Developmental and epileptic encephalopathy, 58

disease

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Also known as DEE58developmental and epileptic encephalopathy 58EIEE58epileptic encephalopathy, early infantile, 58infantile epileptic encephalopathy 58

Summary

Developmental and epileptic encephalopathy, 58 (MONDO:0033367) is a disease caused by NTRK2 (GenCC Strong), with 1 cohort gene.

At a glance

Causal gene: NTRK2 (GenCC Strong)
Cohort genes: 1
ClinVar variants: 27

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 58
Mondo ID	MONDO:0033367
OMIM	617830
DOID	DOID:0080285
UMLS	C4693367
MedGen	1646861
GARD	0016259
Is cancer (heuristic)	no

Also known as: DEE58 · developmental and epileptic encephalopathy 58 · EIEE58 · epileptic encephalopathy, early infantile, 58 · infantile epileptic encephalopathy 58

Data availability: 27 ClinVar variants · 3 GenCC gene-disease records.

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, 58

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

27 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 5 benign/likely benign, 3 likely pathogenic, 2 likely benign, 2 benign, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
268204	NM_006180.6(NTRK2):c.1301A>G (p.Tyr434Cys)	NTRK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3068732	NM_006180.6(NTRK2):c.1652G>A (p.Arg551Gln)	NTRK2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3775287	NM_006180.6(NTRK2):c.720+1G>A	NTRK2	Likely pathogenic	criteria provided, single submitter
983314	NM_006180.6(NTRK2):c.1279G>T (p.Gly427Cys)	NTRK2	Likely pathogenic	criteria provided, single submitter
1341751	NM_006180.6(NTRK2):c.25G>A (p.Gly9Arg)	NTRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1515143	NM_006180.6(NTRK2):c.1549G>A (p.Val517Ile)	NTRK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1696741	NM_006180.6(NTRK2):c.1234A>G (p.Asn412Asp)	NTRK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805145	NM_006180.6(NTRK2):c.1438G>A (p.Gly480Ser)	NTRK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1878576	NM_006180.6(NTRK2):c.1429T>A (p.Ser477Thr)	NTRK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2584557	NM_006180.6(NTRK2):c.1870G>C (p.Val624Leu)	NTRK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2629382	NM_006180.6(NTRK2):c.56G>A (p.Cys19Tyr)	NTRK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2671960	NM_006180.6(NTRK2):c.1306G>C (p.Val436Leu)	NTRK2	Uncertain significance	criteria provided, single submitter
3068730	NM_006180.6(NTRK2):c.1634-3C>G	NTRK2	Uncertain significance	criteria provided, single submitter
3381252	NM_006180.6(NTRK2):c.2192T>G (p.Leu731Arg)	NTRK2	Uncertain significance	criteria provided, single submitter
3597709	NM_006180.6(NTRK2):c.1781G>C (p.Ser594Thr)	NTRK2	Uncertain significance	criteria provided, single submitter
3774556	NM_006180.6(NTRK2):c.1675G>C (p.Glu559Gln)	NTRK2	Uncertain significance	criteria provided, single submitter
4292071	NM_006180.6(NTRK2):c.1639C>G (p.Gln547Glu)	NTRK2	Uncertain significance	criteria provided, single submitter
4819109	NM_006180.6(NTRK2):c.2191_2193delinsGTA (p.Leu731Val)	NTRK2	Uncertain significance	criteria provided, single submitter
1148855	NM_006180.6(NTRK2):c.500C>A (p.Ser167Tyr)	NTRK2	Likely benign	criteria provided, multiple submitters, no conflicts
1249612	NM_006180.6(NTRK2):c.1937+13G>A	NTRK2	Benign	criteria provided, multiple submitters, no conflicts
1276690	NM_006180.6(NTRK2):c.212+40C>T	NTRK2	Benign	criteria provided, multiple submitters, no conflicts
1574065	NM_006180.6(NTRK2):c.288-15T>C	NTRK2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1599583	NM_006180.6(NTRK2):c.1396+10del	NTRK2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
285265	NM_006180.6(NTRK2):c.2113C>T (p.Leu705=)	NTRK2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
285975	NM_006180.6(NTRK2):c.2430C>T (p.Pro810=)	NTRK2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
722021	NM_006180.6(NTRK2):c.1962G>A (p.Leu654=)	NTRK2	Likely benign	criteria provided, multiple submitters, no conflicts
728564	NM_006180.6(NTRK2):c.2478G>A (p.Leu826=)	NTRK2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
NTRK2	Strong	Autosomal dominant	obesity, hyperphagia, and developmental delay	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NTRK2	Orphanet:251615	Pilomyxoid astrocytoma
NTRK2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
NTRK2	Orphanet:697160	Infantile epileptic spasms syndrome
NTRK2	Orphanet:99704	Early-onset obesity-hyperphagia-severe developmental delay syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NTRK2	HGNC:8032	ENSG00000148053	Q16620	BDNF/NT-3 growth factors receptor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NTRK2	BDNF/NT-3 growth factors receptor	Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticit…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NTRK2	Kinase	yes	2.7.10.1	LRRNT, Cys-rich_flank_reg_C, Prot_kinase_dom

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
CA1 field of hippocampus	1
cranial nerve II	1
lateral globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NTRK2	273	broad	marker	cranial nerve II, lateral globus pallidus, CA1 field of hippocampus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NTRK2	5,190

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NTRK2	Q16620	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
BDNF activates NTRK2 (TRKB) signaling	1	5710.0×	8e-04	NTRK2
NTF3 activates NTRK2 (TRKB) signaling	1	5710.0×	8e-04	NTRK2
NTF4 activates NTRK2 (TRKB) signaling	1	5710.0×	8e-04	NTRK2
Activated NTRK2 signals through PLCG1	1	2855.0×	9e-04	NTRK2
NGF-independant TRKA activation	1	2284.0×	9e-04	NTRK2
Activated NTRK2 signals through FYN	1	1903.3×	9e-04	NTRK2
NTRK2 activates RAC1	1	1903.3×	9e-04	NTRK2
Activated NTRK2 signals through CDK5	1	1903.3×	9e-04	NTRK2
Activated NTRK2 signals through PI3K	1	1631.4×	1e-03	NTRK2
Activated NTRK2 signals through RAS	1	1142.0×	0.001	NTRK2
Activated NTRK2 signals through FRS2 and FRS3	1	951.7×	0.001	NTRK2
Constitutive Signaling by Aberrant PI3K in Cancer	1	126.9×	0.009	NTRK2
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	96.8×	0.011	NTRK2
PIP3 activates AKT signaling	1	66.8×	0.015	NTRK2

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
trans-synaptic signaling by BDNF, modulating synaptic transmission	1	5617.3×	0.003	NTRK2
brain-derived neurotrophic factor receptor signaling pathway	1	3370.4×	0.003	NTRK2
mechanoreceptor differentiation	1	3370.4×	0.003	NTRK2
cellular response to brain-derived neurotrophic factor stimulus	1	1872.4×	0.003	NTRK2
glutamate secretion	1	1685.2×	0.003	NTRK2
retinal rod cell development	1	1685.2×	0.003	NTRK2
peripheral nervous system neuron development	1	1532.0×	0.003	NTRK2
neuronal action potential propagation	1	1404.3×	0.003	NTRK2
myelination in peripheral nervous system	1	887.0×	0.003	NTRK2
negative regulation of amyloid-beta formation	1	887.0×	0.003	NTRK2
negative regulation of anoikis	1	887.0×	0.003	NTRK2
central nervous system neuron development	1	802.5×	0.003	NTRK2
positive regulation of axonogenesis	1	581.1×	0.004	NTRK2
feeding behavior	1	543.6×	0.004	NTRK2
regulation of GTPase activity	1	510.7×	0.004	NTRK2
oligodendrocyte differentiation	1	421.3×	0.005	NTRK2
cellular response to amino acid stimulus	1	306.4×	0.006	NTRK2
learning	1	280.9×	0.006	NTRK2
long-term synaptic potentiation	1	280.9×	0.006	NTRK2
vasculogenesis	1	255.3×	0.006	NTRK2
circadian rhythm	1	244.2×	0.006	NTRK2
positive regulation of synapse assembly	1	244.2×	0.006	NTRK2
cerebral cortex development	1	205.5×	0.007	NTRK2
cell surface receptor protein tyrosine kinase signaling pathway	1	173.7×	0.008	NTRK2
protein autophosphorylation	1	145.3×	0.009	NTRK2
positive regulation of neuron projection development	1	137.0×	0.009	NTRK2
neuron migration	1	133.8×	0.009	NTRK2
negative regulation of neuron apoptotic process	1	110.9×	0.011	NTRK2
neuron differentiation	1	100.3×	0.011	NTRK2
positive regulation of MAPK cascade	1	80.6×	0.014	NTRK2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
NTRK2	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NTRK2	50	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	NTRK2
SORAFENIB	4	NTRK2
RUXOLITINIB	4	NTRK2
INFIGRATINIB PHOSPHATE	4	NTRK2
INFIGRATINIB	4	NTRK2
ENTRECTINIB	4	NTRK2
CERITINIB	4	NTRK2
NILOTINIB	4	NTRK2
BOSUTINIB	4	NTRK2
LORLATINIB	4	NTRK2
LAROTRECTINIB	4	NTRK2
LAROTRECTINIB SULFATE	4	NTRK2
REPOTRECTINIB	4	NTRK2
NINTEDANIB	4	NTRK2
SUNITINIB	4	NTRK2
QUIZARTINIB	4	NTRK2
CRIZOTINIB	4	NTRK2
MIDOSTAURIN	4	NTRK2
LINIFANIB	3	NTRK2
DEFACTINIB	3	NTRK2
SITRAVATINIB	3	NTRK2
SURUFATINIB	3	NTRK2
ALISERTIB	3	NTRK2
DOVITINIB	3	NTRK2
LESTAURTINIB	3	NTRK2
DORAMAPIMOD	2	NTRK2
FORETINIB	2	NTRK2
TANDUTINIB	2	NTRK2
SU-014813	2	NTRK2
REBASTINIB	2	NTRK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NTRK2	554	Binding:547, ADMET:5, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NTRK2	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NTRK2	554

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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	NTRK2
SORAFENIB	4	NTRK2
RUXOLITINIB	4	NTRK2
INFIGRATINIB PHOSPHATE	4	NTRK2
INFIGRATINIB	4	NTRK2
ENTRECTINIB	4	NTRK2
CERITINIB	4	NTRK2
NILOTINIB	4	NTRK2
BOSUTINIB	4	NTRK2
LORLATINIB	4	NTRK2
LAROTRECTINIB	4	NTRK2
LAROTRECTINIB SULFATE	4	NTRK2
REPOTRECTINIB	4	NTRK2
NINTEDANIB	4	NTRK2
SUNITINIB	4	NTRK2
QUIZARTINIB	4	NTRK2
CRIZOTINIB	4	NTRK2
MIDOSTAURIN	4	NTRK2
LINIFANIB	3	NTRK2
DEFACTINIB	3	NTRK2
SITRAVATINIB	3	NTRK2
SURUFATINIB	3	NTRK2
ALISERTIB	3	NTRK2
DOVITINIB	3	NTRK2
LESTAURTINIB	3	NTRK2
DORAMAPIMOD	2	NTRK2
FORETINIB	2	NTRK2
TANDUTINIB	2	NTRK2
SU-014813	2	NTRK2
REBASTINIB	2	NTRK2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NTRK2
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: NTRK2