Developmental and epileptic encephalopathy 112

Summary

Developmental and epileptic encephalopathy 112 (MONDO:0957812) is a disease caused by KCNH5 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: KCNH5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy 112
Mondo ID	MONDO:0957812
OMIM	620537
UMLS	C5882700
MedGen	1845523
GARD	0026877
Is cancer (heuristic)	no

Data availability: 16 ClinVar variants · 2 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 112

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, 64, 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 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

16 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 5 pathogenic, 1 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
100784	NM_139318.5(KCNH5):c.980G>A (p.Arg327His)	KCNH5	Pathogenic	criteria provided, multiple submitters, no conflicts
1042182	NM_139318.5(KCNH5):c.998G>A (p.Arg333His)	KCNH5	Pathogenic	criteria provided, multiple submitters, no conflicts
2583108	NM_139318.5(KCNH5):c.2020-4A>G	KCNH5	Pathogenic	no assertion criteria provided
2583110	NM_139318.5(KCNH5):c.1402A>C (p.Thr468Pro)	KCNH5	Pathogenic	no assertion criteria provided
2583111	NM_139318.5(KCNH5):c.1412T>C (p.Phe471Ser)	KCNH5	Pathogenic	no assertion criteria provided
2583163	NM_139318.5(KCNH5):c.1382C>A (p.Ala461Glu)	KCNH5	Likely pathogenic	criteria provided, single submitter
530474	NM_139318.5(KCNH5):c.787G>A (p.Val263Ile)	KCNH5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1014460	NM_139318.5(KCNH5):c.2686C>T (p.His896Tyr)	KCNH5	Uncertain significance	criteria provided, multiple submitters, no conflicts
2583107	NM_139318.5(KCNH5):c.1388T>C (p.Ile463Thr)	KCNH5	Uncertain significance	criteria provided, single submitter
2689287	NM_139318.5(KCNH5):c.478C>T (p.Arg160Ter)	KCNH5	Uncertain significance	criteria provided, single submitter
3238769	NM_139318.5(KCNH5):c.-153A>G	KCNH5	Uncertain significance	criteria provided, single submitter
3773702	NM_139318.5(KCNH5):c.944G>A (p.Gly315Glu)	KCNH5	Uncertain significance	criteria provided, single submitter
4079052	NM_139318.5(KCNH5):c.1211C>T (p.Thr404Ile)	KCNH5	Uncertain significance	criteria provided, single submitter
4293836	NM_139318.5(KCNH5):c.1844A>C (p.Asp615Ala)	KCNH5	Uncertain significance	criteria provided, single submitter
4531484	NM_139318.5(KCNH5):c.1313T>C (p.Ile438Thr)	KCNH5	Uncertain significance	criteria provided, single submitter
4538485	NM_139318.5(KCNH5):c.2182G>A (p.Asp728Asn)	KCNH5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
KCNH5	Strong	Autosomal dominant	developmental and epileptic encephalopathy 112	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNH5	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

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
KCNH5	HGNC:6254	ENSG00000140015	Q8NCM2	Voltage-gated delayed rectifier potassium channel KCNH5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNH5	Voltage-gated delayed rectifier potassium channel KCNH5	Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel that mediates outward-rectifying potassium currents which, on depolarization, reaches a steady-state level and do not inactivate.

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
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNH5	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C

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
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNH5	83	tissue_specific	marker	buccal mucosa cell, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNH5	921

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNH5	Q8NCM2	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Voltage gated Potassium channels	1	243.0×	0.011	KCNH5
Potassium Channels	1	134.3×	0.011	KCNH5
Neuronal System	1	44.3×	0.023	KCNH5

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of G2/M transition of mitotic cell cycle	1	1296.3×	0.003	KCNH5
regulation of membrane potential	1	230.8×	0.007	KCNH5
potassium ion transport	1	191.5×	0.007	KCNH5
potassium ion transmembrane transport	1	135.9×	0.007	KCNH5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNH5	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
KCNH5	21	Binding:20, Toxicity:1

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

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	KCNH5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KCNH5	21	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.