Developmental and epileptic encephalopathy, 8

Summary

Developmental and epileptic encephalopathy, 8 (MONDO:0010375) is a disease caused by ARHGEF9 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ARHGEF9 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 404
• Phenotypes (HPO): 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0002267	Exaggerated startle response	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002384	Focal impaired awareness seizure	Frequent (30-79%)
HP:0007333	Hypoplasia of the frontal lobes	Frequent (30-79%)
HP:0010818	Generalized tonic seizure	Frequent (30-79%)
HP:0012018	EEG with temporal focal spikes	Frequent (30-79%)
HP:0200134	Epileptic encephalopathy	Frequent (30-79%)
HP:0000243	Trigonocephaly	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 8
Mondo ID	MONDO:0010375
MeSH	C564474
OMIM	300607
Orphanet	163985
DOID	DOID:0080215
UMLS	C1845102
MedGen	375581
GARD	0017010
Is cancer (heuristic)	no

Also known as: DEE8 · developmental and epileptic encephalopathy 8 · EIEE8 · epileptic encephalopathy, early infantile, 8 · epileptic encephalopathy, early infantile, type 8 · hyperekplexia-epilepsy syndrome

Data availability: 404 ClinVar variants · 5 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 › X-linked intellectual disability-epilepsy syndrome › developmental and epileptic encephalopathy, 8

Related subtypes (3): developmental and epileptic encephalopathy, 9, syndromic X-linked intellectual disability Hedera type, 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

404 retrieved; paginated sample, class counts are floors:

157 uncertain significance, 150 likely benign, 26 conflicting classifications of pathogenicity, 25 pathogenic, 15 benign, 14 benign/likely benign, 11 likely pathogenic, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1076014	NM_001353921.2(ARHGEF9):c.1150G>T (p.Glu384Ter)	ARHGEF9	Pathogenic	criteria provided, single submitter
11049	NM_001353921.2(ARHGEF9):c.185G>C (p.Gly62Ala)	ARHGEF9	Pathogenic	no assertion criteria provided
1327405	NM_001353921.2(ARHGEF9):c.1409C>G (p.Ser470Ter)	ARHGEF9	Pathogenic	criteria provided, single submitter
1358350	NM_001353921.2(ARHGEF9):c.982_983dup (p.Gly330fs)	ARHGEF9	Pathogenic	criteria provided, single submitter
1453910	NM_001353921.2(ARHGEF9):c.942G>A (p.Trp314Ter)	ARHGEF9	Pathogenic	criteria provided, single submitter
1764342	NM_001353921.2(ARHGEF9):c.890G>A (p.Arg297His)	ARHGEF9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2020245	NM_001353921.2(ARHGEF9):c.1030C>T (p.Gln344Ter)	ARHGEF9	Pathogenic	criteria provided, single submitter
2086900	NM_001353921.2(ARHGEF9):c.1423dup (p.Tyr475fs)	ARHGEF9	Pathogenic	criteria provided, single submitter
2104534	NM_001353921.2(ARHGEF9):c.1269G>A (p.Trp423Ter)	ARHGEF9	Pathogenic	criteria provided, multiple submitters, no conflicts
225050	NM_001353921.2(ARHGEF9):c.1033C>T (p.Arg345Trp)	ARHGEF9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2501758	NM_001353921.2(ARHGEF9):c.928_935del (p.Ser310fs)	ARHGEF9	Pathogenic	criteria provided, single submitter
2584339	NM_001353921.2(ARHGEF9):c.813_814del (p.His271fs)	ARHGEF9	Pathogenic	criteria provided, single submitter
2584341	NM_001353921.2(ARHGEF9):c.402+1G>C	ARHGEF9	Pathogenic	criteria provided, single submitter
2820386	NM_001353921.2(ARHGEF9):c.775C>T (p.Gln259Ter)	ARHGEF9	Pathogenic	criteria provided, multiple submitters, no conflicts
2856404	NM_001353921.2(ARHGEF9):c.216G>A (p.Trp72Ter)	ARHGEF9	Pathogenic	criteria provided, single submitter
29968	NM_001353921.2(ARHGEF9):c.4C>T (p.Gln2Ter)	ARHGEF9	Pathogenic	no assertion criteria provided
3244596	NC_000023.10:g.(?62875354)(62875637_?)del	ARHGEF9	Pathogenic	criteria provided, single submitter
3244607	NC_000023.10:g.(?62857908)(62863948_?)del	ARHGEF9	Pathogenic	criteria provided, single submitter
431121	NM_001353921.2(ARHGEF9):c.886C>T (p.Arg296Ter)	ARHGEF9	Pathogenic	criteria provided, multiple submitters, no conflicts
432195	NM_001353921.2(ARHGEF9):c.332G>A (p.Arg111Gln)	ARHGEF9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4795916	NM_001353921.2(ARHGEF9):c.1099del (p.Leu367fs)	ARHGEF9	Pathogenic	criteria provided, single submitter
4813417	NM_001353921.2(ARHGEF9):c.1138_1141del (p.Val380fs)	ARHGEF9	Pathogenic	criteria provided, single submitter
545451	NM_001353921.2(ARHGEF9):c.920G>A (p.Trp307Ter)	ARHGEF9	Pathogenic	criteria provided, single submitter
568396	NM_001353921.2(ARHGEF9):c.922C>T (p.Gln308Ter)	ARHGEF9	Pathogenic	criteria provided, single submitter
579150	NM_001353921.2(ARHGEF9):c.582+1G>A	ARHGEF9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
648941	NM_001353921.2(ARHGEF9):c.556G>A (p.Glu186Lys)	ARHGEF9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
804015	NM_001353921.2(ARHGEF9):c.178G>T (p.Glu60Ter)	ARHGEF9	Pathogenic	criteria provided, single submitter
804241	NM_001353921.2(ARHGEF9):c.1306del (p.Glu436fs)	ARHGEF9	Pathogenic	criteria provided, multiple submitters, no conflicts
813791	NM_001353921.2(ARHGEF9):c.1351C>T (p.Gln451Ter)	ARHGEF9	Pathogenic	criteria provided, single submitter
837954	NM_001353921.2(ARHGEF9):c.945G>A (p.Glu315=)	ARHGEF9	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
ARHGEF9	Definitive	X-linked	developmental and epileptic encephalopathy, 8	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARHGEF9	Orphanet:163985	Hyperekplexia-epilepsy syndrome
AMER1	Orphanet:2780	Osteopathia striata-cranial sclerosis syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ARHGEF9	HGNC:14561	ENSG00000131089	O43307	Rho guanine nucleotide exchange factor 9	gencc,clinvar
AMER1	HGNC:26837	ENSG00000184675	Q5JTC6	APC membrane recruitment protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARHGEF9	Rho guanine nucleotide exchange factor 9	Acts as a guanine nucleotide exchange factor (GEF) for CDC42.
AMER1	APC membrane recruitment protein 1	Regulator of the canonical Wnt signaling pathway.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARHGEF9	Scaffold/PPI	no		DH_dom, SH3_domain, PH_domain
AMER1	Other/Unknown	no		AMER

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 46	1
CA1 field of hippocampus	1
prefrontal cortex	1
cortical plate	1
myocardium	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARHGEF9	264	ubiquitous	marker	Brodmann (1909) area 46, prefrontal cortex, CA1 field of hippocampus
AMER1	156	ubiquitous	yes	cortical plate, skeletal muscle tissue of rectus abdominis, myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARHGEF9	1,648
AMER1	1,026

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AMER1	Q5JTC6	3
ARHGEF9	O43307	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 45. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Deletions in the AMER1 gene destabilize the destruction complex	1	5710.0×	0.008	AMER1
Signaling by AXIN mutants	1	519.1×	0.009	AMER1
Signaling by CTNNB1 phospho-site mutants	1	519.1×	0.009	AMER1
Signaling by APC mutants	1	519.1×	0.009	AMER1
Signaling by AMER1 mutants	1	519.1×	0.009	AMER1
APC truncation mutants have impaired AXIN binding	1	407.9×	0.009	AMER1
AXIN missense mutants destabilize the destruction complex	1	407.9×	0.009	AMER1
Truncations of AMER1 destabilize the destruction complex	1	407.9×	0.009	AMER1
Signaling by GSK3beta mutants	1	380.7×	0.009	AMER1
CTNNB1 S33 mutants aren’t phosphorylated	1	380.7×	0.009	AMER1
CTNNB1 S37 mutants aren’t phosphorylated	1	380.7×	0.009	AMER1
CTNNB1 S45 mutants aren’t phosphorylated	1	380.7×	0.009	AMER1
CTNNB1 T41 mutants aren’t phosphorylated	1	380.7×	0.009	AMER1
Beta-catenin phosphorylation cascade	1	335.9×	0.010	AMER1
Signaling by WNT in cancer	1	300.5×	0.010	AMER1
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	178.4×	0.016	AMER1
GABA receptor activation	1	158.6×	0.017	ARHGEF9
Cell death signalling via NRAGE, NRIF and NADE	1	109.8×	0.023	ARHGEF9
p75 NTR receptor-mediated signalling	1	93.6×	0.023	ARHGEF9
NRAGE signals death through JNK	1	92.1×	0.023	ARHGEF9
RHOQ GTPase cycle	1	90.6×	0.023	ARHGEF9
Signal Transduction	2	10.2×	0.023	ARHGEF9, AMER1
Degradation of beta-catenin by the destruction complex	1	86.5×	0.023	AMER1
Cellular response to chemical stress	1	71.4×	0.025	AMER1
Death Receptor Signaling	1	69.6×	0.025	ARHGEF9
G alpha (12/13) signalling events	1	68.8×	0.025	ARHGEF9
KEAP1-NFE2L2 pathway	1	60.1×	0.027	AMER1
TCF dependent signaling in response to WNT	1	58.9×	0.027	AMER1
Signaling by WNT	1	56.0×	0.028	AMER1
Neurotransmitter receptors and postsynaptic signal transmission	1	50.1×	0.030	ARHGEF9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mesenchymal cell differentiation involved in kidney development	1	4213.0×	0.003	AMER1
regulation of postsynaptic specialization assembly	1	2106.5×	0.003	ARHGEF9
regulation of canonical Wnt signaling pathway	1	271.8×	0.013	AMER1
adipose tissue development	1	200.6×	0.014	AMER1
bone development	1	138.1×	0.015	AMER1
positive regulation of protein ubiquitination	1	106.7×	0.015	AMER1
positive regulation of protein catabolic process	1	101.5×	0.015	AMER1
positive regulation of canonical Wnt signaling pathway	1	77.3×	0.017	AMER1
regulation of small GTPase mediated signal transduction	1	72.0×	0.017	ARHGEF9
negative regulation of canonical Wnt signaling pathway	1	58.9×	0.019	AMER1
Wnt signaling pathway	1	49.9×	0.020	AMER1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ARHGEF9	0	0
AMER1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	0
E	Difficult family or no structure, no drug	2	ARHGEF9, AMER1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ARHGEF9	0	—
AMER1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.