Developmental and epileptic encephalopathy, 2

disease

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Also known as CDKL5 early infantile epileptic encephalopathyDEE2developmental and epileptic encephalopathy 2, X-linked dominantearly infantile epileptic encephalopathy caused by mutation in CDKL5EIEE2epileptic encephalopathy, early infantile, 2epileptic encephalopathy, early infantile, type 2

Summary

Developmental and epileptic encephalopathy, 2 (MONDO:0010396) is a disease caused by CDKL5 (GenCC Definitive), with 12 cohort genes.

At a glance

Prevalence: Unknown (Worldwide) [Orphanet-validated]
Causal gene: CDKL5 (GenCC Definitive)
Cohort genes: 12
ClinVar variants: 1,180
Phenotypes (HPO): 52

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000		Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.21	Australia	Validated
Prevalence at birth	1-9 / 100 000	2.36	United Kingdom	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0010818	Generalized tonic seizure	Very frequent (80-99%)
HP:0000232	Everted lower lip vermilion	Frequent (30-79%)
HP:0000337	Broad forehead	Frequent (30-79%)
HP:0000490	Deeply set eye	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000817	Reduced eye contact	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0002002	Deep philtrum	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002194	Delayed gross motor development	Frequent (30-79%)
HP:0002421	Poor head control	Frequent (30-79%)
HP:0002521	Hypsarrhythmia	Frequent (30-79%)
HP:0003763	Bruxism	Frequent (30-79%)
HP:0003808	Abnormal muscle tone	Frequent (30-79%)
HP:0006979	Sleep-wake cycle disturbance	Frequent (30-79%)
HP:0007328	Impaired pain sensation	Frequent (30-79%)
HP:0007359	Focal-onset seizure	Frequent (30-79%)
HP:0009852	Broad proximal phalanges of the hand	Frequent (30-79%)
HP:0010841	Multifocal epileptiform discharges	Frequent (30-79%)
HP:0011220	Prominent forehead	Frequent (30-79%)
HP:0011343	Moderate global developmental delay	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0011471	Gastrostomy tube feeding in infancy	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012171	Stereotypical hand wringing	Frequent (30-79%)
HP:0012469	Infantile spasms	Frequent (30-79%)
HP:0012471	Thick vermilion border	Frequent (30-79%)
HP:0032794	Myoclonic seizure	Frequent (30-79%)
HP:0033850	Coldness	Frequent (30-79%)
HP:0100704	Cerebral visual impairment	Frequent (30-79%)
HP:5200061	Tactile hypersensitivity	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000341	Narrow forehead	Occasional (5-29%)
HP:0000348	High forehead	Occasional (5-29%)
HP:0000565	Esotropia	Occasional (5-29%)
HP:0000577	Exotropia	Occasional (5-29%)
HP:0000664	Synophrys	Occasional (5-29%)
HP:0000749	Paroxysmal bursts of laughter	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001822	Hallux valgus	Occasional (5-29%)
HP:0002072	Chorea	Occasional (5-29%)
HP:0002104	Apnea	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002783	Recurrent lower respiratory tract infections	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 2
Mondo ID	MONDO:0010396
MeSH	C564064
OMIM	300672
Orphanet	505652
DOID	DOID:0080467
UMLS	C4750718
MedGen	1663579
GARD	0018617
Is cancer (heuristic)	no

Also known as: CDKL5 early infantile epileptic encephalopathy · DEE2 · developmental and epileptic encephalopathy 2, X-linked dominant · developmental and epileptic encephalopathy, 2 · early infantile epileptic encephalopathy caused by mutation in CDKL5 · EIEE2 · epileptic encephalopathy, early infantile, 2 · epileptic encephalopathy, early infantile, type 2

Data availability: 1,180 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › monogenic epilepsy › developmental and epileptic encephalopathy, 2

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

600 retrieved; paginated sample, class counts are floors:

157 pathogenic, 142 uncertain significance, 138 likely benign, 53 likely pathogenic, 45 benign, 22 pathogenic/likely pathogenic, 22 benign/likely benign, 21 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1006298	NM_001323289.2(CDKL5):c.593G>A (p.Gly198Asp)	CDKL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1020776	NM_001323289.2(CDKL5):c.554+5G>A	CDKL5	Pathogenic	criteria provided, single submitter
1037382	NM_001323289.2(CDKL5):c.424T>G (p.Leu142Val)	CDKL5	Pathogenic	criteria provided, single submitter
1038592	NM_001323289.2(CDKL5):c.412C>G (p.Pro138Ala)	CDKL5	Pathogenic	criteria provided, single submitter
1052408	NM_001323289.2(CDKL5):c.217G>A (p.Val73Met)	CDKL5	Pathogenic	criteria provided, single submitter
1070205	NM_001323289.2(CDKL5):c.2606del (p.Asn869fs)	CDKL5	Pathogenic	criteria provided, single submitter
1070360	NM_001323289.2(CDKL5):c.527G>A (p.Trp176Ter)	CDKL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070858	NC_000023.10:g.(?18582587)(18690188_?)del	CDKL5	Pathogenic	criteria provided, single submitter
1070859	NC_000023.10:g.(?18525211)(18528980_?)dup	CDKL5	Pathogenic	criteria provided, single submitter
1070860	NC_000023.10:g.(?18582587)(18627700_?)dup	CDKL5	Pathogenic	criteria provided, single submitter
1070908	NM_001323289.2(CDKL5):c.1927C>T (p.Gln643Ter)	CDKL5	Pathogenic	criteria provided, single submitter
1071237	NM_001323289.2(CDKL5):c.532C>G (p.Arg178Gly)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
1072615	NM_001323289.2(CDKL5):c.194G>C (p.Arg65Pro)	CDKL5	Pathogenic	criteria provided, single submitter
1072616	NM_001323289.2(CDKL5):c.1976_1977del (p.Val659fs)	CDKL5	Pathogenic	criteria provided, single submitter
1072660	NM_001323289.2(CDKL5):c.1053_1056dup (p.Leu353fs)	CDKL5	Pathogenic	criteria provided, single submitter
1072862	NM_001323289.2(CDKL5):c.513C>G (p.Tyr171Ter)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
1072905	NM_001323289.2(CDKL5):c.1584dup (p.Ser529fs)	CDKL5	Pathogenic	criteria provided, single submitter
1073273	NM_001323289.2(CDKL5):c.554+4A>G	CDKL5	Pathogenic	criteria provided, single submitter
1075877	NM_001323289.2(CDKL5):c.2579_2582dup (p.Leu862fs)	CDKL5	Pathogenic	criteria provided, single submitter
11500	NM_001323289.2(CDKL5):c.2500C>T (p.Gln834Ter)	CDKL5	Pathogenic	reviewed by expert panel
11502	NM_001323289.2(CDKL5):c.119C>T (p.Ala40Val)	CDKL5	Pathogenic	reviewed by expert panel
11503	NM_001323289.2(CDKL5):c.215T>C (p.Ile72Thr)	CDKL5	Pathogenic	reviewed by expert panel
1322054	NM_001323289.2(CDKL5):c.2636del (p.Leu879fs)	CDKL5	Pathogenic	criteria provided, single submitter
1322055	NM_001323289.2(CDKL5):c.745-1G>T	CDKL5	Pathogenic	criteria provided, single submitter
1342902	NM_001323289.2(CDKL5):c.1419del (p.Gln475fs)	CDKL5	Pathogenic	criteria provided, single submitter
1350934	NM_001323289.2(CDKL5):c.1066dup (p.Ala356fs)	CDKL5	Pathogenic	criteria provided, single submitter
1354281	NM_001323289.2(CDKL5):c.993_994dup (p.Ser332fs)	CDKL5	Pathogenic	criteria provided, single submitter
1361871	NM_001323289.2(CDKL5):c.2371C>T (p.Gln791Ter)	CDKL5	Pathogenic	criteria provided, single submitter
1376941	NM_001323289.2(CDKL5):c.2463del (p.Trp821fs)	CDKL5	Pathogenic	criteria provided, single submitter
1400702	NM_001323289.2(CDKL5):c.1896del (p.Gln633fs)	CDKL5	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 32 · 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
CDKL5	Definitive	X-linked	developmental and epileptic encephalopathy, 2	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
RS1	Orphanet:792	X-linked retinoschisis
SNAP25	Orphanet:98914	Presynaptic congenital myasthenic syndromes
CACNA1A	Orphanet:2131	Alternating hemiplegia of childhood
CACNA1A	Orphanet:2382	Lennox-Gastaut syndrome
CACNA1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA1A	Orphanet:569	Familial or sporadic hemiplegic migraine
CACNA1A	Orphanet:71518	Benign paroxysmal torticollis of infancy
CACNA1A	Orphanet:97	Familial paroxysmal ataxia
CACNA1A	Orphanet:98758	Spinocerebellar ataxia type 6
GCK	Orphanet:552	MODY
GCK	Orphanet:79299	Congenital glucokinase-related hyperinsulinism
GCK	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
ADGRG2	Orphanet:48	Congenital bilateral absence of vas deferens
KCNQ2	Orphanet:140927	Self-limited neonatal-infantile epilepsy
KCNQ2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
KCNQ2	Orphanet:1949	Self-limited neonatal epilepsy
KCNQ2	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
KCNQ2	Orphanet:306	Self-limited infantile epilepsy
KCNQ2	Orphanet:439218	KCNQ2-related developmental and epileptic encephalopathy
MECP2	Orphanet:1762	Proximal Xq28 duplication syndrome
MECP2	Orphanet:209370	MECP2-related severe neonatal encephalopathy
MECP2	Orphanet:3077	X-linked intellectual disability-psychosis-macroorchidism syndrome
MECP2	Orphanet:3095	Atypical Rett syndrome
MECP2	Orphanet:536	Systemic lupus erythematosus
MECP2	Orphanet:777	X-linked non-syndromic intellectual disability
MECP2	Orphanet:778	Rett syndrome
ATP6V1A	Orphanet:357074	Autosomal recessive cutis laxa type 2, classic type
ATP6V1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

Cohort genes → proteins

12 cohort genes, 12 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	12

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CDKL5	HGNC:11411	ENSG00000008086	O76039	Cyclin-dependent kinase-like 5	gencc,clinvar
RS1	HGNC:10457	ENSG00000102104	O15537	Retinoschisin	clinvar
SCML1	HGNC:10580	ENSG00000047634	Q9UN30	Sex comb on midleg-like protein 1	clinvar
SCML2	HGNC:10581	ENSG00000102098	Q9UQR0	Sex comb on midleg-like protein 2	clinvar
SNAP25	HGNC:11132	ENSG00000132639	P60880	Synaptosomal-associated protein 25	clinvar
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	clinvar
BEND2	HGNC:28509	ENSG00000177324	Q8NDZ0	BEN domain-containing protein 2	clinvar
GCK	HGNC:4195	ENSG00000106633	P35557	Hexokinase-4	clinvar
ADGRG2	HGNC:4516	ENSG00000173698	Q8IZP9	Adhesion G-protein coupled receptor G2	clinvar
KCNQ2	HGNC:6296	ENSG00000075043	O43526	Potassium voltage-gated channel subfamily KQT member 2	clinvar
MECP2	HGNC:6990	ENSG00000169057	P51608	Methyl-CpG-binding protein 2	clinvar
ATP6V1A	HGNC:851	ENSG00000114573	P38606	V-type proton ATPase catalytic subunit A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDKL5	Cyclin-dependent kinase-like 5	Mediates phosphorylation of MECP2.
RS1	Retinoschisin	Binds negatively charged membrane lipids, such as phosphatidylserine and phosphoinositides.
SCML1	Sex comb on midleg-like protein 1	Putative Polycomb group (PcG) protein.
SCML2	Sex comb on midleg-like protein 2	Putative Polycomb group (PcG) protein.
SNAP25	Synaptosomal-associated protein 25	t-SNARE involved in the molecular regulation of neurotransmitter release.
CACNA1A	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
GCK	Hexokinase-4	Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively).
ADGRG2	Adhesion G-protein coupled receptor G2	Adhesion G-protein coupled receptor (aGPCR) for steroid hormones, such as dehydroepiandrosterone (DHEA; also named 3beta-hydroxyandrost-5-en-17-one) and androstenedione.
KCNQ2	Potassium voltage-gated channel subfamily KQT member 2	Pore-forming subunit of the voltage-gated potassium (Kv) M-channel which is responsible for the M-current, a key controller of neuronal excitability.
MECP2	Methyl-CpG-binding protein 2	Chromosomal protein that binds to methylated DNA.
ATP6V1A	V-type proton ATPase catalytic subunit A	Catalytic subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.

Protein-family classification

Druggable: 5 · Difficult: 0 · Unknown: 7 · Druggable fraction: 0.42

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
Ion channel	2	18.6×	0.020
Kinase	2	4.6×	0.135
GPCR	1	2.0×	0.534
Other/Unknown	7	1.1×	0.550

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDKL5	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
RS1	Other/Unknown	no		FA58C, Galactose-bd-like_sf, Neuropilin_MCO_CoagFactor
SCML1	Other/Unknown	no		SAM, SAM/pointed_sf, SAM_Scm-like
SCML2	Other/Unknown	no		SAM, Mbt, SAM/pointed_sf
SNAP25	Other/Unknown	no		T_SNARE_dom, SNAP-25_dom, SNAP-25_N_SNARE_chord
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
BEND2	Other/Unknown	no		BEN_domain
GCK	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N
ADGRG2	GPCR	yes		GPS, GPCR_2_secretin-like, GPCR_2-like_7TM
KCNQ2	Ion channel	yes		K_chnl_volt-dep_KCNQ, K_chnl_volt-dep_KCNQ2, Ion_trans_dom
MECP2	Other/Unknown	no		Methyl_CpG_DNA-bd, DNA-bd_dom_sf, Me_CpG-bd_MeCP2
ATP6V1A	Other/Unknown	no		ATPase_F1/V1/A1_a/bsu_nucl-bd, ATPase_F1/V1/A1_a/bsu_N, ATPase_V1-cplx_asu

Expression context

Cohort genes with no expression data: 0.

11 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)	12
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	3
Brodmann (1909) area 23	2
male germ line stem cell (sensu Vertebrata) in testis	2
oocyte	2
secondary oocyte	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
cortical plate	1
frontal pole	1
left ovary	1
diaphragm	1
olfactory bulb	1
type B pancreatic cell	1
cerebellum	1
pons	1
leukocyte	1
monocyte	1
adenohypophysis	1
islet of Langerhans	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDKL5	257	ubiquitous	marker	frontal pole, Brodmann (1909) area 23, cortical plate
RS1	34	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, oocyte, secondary oocyte
SCML1	275	ubiquitous	marker	secondary oocyte, oocyte, left ovary
SCML2	228	ubiquitous	yes	olfactory bulb, diaphragm, type B pancreatic cell
SNAP25	220	broad	marker	pons, cerebellar cortex, cerebellum
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
BEND2	30	tissue_specific	marker	monocyte, leukocyte, male germ line stem cell (sensu Vertebrata) in testis
GCK	155	tissue_specific	marker	pituitary gland, adenohypophysis, islet of Langerhans
ADGRG2	182	broad	marker	corpus epididymis, caput epididymis, parotid gland
KCNQ2	183	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
MECP2	277	ubiquitous	marker	paraflocculus, Brodmann (1909) area 10, sural nerve
ATP6V1A	300	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MECP2	5,688
KCNQ2	3,388
ATP6V1A	3,301
GCK	2,245
CDKL5	1,357
RS1	1,317
SCML2	1,156
ADGRG2	723
SCML1	633
BEND2	516

Intra-cohort edges

A	B	Sources
CDKL5	KCNQ2	string_interaction
CDKL5	MECP2	string_interaction
CDKL5	RS1	string_interaction
CDKL5	SCML2	string_interaction

Structural data

PDB: 9 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNQ2	O43526	39
GCK	P35557	35
SNAP25	P60880	14
MECP2	P51608	9
ATP6V1A	P38606	8
SCML2	Q9UQR0	5
CACNA1A	O00555	4
CDKL5	O76039	3
RS1	O15537	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SCML1	Q9UN30	67.08
ADGRG2	Q8IZP9	62.76
BEND2	Q8NDZ0	49.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 60. Enrichment computed across 12 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)	1	1903.3×	0.006	GCK
Loss of MECP2 binding ability to 5hmC-DNA	1	1903.3×	0.006	MECP2
Regulation of insulin secretion	2	73.2×	0.006	SNAP25, CACNA1A
Integration of energy metabolism	2	58.6×	0.006	SNAP25, CACNA1A
Neuronal System	3	22.1×	0.006	SNAP25, CACNA1A, KCNQ2
Toxicity of botulinum toxin type C (botC)	1	634.4×	0.011	SNAP25
Toxicity of botulinum toxin type E (botE)	1	634.4×	0.011	SNAP25
MECP2 regulates transcription of genes involved in GABA signaling	1	634.4×	0.011	MECP2
Toxicity of botulinum toxin type A (botA)	1	475.8×	0.011	SNAP25
Loss of phosphorylation of MECP2 at T308	1	475.8×	0.011	MECP2
Loss of MECP2 binding ability to 5mC-DNA	1	475.8×	0.011	MECP2
MECP2 regulates transcription factors	1	380.7×	0.012	MECP2
Transmission across Chemical Synapses	2	25.4×	0.012	SNAP25, CACNA1A
Loss of MECP2 binding ability to the NCoR/SMRT complex	1	271.9×	0.016	MECP2
Neurotoxicity of clostridium toxins	1	237.9×	0.016	SNAP25
MECP2 regulates transcription of neuronal ligands	1	237.9×	0.016	MECP2
Presynaptic depolarization and calcium channel opening	1	158.6×	0.022	CACNA1A
Uptake and actions of bacterial toxins	1	135.9×	0.024	SNAP25
Acetylcholine Neurotransmitter Release Cycle	1	112.0×	0.025	SNAP25
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	112.0×	0.025	ATP6V1A
Serotonin Neurotransmitter Release Cycle	1	105.7×	0.025	SNAP25
Norepinephrine Neurotransmitter Release Cycle	1	105.7×	0.025	SNAP25
GABA synthesis, release, reuptake and degradation	1	105.7×	0.025	SNAP25
MECP2 regulates neuronal receptors and channels	1	100.2×	0.025	MECP2
Regulation of gene expression in beta cells	1	86.5×	0.028	GCK
Dopamine Neurotransmitter Release Cycle	1	82.8×	0.028	SNAP25
Other interleukin signaling	1	79.3×	0.028	SNAP25
Glutamate Neurotransmitter Release Cycle	1	76.1×	0.028	SNAP25
Neurotransmitter release cycle	1	73.2×	0.028	SNAP25
Insulin receptor recycling	1	63.4×	0.028	ATP6V1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
catecholamine secretion	1	1532.0×	0.015	MECP2
trans-synaptic signaling by BDNF	1	1532.0×	0.015	MECP2
regulation of insulin secretion	2	71.3×	0.015	SNAP25, GCK
long-term synaptic potentiation	2	51.1×	0.015	SNAP25, MECP2
chemical synaptic transmission	3	21.1×	0.015	SNAP25, CACNA1A, KCNQ2
cardiolipin metabolic process	1	766.0×	0.022	MECP2
nervous system process involved in regulation of systemic arterial blood pressure	1	510.7×	0.022	MECP2
biogenic amine metabolic process	1	510.7×	0.022	MECP2
response to other organism	1	510.7×	0.022	MECP2
modulation of chemical synaptic transmission	2	33.3×	0.022	CDKL5, CACNA1A
proprioception	1	383.0×	0.025	MECP2
presynaptic dense core vesicle exocytosis	1	383.0×	0.025	SNAP25
glucocorticoid metabolic process	1	255.3×	0.032	MECP2
glucose catabolic process	1	218.9×	0.032	GCK
inositol metabolic process	1	218.9×	0.032	MECP2
cellular response to increased oxygen levels	1	191.5×	0.032	ATP6V1A
positive regulation of microtubule nucleation	1	191.5×	0.032	MECP2
regulation of potassium ion transport	1	170.2×	0.032	GCK
negative regulation of smooth muscle cell differentiation	1	170.2×	0.032	MECP2
synaptic vesicle fusion to presynaptic active zone membrane	1	153.2×	0.032	SNAP25
Golgi lumen acidification	1	153.2×	0.032	ATP6V1A
NADP+ metabolic process	1	139.3×	0.032	GCK
cellular response to leptin stimulus	1	139.3×	0.032	GCK
neurotransmitter uptake	1	127.7×	0.032	SNAP25
regulation of respiratory gaseous exchange by nervous system process	1	117.8×	0.032	MECP2
L-glutamine metabolic process	1	117.8×	0.032	MECP2
obsolete synaptic vesicle docking	1	117.8×	0.032	SNAP25
glucose 6-phosphate metabolic process	1	117.8×	0.032	GCK
regulation of glycolytic process	1	109.4×	0.032	GCK
endosomal lumen acidification	1	109.4×	0.032	ATP6V1A

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 8

Druggability breadth: 8 of 12 evidence-associated genes (67%) 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
CACNA1A	NIMODIPINE
KCNQ2	FLUPIRTINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDKL5	14	4
GCK	5	2
KCNQ2	4	4
CACNA1A	2	4
RS1	0	0
SCML1	0	0
SCML2	0	0
SNAP25	0	0
BEND2	0	0
ADGRG2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	CDKL5
CAPMATINIB	4	CDKL5
NIMODIPINE	4	CACNA1A
TACRINE	4	CACNA1A
FLUPIRTINE	4	KCNQ2
EZOGABINE	4	KCNQ2
DEFACTINIB	3	CDKL5
ALVOCIDIB	3	CDKL5
LESTAURTINIB	3	CDKL5
RUBOXISTAURIN	3	CDKL5
FLINDOKALNER	3	KCNQ2
AZETUKALNER	3	KCNQ2
FORETINIB	2	CDKL5
RG-547	2	CDKL5
AT-7519	2	CDKL5
TOZASERTIB	2	CDKL5
PIRAGLIATIN	2	GCK
NERIGLIATIN	2	GCK
PF-04991532	2	GCK
AZD-1656	2	GCK
MK-0941 FREE BASE	2	GCK
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
GCK	228	Binding:226, ADMET:1, Functional:1
KCNQ2	145	Binding:136, Functional:7, ADMET:1, Toxicity:1
CDKL5	74	Binding:74
CACNA1A	19	Binding:18, Functional:1
ADGRG2	2	Binding:2
ATP6V1A	2	Binding:2
MECP2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CDKL5	2.7.11.22	cyclin-dependent kinase
GCK	2.7.1.1	hexokinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GCK	228
KCNQ2	145

Pharmacogenomics

Cohort genes with a PharmGKB record: 12; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

25 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
NIMODIPINE	4	CACNA1A
TACRINE	4	CACNA1A
FLUPIRTINE	4	KCNQ2
EZOGABINE	4	KCNQ2
DEFACTINIB	3	CDKL5
ALVOCIDIB	3	CDKL5
LESTAURTINIB	3	CDKL5
RUBOXISTAURIN	3	CDKL5
FLINDOKALNER	3	KCNQ2
AZETUKALNER	3	KCNQ2
FORETINIB	2	CDKL5
RG-547	2	CDKL5
AT-7519	2	CDKL5
TOZASERTIB	2	CDKL5
PIRAGLIATIN	2	GCK
NERIGLIATIN	2	GCK
PF-04991532	2	GCK
AZD-1656	2	GCK
MK-0941 FREE BASE	2	GCK
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)	3	CDKL5, CACNA1A, KCNQ2
B	Phased (≥1) drug, not yet approved	1	GCK
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ADGRG2
E	Difficult family or no structure, no drug	7	RS1, SCML1, SCML2, SNAP25, BEND2, MECP2, ATP6V1A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RS1	0	CDKL5
SCML1	0	—
SCML2	0	—
SNAP25	0	—
BEND2	0	—
ADGRG2	2	—
MECP2	1	—
ATP6V1A	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: CDKL5, RS1, SCML1, SCML2, SNAP25, CACNA1A, BEND2, GCK, ADGRG2, KCNQ2, MECP2, ATP6V1A