Developmental and epileptic encephalopathy, 4

disease

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Also known as DEE4developmental and epileptic encephalopathy 4early infantile epileptic encephalopathy 4early infantile epileptic encephalopathy caused by mutation in STXBP1EIEE4epileptic encephalopathy, early infantile, 4epileptic encephalopathy, early infantile, type 4STXBP1 early infantile epileptic encephalopathySTXBP1-related early-onset encephalopathySTXBP1-related encephalopathy

Summary

Developmental and epileptic encephalopathy, 4 (MONDO:0012812) is a disease caused by STXBP1 (GenCC Definitive), with 8 cohort genes.

At a glance

Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
Causal gene: STXBP1 (GenCC Definitive)
Cohort genes: 8
ClinVar variants: 254
Phenotypes (HPO): 31

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		282	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.6	Worldwide	Validated
Point prevalence	1-9 / 100 000	1.0885	Denmark	Validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0011185	EEG with focal epileptiform discharges	Frequent (30-79%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0002123	Generalized myoclonic seizure	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0002384	Focal impaired awareness seizure	Occasional (5-29%)
HP:0002521	Hypsarrhythmia	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0006989	Dysplastic corpus callosum	Occasional (5-29%)
HP:0010819	Atonic seizure	Occasional (5-29%)
HP:0010841	Multifocal epileptiform discharges	Occasional (5-29%)
HP:0011097	Epileptic spasm	Occasional (5-29%)
HP:0011153	Focal motor seizure	Occasional (5-29%)
HP:0011203	EEG with abnormally slow frequencies	Occasional (5-29%)
HP:0012469	Infantile spasms	Occasional (5-29%)
HP:0012762	Cerebral white matter atrophy	Occasional (5-29%)
HP:0200134	Epileptic encephalopathy	Occasional (5-29%)
HP:0001257	Spasticity	Very rare (<1-4%)
HP:0001332	Dystonia	Very rare (<1-4%)
HP:0002510	Spastic tetraplegia	Very rare (<1-4%)
HP:0007334	Bilateral tonic-clonic seizure with focal onset	Very rare (<1-4%)
HP:0012448	Delayed myelination	Very rare (<1-4%)
HP:0100660	Dyskinesia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 4
Mondo ID	MONDO:0012812
MeSH	C567404
OMIM	612164
Orphanet	599373
DOID	DOID:0080436
NCIT	C162472
SNOMED CT	768666006
UMLS	C2677326
MedGen	436917
GARD	0012900
Is cancer (heuristic)	no

Also known as: DEE4 · developmental and epileptic encephalopathy 4 · developmental and epileptic encephalopathy, 4 · early infantile epileptic encephalopathy 4 · early infantile epileptic encephalopathy caused by mutation in STXBP1 · EIEE4 · epileptic encephalopathy, early infantile, 4 · epileptic encephalopathy, early infantile, type 4 · STXBP1 early infantile epileptic encephalopathy · STXBP1-related early-onset encephalopathy · STXBP1-related encephalopathy

Data availability: 254 ClinVar variants · 4 GenCC gene-disease records · 9 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › Mendelian neurodevelopmental disorder › genetic developmental and epileptic encephalopathy › developmental and epileptic encephalopathy, 4

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

254 retrieved; paginated sample, class counts are floors:

102 pathogenic, 52 uncertain significance, 49 likely pathogenic, 24 pathogenic/likely pathogenic, 15 conflicting classifications of pathogenicity, 6 benign/likely benign, 4 likely benign, 1 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
983307	GRCh37/hg19 9q33.3-34.11(chr9:128512347-130702572)x1	AK1	Pathogenic	no assertion criteria provided
813743	NM_001323289.2(CDKL5):c.1099C>T (p.Leu367=)	CDKL5	Pathogenic	criteria provided, single submitter
625638	GRCh37/hg19 9q34.11(chr9:130335766-130517907)	CFAP157	Pathogenic	criteria provided, single submitter
932281	GRCh37/hg19 9q34.11(chr9:130435492-130485618)x1	CFAP157	Pathogenic	criteria provided, single submitter
625639	GRCh37/hg19 9q33.3(chr9:129414011-129460757)	LMX1B	Pathogenic	criteria provided, single submitter
1202628	NM_001032221.6(STXBP1):c.25delinsCT (p.Val9fs)	LOC130002651	Pathogenic	no assertion criteria provided
1320142	NM_001032221.6(STXBP1):c.37+1G>C	LOC130002651	Pathogenic	criteria provided, single submitter
2019337	NM_001032221.6(STXBP1):c.2T>G (p.Met1Arg)	LOC130002651	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3254733	NM_001032221.6(STXBP1):c.37+1_37+2delinsA	LOC130002651	Pathogenic	criteria provided, single submitter
870412	NM_001032221.6(STXBP1):c.37+2dup	LOC130002651	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4820077	NC_000009.12:g.127625272_127653382del	LOC130002652	Pathogenic	criteria provided, single submitter
598748	Single allele	LRSAM1	Pathogenic	criteria provided, single submitter
1064621	NM_001032221.6(STXBP1):c.1249G>C (p.Gly417Arg)	STXBP1	Pathogenic	criteria provided, single submitter
1163029	NM_001032221.6(STXBP1):c.145_148del (p.Asp49fs)	STXBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1175798	NM_001032221.6(STXBP1):c.842T>C (p.Leu281Pro)	STXBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184507	NM_001032221.6(STXBP1):c.1282C>T (p.Gln428Ter)	STXBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1212923	NM_001032221.6(STXBP1):c.1655G>A (p.Cys552Tyr)	STXBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127076	NM_001032221.6(STXBP1):c.847G>A (p.Glu283Lys)	STXBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1298369	NM_001032221.6(STXBP1):c.122T>G (p.Leu41Arg)	STXBP1	Pathogenic	no assertion criteria provided
1298370	NM_001032221.6(STXBP1):c.1227_1229del (p.Leu410del)	STXBP1	Pathogenic	no assertion criteria provided
1298371	NM_003165.6(STXBP1):c.664-1delG	STXBP1	Pathogenic	no assertion criteria provided
1298373	NM_001032221.6(STXBP1):c.733C>A (p.His245Asn)	STXBP1	Pathogenic	no assertion criteria provided
1341561	NM_001032221.6(STXBP1):c.898del (p.Ser300fs)	STXBP1	Pathogenic	no assertion criteria provided
160070	NM_001032221.6(STXBP1):c.734A>G (p.His245Arg)	STXBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
160071	NM_001032221.6(STXBP1):c.754_755del (p.Met252fs)	STXBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1677247	NM_001032221.6(STXBP1):c.963+2T>C	STXBP1	Pathogenic	no assertion criteria provided
167725	NM_001032221.6(STXBP1):c.1029+1G>T	STXBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1686236	NM_001032221.6(STXBP1):c.795-2A>C	STXBP1	Pathogenic	criteria provided, single submitter
1686237	NM_001032221.6(STXBP1):c.1108C>T (p.Gln370Ter)	STXBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1691863	NM_001032221.6(STXBP1):c.1672delinsAACGGAAAGTGGGAGGTGGGAGG (p.Gln558fs)	STXBP1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 12 · 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
STXBP1	Definitive	Autosomal recessive	developmental and epileptic encephalopathy, 4	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STXBP1	Orphanet:495818	9q33.3q34.11 microdeletion syndrome
STXBP1	Orphanet:599373	STXBP1-related encephalopathy
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
ZP2	Orphanet:404466	Female infertility due to zona pellucida defect
LRSAM1	Orphanet:300319	Charcot-Marie-Tooth disease type 2P
AK1	Orphanet:86817	Hemolytic anemia due to adenylate kinase deficiency
LMX1B	Orphanet:2613	Nail-patella-like renal disease
LMX1B	Orphanet:2614	Nail-patella syndrome
LMX1B	Orphanet:495818	9q33.3q34.11 microdeletion syndrome

Cohort genes → proteins

8 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STXBP1	HGNC:11444	ENSG00000136854	P61764	Syntaxin-binding protein 1	gencc,clinvar
CDKL5	HGNC:11411	ENSG00000008086	O76039	Cyclin-dependent kinase-like 5	clinvar
ZP2	HGNC:13188	ENSG00000103310	Q05996	Zona pellucida sperm-binding protein 2	clinvar
LRSAM1	HGNC:25135	ENSG00000148356	Q6UWE0	E3 ubiquitin-protein ligase LRSAM1	clinvar
CFAP157	HGNC:27843	ENSG00000160401	Q5JU67	Cilia- and flagella-associated protein 157	clinvar
AK1	HGNC:361	ENSG00000106992	P00568	Adenylate kinase isoenzyme 1	clinvar
MIR3911	HGNC:38962	ENSG00000283874		microRNA 3911	clinvar
LMX1B	HGNC:6654	ENSG00000136944	O60663	LIM homeobox transcription factor 1-beta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STXBP1	Syntaxin-binding protein 1	Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins.
CDKL5	Cyclin-dependent kinase-like 5	Mediates phosphorylation of MECP2.
ZP2	Zona pellucida sperm-binding protein 2	Component of the zona pellucida, an extracellular matrix surrounding oocytes which mediates sperm binding, induction of the acrosome reaction and prevents post-fertilization polyspermy.
LRSAM1	E3 ubiquitin-protein ligase LRSAM1	E3 ubiquitin-protein ligase that mediates monoubiquitination of TSG101 at multiple sites, leading to inactivate the ability of TSG101 to sort endocytic (EGF receptors) and exocytic (HIV-1 viral proteins) cargos.
CFAP157	Cilia- and flagella-associated protein 157	Specifically required during spermatogenesis for flagellum morphogenesis and sperm motility.
AK1	Adenylate kinase isoenzyme 1	Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP.
LMX1B	LIM homeobox transcription factor 1-beta	Transcription factor involved in the regulation of podocyte-expressed genes.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 4 · Druggable fraction: 0.25

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	6.9×	0.094
Transcription factor	2	2.1×	0.377
Other/Unknown	4	0.9×	0.755

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STXBP1	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
CDKL5	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
ZP2	Other/Unknown	no		ZP_dom, ZP_dom_CS, ZP-C_dom
LRSAM1	Transcription factor	no		Leu-rich_rpt, SAM, Znf_RING
CFAP157	Other/Unknown	no		CFAP157
AK1	Kinase	yes	2.7.4.3	Adenylat/UMP-CMP_kin, AK1/5, P-loop_NTPase
MIR3911	Other/Unknown	no
LMX1B	Transcription factor	no		HD, Znf_LIM, Homeodomain-like_sf

Expression context

Cohort genes with no expression data: 0.

5 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	3
Brodmann (1909) area 23	2
apex of heart	2
lateral nuclear group of thalamus	1
middle temporal gyrus	1
cortical plate	1
frontal pole	1
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1
skin of leg	1
bronchial epithelial cell	1
bronchus	1
right uterine tube	1
gastrocnemius	1
hindlimb stylopod muscle	1
myometrium	1
subcutaneous adipose tissue	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STXBP1	287	ubiquitous	marker	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
CDKL5	257	ubiquitous	marker	frontal pole, Brodmann (1909) area 23, cortical plate
ZP2	63	tissue_specific	yes	cerebellar cortex, cerebellum, cerebellar hemisphere
LRSAM1	192	ubiquitous	yes	apex of heart, sural nerve, skin of leg
CFAP157	174	tissue_specific	marker	right uterine tube, bronchial epithelial cell, bronchus
AK1	144	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, gastrocnemius
MIR3911	50		yes	sural nerve, subcutaneous adipose tissue, myometrium
LMX1B	74	broad	marker	sural nerve, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AK1	3,526
STXBP1	3,003
LRSAM1	2,095
LMX1B	1,514
ZP2	1,426
CDKL5	1,357
CFAP157	425
MIR3911	0

Intra-cohort edges

A	B	Sources
AK1	LMX1B	string_interaction
CDKL5	STXBP1	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AK1	P00568	5
CDKL5	O76039	3
ZP2	Q05996	2
STXBP1	P61764	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CFAP157	Q5JU67	78.75
LRSAM1	Q6UWE0	78.47
LMX1B	O60663	70.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 8 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
Interaction With Cumulus Cells And The Zona Pellucida	1	259.6×	0.025	ZP2
Acetylcholine Neurotransmitter Release Cycle	1	167.9×	0.025	STXBP1
Serotonin Neurotransmitter Release Cycle	1	158.6×	0.025	STXBP1
Norepinephrine Neurotransmitter Release Cycle	1	158.6×	0.025	STXBP1
GABA synthesis, release, reuptake and degradation	1	158.6×	0.025	STXBP1
Dopamine Neurotransmitter Release Cycle	1	124.1×	0.025	STXBP1
Glutamate Neurotransmitter Release Cycle	1	114.2×	0.025	STXBP1
Interconversion of nucleotide di- and triphosphates	1	89.2×	0.026	AK1
M-decay: degradation of maternal mRNAs by maternally stored factors	1	81.6×	0.026	ZP2
Metabolism of nucleotides	1	75.1×	0.026	AK1
Protein-protein interactions at synapses	1	66.4×	0.027	STXBP1
Regulation of insulin secretion	1	54.9×	0.030	STXBP1
Neurexins and neuroligins	1	49.2×	0.031	STXBP1
Integration of energy metabolism	1	43.9×	0.032	STXBP1
Metabolism	2	5.8×	0.053	STXBP1, AK1
Class I MHC mediated antigen processing & presentation	1	17.5×	0.070	LRSAM1
Neuronal System	1	11.1×	0.103	STXBP1
Antigen processing: Ubiquitination & Proteasome degradation	1	9.3×	0.115	LRSAM1
Adaptive Immune System	1	7.5×	0.134	LRSAM1
Immune System	1	3.2×	0.275	LRSAM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete positive regulation of vesicle docking	1	2407.4×	0.012	STXBP1
regulation of acrosomal vesicle exocytosis	1	2407.4×	0.012	STXBP1
positive regulation of glutamate secretion, neurotransmission	1	1203.7×	0.013	STXBP1
axon target recognition	1	802.5×	0.013	STXBP1
negative regulation of synaptic transmission, GABAergic	1	601.9×	0.013	STXBP1
presynaptic dense core vesicle exocytosis	1	601.9×	0.013	STXBP1
platelet degranulation	1	481.5×	0.013	STXBP1
developmental process involved in reproduction	1	481.5×	0.013	STXBP1
prevention of polyspermy	1	401.2×	0.013	ZP2
ADP biosynthetic process	1	343.9×	0.013	AK1
nucleoside triphosphate biosynthetic process	1	300.9×	0.013	AK1
regulation of synaptic vesicle fusion to presynaptic active zone membrane	1	300.9×	0.013	STXBP1
positive regulation of xenophagy	1	300.9×	0.013	LRSAM1
synaptic vesicle maturation	1	267.5×	0.013	STXBP1
AMP metabolic process	1	267.5×	0.013	AK1
viral budding	1	267.5×	0.013	LRSAM1
ubiquitin-dependent endocytosis	1	267.5×	0.013	LRSAM1
regulation of synaptic vesicle priming	1	240.7×	0.013	STXBP1
nucleobase-containing small molecule interconversion	1	240.7×	0.013	AK1
positive regulation of mast cell degranulation	1	218.9×	0.013	STXBP1
SNARE complex assembly	1	200.6×	0.014	STXBP1
regulation of SNARE complex assembly	1	185.2×	0.014	STXBP1
positive regulation of calcium ion-dependent exocytosis	1	185.2×	0.014	STXBP1
regulation of dendrite development	1	141.6×	0.017	CDKL5
negative regulation of endocytosis	1	133.8×	0.017	LRSAM1
positive regulation of dendrite morphogenesis	1	126.7×	0.017	CDKL5
long-term synaptic depression	1	126.7×	0.017	STXBP1
synaptic vesicle priming	1	114.6×	0.018	STXBP1
positive regulation of autophagosome assembly	1	114.6×	0.018	LRSAM1
obsolete vesicle docking involved in exocytosis	1	96.3×	0.020	STXBP1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 7

Druggability breadth: 3 of 8 evidence-associated genes (38%) 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
CDKL5	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDKL5	14	4
STXBP1	0	0
ZP2	0	0
LRSAM1	0	0
CFAP157	0	0
AK1	0	0
MIR3911	0	0
LMX1B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	CDKL5
CAPMATINIB	4	CDKL5
DEFACTINIB	3	CDKL5
ALVOCIDIB	3	CDKL5
LESTAURTINIB	3	CDKL5
RUBOXISTAURIN	3	CDKL5
FORETINIB	2	CDKL5
RG-547	2	CDKL5
AT-7519	2	CDKL5
TOZASERTIB	2	CDKL5
BMS-387032	1	CDKL5
PF-03758309	1	CDKL5
5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-	1	CDKL5
AST-487	1	CDKL5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CDKL5	74	Binding:74
AK1	3	Binding:3
STXBP1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CDKL5	2.7.11.22	cyclin-dependent kinase
AK1	2.7.4.3	adenylate kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

14 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)
FEDRATINIB	4	CDKL5
CAPMATINIB	4	CDKL5
DEFACTINIB	3	CDKL5
ALVOCIDIB	3	CDKL5
LESTAURTINIB	3	CDKL5
RUBOXISTAURIN	3	CDKL5
FORETINIB	2	CDKL5
RG-547	2	CDKL5
AT-7519	2	CDKL5
TOZASERTIB	2	CDKL5
BMS-387032	1	CDKL5
PF-03758309	1	CDKL5
5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-	1	CDKL5
AST-487	1	CDKL5

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CDKL5
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	AK1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	STXBP1, ZP2, LRSAM1, CFAP157, MIR3911, LMX1B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
STXBP1	1	—
ZP2	0	—
LRSAM1	0	—
CFAP157	0	—
AK1	3	—
MIR3911	0	—
LMX1B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: STXBP1, CDKL5, ZP2, LRSAM1, CFAP157, AK1, MIR3911, LMX1B