Developmental and epileptic encephalopathy, 57

disease

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Also known as DEE57developmental and epileptic encephalopathy 57EIEE57epileptic encephalopathy, early infantile, 57infantile epileptic encephalopathy 57

Summary

Developmental and epileptic encephalopathy, 57 (MONDO:0033366) is a disease caused by KCNT2 (GenCC Strong), with 2 cohort genes.

At a glance

Causal gene: KCNT2 (GenCC Strong)
Cohort genes: 2
ClinVar variants: 49

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 57
Mondo ID	MONDO:0033366
OMIM	617771
DOID	DOID:0080284
UMLS	C4540411
MedGen	1621769
GARD	0025796
Is cancer (heuristic)	no

Also known as: DEE57 · developmental and epileptic encephalopathy 57 · EIEE57 · epileptic encephalopathy, early infantile, 57 · infantile epileptic encephalopathy 57

Data availability: 49 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 disease › hereditary neurological disease › Mendelian neurodevelopmental disorder › genetic developmental and epileptic encephalopathy › developmental and epileptic encephalopathy, 57

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

49 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 9 likely pathogenic, 4 conflicting classifications of pathogenicity, 3 pathogenic, 1 benign, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
236299	NM_198503.5(KCNT2):c.720T>A (p.Phe240Leu)	KCNT2	Pathogenic	criteria provided, single submitter
695094	NM_198503.5(KCNT2):c.143_144del (p.Leu48fs)	KCNT2	Pathogenic	criteria provided, multiple submitters, no conflicts
987968	NM_198503.5(KCNT2):c.569G>C (p.Arg190Pro)	KCNT2	Pathogenic	criteria provided, single submitter
2157768	NM_182916.3(TRNT1):c.1234C>T (p.Arg412Ter)	TRNT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1177518	NM_198503.5(KCNT2):c.1731_1738del (p.Phe578fs)	KCNT2	Likely pathogenic	no assertion criteria provided
1320260	NM_198503.5(KCNT2):c.2501_2507del (p.Ser834fs)	KCNT2	Likely pathogenic	criteria provided, single submitter
1679226	NM_198503.5(KCNT2):c.1096A>G (p.Lys366Glu)	KCNT2	Likely pathogenic	criteria provided, single submitter
1685358	NM_198503.5(KCNT2):c.914G>C (p.Cys305Ser)	KCNT2	Likely pathogenic	criteria provided, single submitter
1802558	NM_198503.5(KCNT2):c.1667C>T (p.Thr556Ile)	KCNT2	Likely pathogenic	criteria provided, single submitter
3238854	NM_198503.5(KCNT2):c.800T>A (p.Leu267His)	KCNT2	Likely pathogenic	criteria provided, single submitter
4531370	NM_198503.5(KCNT2):c.2836A>T (p.Lys946Ter)	KCNT2	Likely pathogenic	criteria provided, single submitter
4755521	NM_198503.5(KCNT2):c.1244del (p.Leu415fs)	KCNT2	Likely pathogenic	criteria provided, single submitter
695093	NM_198503.5(KCNT2):c.1690A>T (p.Lys564Ter)	KCNT2	Likely pathogenic	criteria provided, single submitter
2444068	NM_198503.5(KCNT2):c.3055C>T (p.Arg1019Ter)	KCNT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2639678	NM_198503.5(KCNT2):c.1478T>C (p.Val493Ala)	KCNT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
801588	NM_198503.5(KCNT2):c.725C>A (p.Thr242Asn)	KCNT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
806297	NM_198503.5(KCNT2):c.569G>A (p.Arg190His)	KCNT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027925	NM_198503.5(KCNT2):c.976A>G (p.Arg326Gly)	KCNT2	Uncertain significance	criteria provided, single submitter
1033261	NM_198503.5(KCNT2):c.1295-18C>T	KCNT2	Uncertain significance	criteria provided, single submitter
1213788	NM_198503.5(KCNT2):c.2680G>A (p.Asp894Asn)	KCNT2	Uncertain significance	criteria provided, single submitter
1341792	NM_198503.5(KCNT2):c.2674A>G (p.Met892Val)	KCNT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679579	NM_198503.5(KCNT2):c.2831A>G (p.Tyr944Cys)	KCNT2	Uncertain significance	criteria provided, single submitter
1683757	NM_198503.5(KCNT2):c.1034G>A (p.Arg345Gln)	KCNT2	Uncertain significance	criteria provided, single submitter
1683758	NM_198503.5(KCNT2):c.1109T>G (p.Leu370Arg)	KCNT2	Uncertain significance	criteria provided, single submitter
1700479	NM_198503.5(KCNT2):c.2636G>A (p.Arg879Gln)	KCNT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1710240	NM_198503.5(KCNT2):c.1621C>T (p.Arg541Ter)	KCNT2	Uncertain significance	criteria provided, single submitter
1803150	NM_198503.5(KCNT2):c.827del (p.Gln276fs)	KCNT2	Uncertain significance	criteria provided, single submitter
1805425	NM_198503.5(KCNT2):c.433del (p.Ile145fs)	KCNT2	Uncertain significance	criteria provided, single submitter
1805731	NM_198503.5(KCNT2):c.3289G>A (p.Asp1097Asn)	KCNT2	Uncertain significance	criteria provided, single submitter
2433045	NM_198503.5(KCNT2):c.87C>G (p.Asn29Lys)	KCNT2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
KCNT2	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 57	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRNT1	Orphanet:369861	Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay 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
KCNT2	HGNC:18866	ENSG00000162687	Q6UVM3	Potassium channel subfamily T member 2	gencc,clinvar
TRNT1	HGNC:17341	ENSG00000072756	Q96Q11	CCA tRNA nucleotidyltransferase 1, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNT2	Potassium channel subfamily T member 2	Sodium-activated and chloride-activated potassium channel.
TRNT1	CCA tRNA nucleotidyltransferase 1, mitochondrial	Nucleotidyltransferase that catalyzes the addition and repair of the essential 3’-terminal CCA sequence in tRNAs, which is necessary for the attachment of amino acids to the 3’ terminus of tRNA molecules, using CTP and ATP as substrates. t…

Protein-family classification

Druggable: 2 · 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
Ion channel	1	55.8×	0.036
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNT2	Ion channel	yes		RCK_N, K_chnl_BK_asu, K_chnl_dom
TRNT1	Enzyme (other)	yes	2.7.7.72	PolA_pol_head_dom, PolyA_RNA-bd, NT_sf

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)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	2
cartilage tissue	1
parietal pleura	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNT2	206	broad	marker	parietal pleura, endothelial cell, cartilage tissue
TRNT1	254	ubiquitous	marker	endothelial cell, secondary oocyte, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRNT1	2,982
KCNT2	1,014

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRNT1	Q96Q11	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCNT2	Q6UVM3	76.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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
tRNA processing in the mitochondrion	1	2284.0×	9e-04	TRNT1
tRNA processing in the nucleus	1	196.9×	0.005	TRNT1

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
tRNA 3’-terminal CCA addition	1	8426.0×	4e-04	TRNT1
tRNA surveillance	1	8426.0×	4e-04	TRNT1
mitochondrial tRNA 3’-end processing	1	2106.5×	0.001	TRNT1
tRNA 3’-end processing	1	1685.2×	0.001	TRNT1
potassium ion export across plasma membrane	1	526.6×	0.003	KCNT2
rescue of stalled cytosolic ribosome	1	240.7×	0.005	TRNT1
potassium ion transmembrane transport	1	68.0×	0.015	KCNT2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNT2	0	0
TRNT1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KCNT2	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TRNT1	2.7.7.72	CCA tRNA nucleotidyltransferase

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	1	TRNT1
D	Druggable family + AlphaFold only, no drug	1	KCNT2
E	Difficult family or no structure, no drug	0

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)
KCNT2	7	—
TRNT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: KCNT2, TRNT1