Developmental and epileptic encephalopathy, 9

Summary

Developmental and epileptic encephalopathy, 9 (MONDO:0010246) is a disease caused by PCDH19 (GenCC Definitive), with 6 cohort genes.

At a glance

• Causal gene: PCDH19 (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 1,287

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 9
Mondo ID	MONDO:0010246
MeSH	C564715
OMIM	300088
Orphanet	101039
DOID	DOID:0060848
UMLS	C1848137
MedGen	338393
GARD	0010806
Is cancer (heuristic)	no

Also known as: DEE9 · developmental and epileptic encephalopathy 9 · developmental and epileptic encephalopathy, 9 · early infantile epileptic encephalopathy caused by mutation in PCDH19 · early infantile epileptic encephalopathy type 9 · EFMR · EIEE9 · epilepsy and intellectual disability limited to females · epilepsy and mental retardation limited to females · epilepsy, female restricted, with intellectual disability · epilepsy, female restricted, with mental retardation · epilepsy, female-restricted, with mental retardation · epileptic encephalopathy, early infantile, 9 · epileptic encephalopathy, early infantile, type 9 · familial epilepsy and intellectual disability limited to females · familial epilepsy and mental retardation limited to females · female restricted epilepsy with intellectual deficit · female restricted epilepsy with intellectual disability · Juberg-Hellman syndrome · PCDH19 early infantile epileptic encephalopathy (+3 more)

Data availability: 1,287 ClinVar variants · 4 GenCC gene-disease records · 12 cell lines.

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 › X-linked intellectual disability-epilepsy syndrome › developmental and epileptic encephalopathy, 9

Related subtypes (3): syndromic X-linked intellectual disability Hedera type, developmental and epileptic encephalopathy, 8, X-linked dominant intellectual disability-epilepsy 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

600 retrieved; paginated sample, class counts are floors:

239 uncertain significance, 144 likely benign, 126 pathogenic, 41 conflicting classifications of pathogenicity, 20 likely pathogenic, 15 benign/likely benign, 10 pathogenic/likely pathogenic, 3 benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
2423943	NC_000023.10:g.(?99551275)(100099087_?)del	CSTF2	Pathogenic	criteria provided, single submitter
1330214	Single allele	DIAPH2	Pathogenic	criteria provided, single submitter
1070779	NM_001184880.2(PCDH19):c.2575C>T (p.Gln859Ter)	LOC125467768	Pathogenic	criteria provided, multiple submitters, no conflicts
1074862	NM_001184880.2(PCDH19):c.2338A>T (p.Lys780Ter)	LOC125467768	Pathogenic	criteria provided, single submitter
1074865	NM_001184880.2(PCDH19):c.2502del (p.Asn834fs)	LOC125467768	Pathogenic	criteria provided, single submitter
1320065	NM_001184880.2(PCDH19):c.2391_2392del (p.Asp797fs)	LOC125467768	Pathogenic	criteria provided, single submitter
1414354	NM_001184880.2(PCDH19):c.2263G>T (p.Glu755Ter)	LOC125467768	Pathogenic	criteria provided, single submitter
1454530	NM_001184880.2(PCDH19):c.2558del (p.Phe853fs)	LOC125467768	Pathogenic	criteria provided, single submitter
1810254	NM_001184880.2(PCDH19):c.2566C>T (p.Gln856Ter)	LOC125467768	Pathogenic	criteria provided, single submitter
2002870	NM_001184880.2(PCDH19):c.2512del (p.Gln838fs)	LOC125467768	Pathogenic	criteria provided, single submitter
2008360	NM_001184880.2(PCDH19):c.2344_2351dup (p.Asn784fs)	LOC125467768	Pathogenic	criteria provided, single submitter
206360	NM_001184880.2(PCDH19):c.2399del (p.Asn800fs)	LOC125467768	Pathogenic	criteria provided, multiple submitters, no conflicts
2090657	NM_001184880.2(PCDH19):c.2452C>T (p.Gln818Ter)	LOC125467768	Pathogenic	criteria provided, single submitter
2135912	NM_001184880.2(PCDH19):c.2581_2582delinsG (p.Pro861fs)	LOC125467768	Pathogenic	criteria provided, single submitter
2574121	NM_001184880.2(PCDH19):c.2587del (p.Asp862_Leu863insTer)	LOC125467768	Pathogenic	criteria provided, single submitter
1002551	NM_001184880.2(PCDH19):c.688G>A (p.Asp230Asn)	PCDH19	Pathogenic	criteria provided, single submitter
1021031	NM_001184880.2(PCDH19):c.445C>T (p.Pro149Ser)	PCDH19	Pathogenic	criteria provided, single submitter
1023566	NM_001184880.2(PCDH19):c.1682C>T (p.Pro561Leu)	PCDH19	Pathogenic	criteria provided, multiple submitters, no conflicts
1045922	NM_001184880.2(PCDH19):c.1240G>A (p.Glu414Lys)	PCDH19	Pathogenic	criteria provided, single submitter
1059075	NM_001184880.2(PCDH19):c.1297C>A (p.Leu433Met)	PCDH19	Pathogenic	criteria provided, single submitter
1067709	NM_001184880.2(PCDH19):c.3G>A (p.Met1Ile)	PCDH19	Pathogenic	criteria provided, single submitter
1068161	NM_001184880.2(PCDH19):c.696T>G (p.Asn232Lys)	PCDH19	Pathogenic	criteria provided, single submitter
1069328	NM_001184880.2(PCDH19):c.1671del (p.Asn557fs)	PCDH19	Pathogenic	criteria provided, single submitter
1069939	NM_001184880.2(PCDH19):c.1985_1995del (p.Leu662fs)	PCDH19	Pathogenic	criteria provided, single submitter
1070780	NM_001184880.2(PCDH19):c.1425_1426del (p.Ser476fs)	PCDH19	Pathogenic	criteria provided, single submitter
1070981	NM_001184880.2(PCDH19):c.291dup (p.Lys98fs)	PCDH19	Pathogenic	criteria provided, single submitter
1071350	NM_001184880.2(PCDH19):c.1416_1420del (p.Leu473fs)	PCDH19	Pathogenic	criteria provided, single submitter
1071427	NM_001184880.2(PCDH19):c.1681C>T (p.Pro561Ser)	PCDH19	Pathogenic	criteria provided, multiple submitters, no conflicts
1071428	NM_001184880.2(PCDH19):c.1022A>G (p.Asp341Gly)	PCDH19	Pathogenic	criteria provided, single submitter
1071429	NM_001184880.2(PCDH19):c.746A>G (p.Glu249Gly)	PCDH19	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
PCDH19	Definitive	X-linked	developmental and epileptic encephalopathy, 9	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PCDH19	Orphanet:33069	Dravet syndrome
PCDH19	Orphanet:714652	PCDH19 clustering epilepsy
KCNC2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PCDH19	HGNC:14270	ENSG00000165194	Q8TAB3	Protocadherin-19	gencc,clinvar
TSPAN6	HGNC:11858	ENSG00000000003	O43657	Tetraspanin-6	clinvar
CSTF2	HGNC:2484	ENSG00000101811	P33240	Cleavage stimulation factor subunit 2	clinvar
DIAPH2	HGNC:2877	ENSG00000147202	O60879	Protein diaphanous homolog 2	clinvar
ARL13A	HGNC:31709	ENSG00000174225	Q5H913	ADP-ribosylation factor-like protein 13A	clinvar
KCNC2	HGNC:6234	ENSG00000166006	Q96PR1	Voltage-gated potassium channel KCNC2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PCDH19	Protocadherin-19	Calcium-dependent cell-adhesion protein.
CSTF2	Cleavage stimulation factor subunit 2	One of the multiple factors required for polyadenylation and 3’-end cleavage of mammalian pre-mRNAs.
DIAPH2	Protein diaphanous homolog 2	Could be involved in oogenesis.
KCNC2	Voltage-gated potassium channel KCNC2	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 5 · Druggable fraction: 0.17

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	1	18.6×	0.105
Other/Unknown	5	1.5×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PCDH19	Other/Unknown	no		Cadherin-like_dom, Cadherin_N, Cadherin-like_sf
TSPAN6	Other/Unknown	no		Tetraspanin_animals, Tetraspanin_EC2_sf, Tetraspanin/Peripherin
CSTF2	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, CSTF2_hinge
DIAPH2	Other/Unknown	no		FH3_dom, GTPase-bd, ARM-like
ARL13A	Other/Unknown	no		Small_GTPase_ARF/SAR, P-loop_NTPase, Ciliary_GTPase
KCNC2	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv

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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	2
cortical plate	1
entorhinal cortex	1
middle temporal gyrus	1
parotid gland	1
sperm	1
oocyte	1
oral cavity	1
secondary oocyte	1
buccal mucosa cell	1
parietal pleura	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
Brodmann (1909) area 9	1
anterior cingulate cortex	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PCDH19	175	broad	marker	cortical plate, entorhinal cortex, middle temporal gyrus
TSPAN6	279	ubiquitous	marker	sperm, parotid gland, bronchial epithelial cell
CSTF2	248	ubiquitous	marker	oocyte, secondary oocyte, oral cavity
DIAPH2	286	ubiquitous	marker	buccal mucosa cell, parietal pleura, bronchial epithelial cell
ARL13A	129	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, left testis
KCNC2	69	tissue_specific	marker	prefrontal cortex, Brodmann (1909) area 9, anterior cingulate cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CSTF2	3,596
KCNC2	2,436
DIAPH2	1,769
PCDH19	1,130
TSPAN6	1,046
ARL13A	527

Structural data

PDB: 2 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CSTF2	P33240	4
PCDH19	Q8TAB3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TSPAN6	O43657	88.17
DIAPH2	O60879	76.09
ARL13A	Q5H913	70.91
KCNC2	Q96PR1	68.26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 6 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
Formation of the nephric duct	1	158.6×	0.034	PCDH19
Processing of Intronless Pre-mRNAs	1	142.8×	0.034	CSTF2
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	66.4×	0.034	KCNC2
RHOF GTPase cycle	1	64.9×	0.034	DIAPH2
Voltage gated Potassium channels	1	60.7×	0.034	KCNC2
Regulation of insulin secretion	1	54.9×	0.034	KCNC2
RNA Polymerase II Transcription Termination	1	54.9×	0.034	CSTF2
RHOD GTPase cycle	1	51.0×	0.034	DIAPH2
tRNA processing in the nucleus	1	49.2×	0.034	CSTF2
mRNA 3’-end processing	1	49.2×	0.034	CSTF2
Integration of energy metabolism	1	43.9×	0.035	KCNC2
Potassium Channels	1	33.6×	0.042	KCNC2
mRNA Polyadenylation	1	22.0×	0.059	CSTF2
RHO GTPases Activate Formins	1	19.4×	0.061	DIAPH2
Dengue Virus-Host Interactions	1	11.4×	0.093	CSTF2
Neuronal System	1	11.1×	0.093	KCNC2
Metabolism	1	2.9×	0.302	KCNC2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of action potential firing rate	1	936.2×	0.010	KCNC2
response to nerve growth factor	1	936.2×	0.010	KCNC2
globus pallidus development	1	561.7×	0.010	KCNC2
cellular response to ammonium ion	1	561.7×	0.010	KCNC2
receptor localization to non-motile cilium	1	561.7×	0.010	ARL13A
negative regulation of cytoplasmic pattern recognition receptor signaling pathway	1	401.2×	0.010	TSPAN6
response to kainic acid	1	401.2×	0.010	KCNC2
response to light intensity	1	351.1×	0.010	KCNC2
response to amine	1	312.1×	0.010	KCNC2
membrane hyperpolarization	1	312.1×	0.010	KCNC2
nitric oxide-cGMP-mediated signaling	1	255.3×	0.010	KCNC2
response to magnesium ion	1	234.1×	0.010	KCNC2
cellular response to toxic substance	1	234.1×	0.010	KCNC2
optic nerve development	1	200.6×	0.011	KCNC2
protein heterooligomerization	1	175.5×	0.012	KCNC2
positive regulation of potassium ion transmembrane transport	1	165.2×	0.012	KCNC2
cellular response to nitric oxide	1	156.0×	0.012	KCNC2
female gamete generation	1	133.8×	0.013	DIAPH2
mRNA 3’-end processing	1	93.6×	0.018	CSTF2
actin filament polymerization	1	80.2×	0.019	DIAPH2
cellular response to nerve growth factor stimulus	1	78.0×	0.019	CSTF2
oogenesis	1	63.8×	0.023	DIAPH2
action potential	1	59.8×	0.023	KCNC2
non-motile cilium assembly	1	48.4×	0.027	ARL13A
potassium ion transport	1	31.9×	0.040	KCNC2
negative regulation of canonical NF-kappaB signal transduction	1	28.7×	0.042	TSPAN6
response to ethanol	1	24.4×	0.048	KCNC2
homophilic cell-cell adhesion	1	23.4×	0.048	PCDH19
potassium ion transmembrane transport	1	22.6×	0.048	KCNC2
protein homooligomerization	1	20.4×	0.051	KCNC2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 1 of 6 evidence-associated genes (17%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PCDH19	0	0
TSPAN6	0	0
CSTF2	0	0
DIAPH2	0	0
ARL13A	0	0
KCNC2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNC2	32	Binding:31, Toxicity:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	KCNC2
E	Difficult family or no structure, no drug	5	PCDH19, TSPAN6, CSTF2, DIAPH2, ARL13A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PCDH19	0	—
TSPAN6	0	—
CSTF2	0	—
DIAPH2	0	—
ARL13A	0	—
KCNC2	32	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.