Developmental and epileptic encephalopathy, 64

disease
On this page

Also known as DEE64developmental and epileptic encephalopathy 64EIEE64epileptic encephalopathy, early infantile, 64RHOBTB2 syndromeRHOBTB2-associated neurodevelopmental disordersRHOBTB2-related disorders

Summary

Developmental and epileptic encephalopathy, 64 (MONDO:0033373) is a disease caused by RHOBTB2 (GenCC Strong), with 2 cohort genes.

At a glance

  • Causal gene: RHOBTB2 (GenCC Strong)
  • Cohort genes: 2
  • ClinVar variants: 57

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

FieldValue
Canonical namedevelopmental and epileptic encephalopathy, 64
Mondo IDMONDO:0033373
OMIM618004
DOIDDOID:0070375
UMLSC4693899
MedGen1633501
GARD0013681
Is cancer (heuristic)no

Also known as: DEE64 · developmental and epileptic encephalopathy 64 · EIEE64 · epileptic encephalopathy, early infantile, 64 · RHOBTB2 syndrome · RHOBTB2-associated neurodevelopmental disorders · RHOBTB2-related disorders

Data availability: 57 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary diseasehereditary neurological diseaseMendelian neurodevelopmental disordergenetic developmental and epileptic encephalopathydevelopmental and epileptic encephalopathy, 64

Related subtypes (104): developmental and epileptic encephalopathy, 9, developmental and epileptic encephalopathy, 8, developmental and epileptic encephalopathy, 2, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, developmental and epileptic encephalopathy, 1, developmental and epileptic encephalopathy, 3, developmental and epileptic encephalopathy, 4, microcephaly, seizures, and developmental delay, developmental and epileptic encephalopathy, 5, developmental and epileptic encephalopathy, 7, developmental and epileptic encephalopathy, 11, neonatal-onset encephalopathy with rigidity and seizures, developmental and epileptic encephalopathy, 14, developmental and epileptic encephalopathy, 15, developmental and epileptic encephalopathy, 17, developmental and epileptic encephalopathy, 18, developmental and epileptic encephalopathy, 19, developmental and epileptic encephalopathy, 23, developmental and epileptic encephalopathy, 27, developmental and epileptic encephalopathy, 30, developmental and epileptic encephalopathy, 50, developmental and epileptic encephalopathy, 35, developmental and epileptic encephalopathy, 37, developmental and epileptic encephalopathy, 38, developmental and epileptic encephalopathy, 40, developmental and epileptic encephalopathy, 48, developmental and epileptic encephalopathy, 49, developmental and epileptic encephalopathy, 51, Lennox-Gastaut syndrome, developmental and epileptic encephalopathy 91, developmental and epileptic encephalopathy 92, developmental and epileptic encephalopathy 93, developmental and epileptic encephalopathy 96, developmental and epileptic encephalopathy, 90, developmental and epileptic encephalopathy, 85, with or without midline brain defects, developmental and epileptic encephalopathy, 67, developmental and epileptic encephalopathy, 86, developmental and epileptic encephalopathy, 87, developmental and epileptic encephalopathy, 88, developmental and epileptic encephalopathy 6B, developmental and epileptic encephalopathy 97, developmental and epileptic encephalopathy 98, developmental and epileptic encephalopathy 99, developmental and epileptic encephalopathy 100, developmental and epileptic encephalopathy 101, developmental and epileptic encephalopathy 89, developmental and epileptic encephalopathy 102, developmental and epileptic encephalopathy 103, developmental and epileptic encephalopathy 104, developmental and epileptic encephalopathy 105 with hypopituitarism, developmental and epileptic encephalopathy 106, developmental and epileptic encephalopathy 107, developmental and epileptic encephalopathy, 68, developmental and epileptic encephalopathy, 69, developmental and epileptic encephalopathy, 70, developmental and epileptic encephalopathy, 71, developmental and epileptic encephalopathy, 72, developmental and epileptic encephalopathy, 74, developmental and epileptic encephalopathy, 75, developmental and epileptic encephalopathy, 76, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 78, developmental and epileptic encephalopathy, 79, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 81, developmental and epileptic encephalopathy, 82, developmental and epileptic encephalopathy, 83, developmental and epileptic encephalopathy, 84, developmental and epileptic encephalopathy, 52, developmental and epileptic encephalopathy, 53, developmental and epileptic encephalopathy, 54, developmental and epileptic encephalopathy, 55, developmental and epileptic encephalopathy, 56, developmental and epileptic encephalopathy, 57, developmental and epileptic encephalopathy, 58, developmental and epileptic encephalopathy, 59, developmental and epileptic encephalopathy, 60, developmental and epileptic encephalopathy, 61, developmental and epileptic encephalopathy, 62, developmental and epileptic encephalopathy, 63, developmental and epileptic encephalopathy, 65, developmental and epileptic encephalopathy, 73, developmental and epileptic encephalopathy, 66, developmental and epileptic encephalopathy, 6A, non-neonatal early infantile epileptic encephalopathy, Dravet syndrome, neonatal-onset developmental and epileptic encephalopathy, hemiplegic migraine-developmental and epileptic encephalopathy spectrum, DNM1-encephalopathy and neurodevelopmental disorder, TMEM63B-related developmental and epileptic encephalopathy with anemia, developmental and epileptic encephalopathy 108, developmental and epileptic encephalopathy 109, developmental and epileptic encephalopathy 110, developmental and epileptic encephalopathy 111, developmental and epileptic encephalopathy 112, developmental and epileptic encephalopathy 113, developmental and epileptic encephalopathy 114, developmental and epileptic encephalopathy 115, developmental and epileptic encephalopathy 116, developmental and epileptic encephalopathy 118, developmental and epileptic encephalopathy 120, developmental and epileptic encephalopathy 121, developmental and epileptic encephalopathy 119

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

57 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 10 conflicting classifications of pathogenicity, 5 likely pathogenic, 5 pathogenic/likely pathogenic, 3 benign, 2 benign/likely benign, 1 pathogenic, 1 not provided

ClinVarVariant (HGVS)GeneClassificationReview
495261NM_015178.3(RHOBTB2):c.1465C>T (p.Arg489Trp)RHOBTB2Pathogenic/Likely pathogeniccriteria provided, multiple submitters, no conflicts
521853NM_015178.3(RHOBTB2):c.1462A>G (p.Asn488Asp)RHOBTB2Pathogenic/Likely pathogeniccriteria provided, multiple submitters, no conflicts
545417NM_015178.3(RHOBTB2):c.1382G>A (p.Arg461His)RHOBTB2Pathogenic/Likely pathogeniccriteria provided, multiple submitters, no conflicts
545418NM_015178.3(RHOBTB2):c.1466G>A (p.Arg489Gln)RHOBTB2Pathogeniccriteria provided, multiple submitters, no conflicts
617912NM_015178.3(RHOBTB2):c.1453C>T (p.Arg485Cys)RHOBTB2Pathogenic/Likely pathogeniccriteria provided, multiple submitters, no conflicts
870711NM_015178.3(RHOBTB2):c.1465C>G (p.Arg489Gly)RHOBTB2Pathogenic/Likely pathogeniccriteria provided, multiple submitters, no conflicts
2443571NM_015178.3(RHOBTB2):c.280C>T (p.Arg94Cys)RHOBTB2Likely pathogeniccriteria provided, multiple submitters, no conflicts
2584435NM_015178.3(RHOBTB2):c.103G>T (p.Ala35Ser)RHOBTB2Likely pathogeniccriteria provided, single submitter
4057336NM_015178.3(RHOBTB2):c.656C>T (p.Ser219Phe)RHOBTB2Likely pathogeniccriteria provided, single submitter
545421NM_015178.3(RHOBTB2):c.1355C>G (p.Ala452Gly)RHOBTB2Likely pathogeniccriteria provided, single submitter
800793NM_015178.3(RHOBTB2):c.394C>T (p.Arg132Ter)RHOBTB2Likely pathogeniccriteria provided, single submitter
1341816NM_015178.3(RHOBTB2):c.1039G>A (p.Val347Met)RHOBTB2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
1491653NM_015178.3(RHOBTB2):c.332A>G (p.Asn111Ser)RHOBTB2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
1515448NM_015178.3(RHOBTB2):c.1382G>C (p.Arg461Pro)RHOBTB2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
1560552NM_015178.3(RHOBTB2):c.1948A>G (p.Met650Val)RHOBTB2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
1574728NM_015178.3(RHOBTB2):c.1681G>A (p.Gly561Ser)RHOBTB2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
1918911NM_015178.3(RHOBTB2):c.482+5G>ARHOBTB2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
1983501NM_015178.3(RHOBTB2):c.1660G>A (p.Val554Met)RHOBTB2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
2121105NM_015178.3(RHOBTB2):c.713C>T (p.Pro238Leu)RHOBTB2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
932476NM_015178.3(RHOBTB2):c.1376A>G (p.Asp459Gly)RHOBTB2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
992813NM_015178.3(RHOBTB2):c.1150C>T (p.Arg384Cys)RHOBTB2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
1027644NM_015178.3(RHOBTB2):c.208C>T (p.Arg70Ter)RHOBTB2Uncertain significancecriteria provided, multiple submitters, no conflicts
1027750NM_015178.3(RHOBTB2):c.56T>C (p.Val19Ala)RHOBTB2Uncertain significancecriteria provided, multiple submitters, no conflicts
1027751NM_015178.3(RHOBTB2):c.2102G>C (p.Trp701Ser)RHOBTB2Uncertain significancecriteria provided, multiple submitters, no conflicts
1098681NM_015178.3(RHOBTB2):c.2038C>T (p.Arg680Trp)RHOBTB2Uncertain significancecriteria provided, multiple submitters, no conflicts
1341709NM_015178.3(RHOBTB2):c.1541A>G (p.His514Arg)RHOBTB2Uncertain significancecriteria provided, single submitter
1342421NM_015178.3(RHOBTB2):c.1488del (p.Gly497fs)RHOBTB2Uncertain significancecriteria provided, single submitter
1439048NM_015178.3(RHOBTB2):c.1834G>A (p.Val612Ile)RHOBTB2Uncertain significancecriteria provided, multiple submitters, no conflicts
1512261NM_015178.3(RHOBTB2):c.935G>T (p.Gly312Val)RHOBTB2Uncertain significancecriteria provided, multiple submitters, no conflicts
1699026NM_015178.3(RHOBTB2):c.1216A>G (p.Thr406Ala)RHOBTB2Uncertain significancecriteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 6 · 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.

GeneClassificationInheritanceDiseaseRecords
RHOBTB2StrongAutosomal dominantdevelopmental and epileptic encephalopathy, 645

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
RHOBTB2Orphanet:1934Early infantile developmental and epileptic encephalopathy
RHOBTB2Orphanet:2131Alternating hemiplegia of childhood
SCN8AOrphanet:178469Autosomal dominant non-syndromic intellectual disability
SCN8AOrphanet:306Self-limited infantile epilepsy
SCN8AOrphanet:352582Familial infantile myoclonic epilepsy
SCN8AOrphanet:442835Non-specific early-onset epileptic encephalopathy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

SubsetGenes
multi_evidence2

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
RHOBTB2HGNC:18756ENSG00000008853Q9BYZ6Rho-related BTB domain-containing protein 2gencc,clinvar
SCN8AHGNC:10596ENSG00000196876Q9UQD0Sodium channel protein type 8 subunit alphaclinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
RHOBTB2Rho-related BTB domain-containing protein 2Regulator of cell proliferation and apoptosis.
SCN8ASodium channel protein type 8 subunit alphaPore-forming subunit of a voltage-gated sodium channel complex assuming opened or closed conformations in response to the voltage difference across membranes and through which sodium ions selectively pass along their electrochemical gradie…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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.

FamilyGenesFoldFDR
Ion channel155.8×0.036
Other/Unknown10.9×0.805

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
RHOBTB2Other/UnknownnoBTB/POZ_dom, Small_GTPase, Small_GTPase_Rho
SCN8AIon channelyesIQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)2
unknown0

Top tissues across cohort

TissueCohort genes
right frontal lobe1
upper lobe of left lung1
upper lobe of lung1
Brodmann (1909) area 231
middle temporal gyrus1
postcentral gyrus1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
RHOBTB2213ubiquitousmarkerupper lobe of left lung, upper lobe of lung, right frontal lobe
SCN8A194ubiquitousmarkerBrodmann (1909) area 23, middle temporal gyrus, postcentral gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

SymbolInteractor count
RHOBTB22,577
SCN8A2,120

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
SCN8AQ9UQD07

AlphaFold-only cohort genes (top 30 by pLDDT)

SymbolUniProtpLDDT
RHOBTB2Q9BYZ681.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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.

PathwayCohort genesFoldFDRSample cohort genes
RHOBTB2 GTPase cycle1237.9×0.017RHOBTB2
Interaction between L1 and Ankyrins1184.2×0.017SCN8A
Phase 0 - rapid depolarisation1173.0×0.017SCN8A
L1CAM interactions160.1×0.033SCN8A
Cardiac conduction154.4×0.033SCN8A
Muscle contraction138.6×0.039SCN8A
Axon guidance122.6×0.052SCN8A
Nervous system development121.5×0.052SCN8A
Developmental Biology17.2×0.134SCN8A

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 termCohort genesFoldFDRSample cohort genes
cortical cytoskeleton organization1842.6×0.017RHOBTB2
cardiac muscle cell action potential involved in contraction1351.1×0.017SCN8A
peripheral nervous system development1290.6×0.017SCN8A
establishment or maintenance of cell polarity1200.6×0.017RHOBTB2
action potential1179.3×0.017SCN8A
sodium ion transport1135.9×0.017SCN8A
myelination1125.8×0.017SCN8A
sodium ion transmembrane transport1101.5×0.018SCN8A
small GTPase-mediated signal transduction191.6×0.018RHOBTB2
regulation of actin cytoskeleton organization178.8×0.019RHOBTB2
regulation of cell shape161.5×0.021RHOBTB2
actin filament organization159.3×0.021RHOBTB2
ubiquitin-dependent protein catabolic process137.1×0.031RHOBTB2
protein ubiquitination120.7×0.051RHOBTB2
signal transduction18.0×0.121RHOBTB2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 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.

SymbolExample approved molecule
SCN8AIMIPRAMINE

Top cohort targets by molecule count

SymbolMoleculesMax phase
SCN8A254
RHOBTB200

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
IMIPRAMINE4SCN8A
SERTINDOLE4SCN8A
PIMOZIDE4SCN8A
NIFEDIPINE4SCN8A
DILTIAZEM4SCN8A
MIBEFRADIL4SCN8A
HALOPERIDOL4SCN8A
MEXILETINE4SCN8A
AMITRIPTYLINE4SCN8A
AMIODARONE4SCN8A
CHLORPROMAZINE4SCN8A
TETRACAINE4SCN8A
TEDISAMIL3SCN8A
NITRENDIPINE3SCN8A
AJMALINE3SCN8A
VIXOTRIGINE3SCN8A
ELECLAZINE3SCN8A
TETRODOTOXIN3SCN8A
CIFENLINE2SCN8A
PF-050897712SCN8A
FUNAPIDE2SCN8A
DS-19712SCN8A
ZANDATRIGINE2SCN8A
PF-051501221SCN8A
PF-051864621SCN8A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

SymbolAssaysType breakdown
SCN8A173Binding:148, Functional:16, ADMET:7, Toxicity:2

Cohort genes with high screening signal

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

SymbolChEMBL assays
SCN8A173

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

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.

CompoundMax phaseCohort target (bioactivity)
IMIPRAMINE4SCN8A
SERTINDOLE4SCN8A
PIMOZIDE4SCN8A
NIFEDIPINE4SCN8A
DILTIAZEM4SCN8A
MIBEFRADIL4SCN8A
HALOPERIDOL4SCN8A
MEXILETINE4SCN8A
AMITRIPTYLINE4SCN8A
AMIODARONE4SCN8A
CHLORPROMAZINE4SCN8A
TETRACAINE4SCN8A
TEDISAMIL3SCN8A
NITRENDIPINE3SCN8A
AJMALINE3SCN8A
VIXOTRIGINE3SCN8A
ELECLAZINE3SCN8A
TETRODOTOXIN3SCN8A
CIFENLINE2SCN8A
PF-050897712SCN8A
FUNAPIDE2SCN8A
DS-19712SCN8A
ZANDATRIGINE2SCN8A
PF-051501221SCN8A
PF-051864621SCN8A

Druggability pyramid

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

TierDefinitionGenesSymbols
AApproved (phase 4 drug)1SCN8A
BPhased (≥1) drug, not yet approved0
CDruggable family + PDB, no drug0
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug1RHOBTB2

Undrugged target profiles

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

SymbolChEMBL assaysDrugged partners (top 3)
RHOBTB20

Clinical trials & evidence

Clinical trials

Clinical trials: 0.