome, phakomatosis pigmentokeratotica, phakomatosis pigmentovascularis, PTEN hamartoma tumor syndrome, marfanoid habitus-inguinal hernia-advanced bone age syndrome, neurofibromatosis type 1, multiple congenital anomalies/dysmorphic syndrome, congenital limb malformation, hereditary hemorrhagic telangiectasia, urogenital tract malformation, congenital anomaly of kidney and urinary tract, anotia, central nervous system malformation, Ehlers-Danlos syndrome, X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome, joint laxity, short stature, and myopia, diaphragmatic malformation, abdominal wall malformation, port-wine nevi-mega cisterna magna-hydrocephalus syndrome, conjoined twins, TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations

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

95 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 19 conflicting classifications of pathogenicity, 12 likely pathogenic, 8 pathogenic, 6 benign/likely benign, 4 likely benign, 4 not provided, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
694680	NM_004273.5(CHST3):c.1254GAA[1] (p.Lys419del)	CHST3	Pathogenic	criteria provided, single submitter
16338	NM_000142.5(FGFR3):c.1620C>G (p.Asn540Lys)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21278	NM_001457.4(FLNB):c.1081G>A (p.Gly361Ser)	FLNB	Pathogenic	criteria provided, single submitter
21292	NM_001457.4(FLNB):c.5500G>A (p.Gly1834Arg)	FLNB	Pathogenic	no assertion criteria provided
38961	NM_001457.4(FLNB):c.502G>A (p.Gly168Ser)	FLNB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
432006	NM_001457.4(FLNB):c.1082G>A (p.Gly361Asp)	FLNB	Pathogenic	criteria provided, multiple submitters, no conflicts
522782	NM_001457.4(FLNB):c.5072G>A (p.Gly1691Asp)	FLNB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6399	NM_001457.4(FLNB):c.4756G>A (p.Gly1586Arg)	FLNB	Pathogenic	no assertion criteria provided
6405	NM_001457.4(FLNB):c.679G>A (p.Glu227Lys)	FLNB	Pathogenic	criteria provided, multiple submitters, no conflicts
6406	NM_001457.4(FLNB):c.5071G>A (p.Gly1691Ser)	FLNB	Pathogenic	criteria provided, multiple submitters, no conflicts
694710	NM_001457.4(FLNB):c.4928C>T (p.Ala1643Val)	FLNB	Pathogenic	criteria provided, single submitter
1683438	NM_001457.4(FLNB):c.4570G>A (p.Gly1524Ser)	FLNB	Likely pathogenic	criteria provided, single submitter
1683439	NM_001457.4(FLNB):c.591T>A (p.Asn197Lys)	FLNB	Likely pathogenic	criteria provided, single submitter
1683442	NM_001457.4(FLNB):c.4550C>A (p.Ala1517Asp)	FLNB	Likely pathogenic	criteria provided, single submitter
1705102	NM_001457.4(FLNB):c.4604G>A (p.Ser1535Asn)	FLNB	Likely pathogenic	criteria provided, single submitter
21281	NM_001457.4(FLNB):c.4292T>G (p.Leu1431Arg)	FLNB	Likely pathogenic	criteria provided, single submitter
21283	NM_001457.4(FLNB):c.4713_4715del (p.Asn1571del)	FLNB	Likely pathogenic	criteria provided, single submitter
2882122	NM_001457.4(FLNB):c.2806G>A (p.Val936Met)	FLNB	Likely pathogenic	criteria provided, single submitter
3376886	NM_001457.4(FLNB):c.4861+2T>G	FLNB	Likely pathogenic	criteria provided, single submitter
3384082	NM_001457.4(FLNB):c.4545T>A (p.Tyr1515Ter)	FLNB	Likely pathogenic	criteria provided, single submitter
3893190	NM_001457.4(FLNB):c.492C>A (p.Asn164Lys)	FLNB	Likely pathogenic	criteria provided, single submitter
4531201	NM_001457.4(FLNB):c.1081G>T (p.Gly361Cys)	FLNB	Likely pathogenic	criteria provided, single submitter
6398	NM_001457.4(FLNB):c.482T>G (p.Phe161Cys)	FLNB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048081	NM_001457.4(FLNB):c.501C>A (p.Asp167Glu)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1306802	NM_001457.4(FLNB):c.3325G>A (p.Val1109Ile)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1342377	NM_001457.4(FLNB):c.5059T>C (p.Tyr1687His)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1356262	NM_001457.4(FLNB):c.1887C>G (p.Asp629Glu)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1417463	NM_001457.4(FLNB):c.7036C>T (p.Arg2346Cys)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194935	NM_001457.4(FLNB):c.2773G>T (p.Gly925Cys)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2413304	NM_001457.4(FLNB):c.4222G>A (p.Gly1408Ser)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 20 · 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
FLNB	Strong	Autosomal dominant	Larsen syndrome	13
GZF1	Strong	Autosomal recessive	Larsen syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GZF1	Orphanet:527450	Severe myopia-generalized joint laxity-short stature syndrome
FLNB	Orphanet:1190	Atelosteogenesis type I
FLNB	Orphanet:1263	Boomerang dysplasia
FLNB	Orphanet:3275	Spondylocarpotarsal synostosis
FLNB	Orphanet:503	Larsen syndrome
FLNB	Orphanet:56305	Atelosteogenesis type III
CHST3	Orphanet:263463	CHST3-related skeletal dysplasia
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

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GZF1	HGNC:15808	ENSG00000125812	Q9H116	GDNF-inducible zinc finger protein 1	gencc,clinvar
FLNB	HGNC:3755	ENSG00000136068	O75369	Filamin-B	gencc,clinvar
CHST3	HGNC:1971	ENSG00000122863	Q7LGC8	Carbohydrate sulfotransferase 3	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)
GZF1	GDNF-inducible zinc finger protein 1	Transcriptional repressor that binds the GZF1 responsive element (GRE) (consensus: 5’-TGCGCN[TG][CA]TATA-3’).
FLNB	Filamin-B	Connects cell membrane constituents to the actin cytoskeleton.
CHST3	Carbohydrate sulfotransferase 3	Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of the N-acetylgalactosamine (GalNAc) residue of chondroitin.
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: 1 · Unknown: 0 · Druggable fraction: 0.75

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
Antibody/Immunoglobulin	1	7.3×	0.273
Kinase	1	6.9×	0.273
Enzyme (other)	1	3.0×	0.392
Transcription factor	1	2.1×	0.403

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GZF1	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type
FLNB	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
CHST3	Enzyme (other)	yes	2.8.2.17	Sulfotransferase_dom, Carbohydrate_sulfotransferase, P-loop_NTPase
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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	1
left ventricle myocardium	1
sperm	1
mucosa of transverse colon	1
tibial nerve	1
transverse colon	1
cartilage tissue	1
tibia	1
ventricular zone	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
GZF1	249	ubiquitous	marker	sperm, left ventricle myocardium, endothelial cell
FLNB	290	ubiquitous	marker	mucosa of transverse colon, tibial nerve, transverse colon
CHST3	233	ubiquitous	marker	tibia, cartilage tissue, ventricular zone
FGFR3	262	broad	marker	upper leg skin, skin of hip, upper arm skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGFR3	4,510
FLNB	2,927
GZF1	1,077
CHST3	579

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLNB	O75369	23
FGFR3	P22607	15

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CHST3	Q7LGC8	80.58
GZF1	Q9H116	60.05

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 4 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
t(4;14) translocations of FGFR3	1	3806.7×	0.003	FGFR3
Signaling by FGFR3 fusions in cancer	1	3806.7×	0.003	FGFR3
FGFR3b ligand binding and activation	1	543.8×	0.010	FGFR3
Defective CHST3 causes SEDCJD	1	475.8×	0.010	CHST3
Signaling by activated point mutants of FGFR3	1	317.2×	0.010	FGFR3
FGFR3c ligand binding and activation	1	292.8×	0.010	FGFR3
Phospholipase C-mediated cascade; FGFR3	1	292.8×	0.010	FGFR3
PI-3K cascade:FGFR3	1	211.5×	0.010	FGFR3
SHC-mediated cascade:FGFR3	1	200.3×	0.010	FGFR3
CS-GAG biosynthesis	1	181.3×	0.010	CHST3
FRS-mediated FGFR3 signaling	1	181.3×	0.010	FGFR3
Signaling by FGFR3 in disease	1	165.5×	0.010	FGFR3
Negative regulation of FGFR3 signaling	1	146.4×	0.010	FGFR3
Keratan sulfate biosynthesis	1	126.9×	0.011	CHST3
PI3K Cascade	1	90.6×	0.015	FGFR3
ISG15 antiviral mechanism	1	50.1×	0.025	FLNB
Constitutive Signaling by Aberrant PI3K in Cancer	1	42.3×	0.028	FGFR3
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	32.3×	0.034	FGFR3
PIP3 activates AKT signaling	1	22.3×	0.047	FGFR3
RAF/MAP kinase cascade	1	20.4×	0.048	FGFR3

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of developmental growth	1	4213.0×	0.009	FGFR3
fibroblast growth factor receptor apoptotic signaling pathway	1	2106.5×	0.009	FGFR3
bone maturation	1	1404.3×	0.009	FGFR3
positive regulation of phospholipase activity	1	842.6×	0.011	FGFR3
endochondral bone growth	1	421.3×	0.014	FGFR3
keratinocyte development	1	383.0×	0.014	FLNB
N-acetylglucosamine metabolic process	1	300.9×	0.014	CHST3
sulfur compound metabolic process	1	280.9×	0.014	CHST3
chondrocyte proliferation	1	263.3×	0.014	FGFR3
keratan sulfate proteoglycan biosynthetic process	1	247.8×	0.014	CHST3
epithelial cell morphogenesis	1	234.1×	0.014	FLNB
positive regulation of tyrosine phosphorylation of STAT protein	1	183.2×	0.016	FGFR3
chondroitin sulfate proteoglycan biosynthetic process	1	156.0×	0.017	CHST3
bone morphogenesis	1	150.5×	0.017	FGFR3
endochondral ossification	1	135.9×	0.018	FGFR3
T cell homeostasis	1	113.9×	0.020	CHST3
branching involved in ureteric bud morphogenesis	1	91.6×	0.023	GZF1
chondrocyte differentiation	1	75.2×	0.024	FGFR3
cell surface receptor signaling pathway via JAK-STAT	1	72.6×	0.024	FGFR3
skeletal muscle tissue development	1	72.6×	0.024	FLNB
fibroblast growth factor receptor signaling pathway	1	71.4×	0.024	FGFR3
bone mineralization	1	68.0×	0.024	FGFR3
cellular response to type II interferon	1	52.0×	0.030	FLNB
MAPK cascade	1	38.3×	0.039	FGFR3
carbohydrate metabolic process	1	34.0×	0.042	CHST3
skeletal system development	1	31.4×	0.044	FGFR3
positive regulation of ERK1 and ERK2 cascade	1	21.3×	0.060	FGFR3
positive regulation of MAPK cascade	1	20.2×	0.060	FGFR3
actin cytoskeleton organization	1	19.8×	0.060	FLNB
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	19.6×	0.060	FGFR3

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR3	64	4
GZF1	0	0
FLNB	0	0
CHST3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	FGFR3
PEMIGATINIB	4	FGFR3
NINTEDANIB	4	FGFR3
FEDRATINIB	4	FGFR3
LENVATINIB	4	FGFR3
AXITINIB	4	FGFR3
SORAFENIB	4	FGFR3
INFIGRATINIB PHOSPHATE	4	FGFR3
INFIGRATINIB	4	FGFR3
ENTRECTINIB	4	FGFR3
CERITINIB	4	FGFR3
VANDETANIB	4	FGFR3
NINTEDANIB ESYLATE	4	FGFR3
BRIGATINIB	4	FGFR3
ERDAFITINIB	4	FGFR3
FUTIBATINIB	4	FGFR3
PAZOPANIB	4	FGFR3
SUNITINIB	4	FGFR3
DASATINIB	4	FGFR3
CRIZOTINIB	4	FGFR3
MIDOSTAURIN	4	FGFR3
LINIFANIB	3	FGFR3
SEMAXANIB	3	FGFR3
BRIVANIB	3	FGFR3
ALISERTIB	3	FGFR3
CEDIRANIB	3	FGFR3
DOVITINIB	3	FGFR3
LESTAURTINIB	3	FGFR3
TANDUTINIB	2	FGFR3
FORETINIB	2	FGFR3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
FGFR3	975	Binding:948, Functional:18, ADMET:9
FLNB	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CHST3	2.8.2.17	chondroitin 6-sulfotransferase
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
FGFR3	975

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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
FEDRATINIB	4	FGFR3
LENVATINIB	4	FGFR3
AXITINIB	4	FGFR3
SORAFENIB	4	FGFR3
INFIGRATINIB PHOSPHATE	4	FGFR3
INFIGRATINIB	4	FGFR3
ENTRECTINIB	4	FGFR3
CERITINIB	4	FGFR3
VANDETANIB	4	FGFR3
NINTEDANIB ESYLATE	4	FGFR3
BRIGATINIB	4	FGFR3
ERDAFITINIB	4	FGFR3
FUTIBATINIB	4	FGFR3
PAZOPANIB	4	FGFR3
SUNITINIB	4	FGFR3
DASATINIB	4	FGFR3
CRIZOTINIB	4	FGFR3
MIDOSTAURIN	4	FGFR3
LINIFANIB	3	FGFR3
SEMAXANIB	3	FGFR3
BRIVANIB	3	FGFR3
ALISERTIB	3	FGFR3
CEDIRANIB	3	FGFR3
DOVITINIB	3	FGFR3
LESTAURTINIB	3	FGFR3
TANDUTINIB	2	FGFR3
FORETINIB	2	FGFR3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	FGFR3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	FLNB
D	Druggable family + AlphaFold only, no drug	1	CHST3
E	Difficult family or no structure, no drug	1	GZF1

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)
GZF1	0	—
FLNB	2	—
CHST3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05052554	PHASE1	WITHDRAWN	Study With QR-504a to Evaluate Safety, Tolerability & Corneal Endothelium Molecular Biomarker(s) in Subjects With FECD3