Developmental and epileptic encephalopathy, 34

Summary

Developmental and epileptic encephalopathy, 34 (MONDO:0014718) is a disease caused by SLC12A5 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: SLC12A5 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 909

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 34
Mondo ID	MONDO:0014718
OMIM	616645
DOID	DOID:0080460
UMLS	C4225257
MedGen	899149
GARD	0016147
Is cancer (heuristic)	no

Also known as: DEE34 · developmental and epileptic encephalopathy 34 · early infantile epileptic encephalopathy caused by mutation in SLC12A5 · EIEE34 · epileptic encephalopathy, early infantile, 34 · epileptic encephalopathy, early infantile, 34; EIEE34 · epileptic encephalopathy, early infantile, type 34 · SLC12A5 early infantile epileptic encephalopathy

Data availability: 909 ClinVar variants · 4 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 › epilepsy syndrome › neonatal epilepsy syndrome › malignant migrating partial seizures of infancy › developmental and epileptic encephalopathy, 34

Related subtypes (2): developmental and epileptic encephalopathy, 12, developmental and epileptic encephalopathy, 16

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

600 retrieved; paginated sample, class counts are floors:

349 likely benign, 203 uncertain significance, 19 pathogenic, 11 benign, 11 likely pathogenic, 6 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070214	NM_020708.5(SLC12A5):c.531_532insT (p.Gly178fs)	SLC12A5	Pathogenic	criteria provided, single submitter
1071231	NM_020708.5(SLC12A5):c.1492dup (p.Ala498fs)	SLC12A5	Pathogenic	criteria provided, single submitter
1073166	NM_020708.5(SLC12A5):c.2490G>A (p.Trp830Ter)	SLC12A5	Pathogenic	criteria provided, single submitter
1076121	NM_020708.5(SLC12A5):c.1845G>A (p.Trp615Ter)	SLC12A5	Pathogenic	criteria provided, single submitter
1362846	NM_020708.5(SLC12A5):c.2519del (p.Leu840fs)	SLC12A5	Pathogenic	criteria provided, single submitter
1364059	NM_020708.5(SLC12A5):c.2301_2302del (p.His768fs)	SLC12A5	Pathogenic	criteria provided, single submitter
1400790	NM_020708.5(SLC12A5):c.1888A>T (p.Lys630Ter)	SLC12A5	Pathogenic	criteria provided, single submitter
1404857	NM_020708.5(SLC12A5):c.2894_2898del (p.Glu965fs)	SLC12A5	Pathogenic	criteria provided, single submitter
1706538	NM_020708.5(SLC12A5):c.2017C>T (p.Gln673Ter)	SLC12A5	Pathogenic	criteria provided, single submitter
2042998	NM_020708.5(SLC12A5):c.962del (p.Phe321fs)	SLC12A5	Pathogenic	criteria provided, single submitter
2053420	NM_020708.5(SLC12A5):c.1287del (p.Lys429fs)	SLC12A5	Pathogenic	criteria provided, single submitter
2054215	NM_020708.5(SLC12A5):c.3159_3180del (p.Ala1053_Val1054insTer)	SLC12A5	Pathogenic	criteria provided, single submitter
2067002	NM_020708.5(SLC12A5):c.2708_2709del (p.Thr902_Tyr903insTer)	SLC12A5	Pathogenic	criteria provided, single submitter
2099159	NM_020708.5(SLC12A5):c.966C>A (p.Cys322Ter)	SLC12A5	Pathogenic	criteria provided, single submitter
2123969	NM_020708.5(SLC12A5):c.1936C>T (p.Arg646Ter)	SLC12A5	Pathogenic	criteria provided, single submitter
217906	NM_020708.5(SLC12A5):c.863T>A (p.Leu288His)	SLC12A5	Pathogenic	no assertion criteria provided
2433374	NM_020708.5(SLC12A5):c.2812C>T (p.Arg938Ter)	SLC12A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2746599	NM_020708.5(SLC12A5):c.1787G>A (p.Trp596Ter)	SLC12A5	Pathogenic	criteria provided, single submitter
2825133	NM_020708.5(SLC12A5):c.2297del (p.Leu766fs)	SLC12A5	Pathogenic	criteria provided, single submitter
3640285	NM_020708.5(SLC12A5):c.2009G>A (p.Trp670Ter)	SLC12A5	Pathogenic	criteria provided, multiple submitters, no conflicts
1476182	NM_020708.5(SLC12A5):c.2012+1G>T	SLC12A5	Likely pathogenic	criteria provided, single submitter
1706537	NM_020708.5(SLC12A5):c.626C>T (p.Pro209Leu)	SLC12A5	Likely pathogenic	criteria provided, single submitter
2032760	NM_020708.5(SLC12A5):c.53-2A>C	SLC12A5	Likely pathogenic	criteria provided, single submitter
2072064	NM_020708.5(SLC12A5):c.854+1G>A	SLC12A5	Likely pathogenic	criteria provided, single submitter
2093602	NM_020708.5(SLC12A5):c.147+1G>A	SLC12A5	Likely pathogenic	criteria provided, single submitter
217904	NM_020708.5(SLC12A5):c.1208T>C (p.Leu403Pro)	SLC12A5	Likely pathogenic	criteria provided, single submitter
217905	NM_020708.5(SLC12A5):c.1583G>A (p.Gly528Asp)	SLC12A5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2417183	NM_020708.5(SLC12A5):c.3110+1G>A	SLC12A5	Likely pathogenic	criteria provided, single submitter
2767441	NM_020708.5(SLC12A5):c.1337-2A>G	SLC12A5	Likely pathogenic	criteria provided, single submitter
3256539	NM_020708.5(SLC12A5):c.1030C>T (p.Gln344Ter)	SLC12A5	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
SLC12A5	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 34	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC12A5	Orphanet:293181	Epilepsy of infancy with migrating focal seizures

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC12A5	HGNC:13818	ENSG00000124140	Q9H2X9	Solute carrier family 12 member 5	gencc,clinvar
SLC12A5-AS1	HGNC:53143	ENSG00000204044		SLC12A5 and MMP9 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC12A5	Solute carrier family 12 member 5	Mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl(-) homeostasis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC12A5	Other/Unknown	no		KCL_cotranspt, AA-permease/SLC12A_dom, SLC12A_fam
SLC12A5-AS1	Other/Unknown	no

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
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
bone marrow cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC12A5	205	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
SLC12A5-AS1	108		marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC12A5	2,287
SLC12A5-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC12A5	Q9H2X9	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Cation-coupled Chloride cotransporters	1	1631.4×	0.002	SLC12A5
R-HSA-425393	1	129.8×	0.015	SLC12A5
SLC-mediated transmembrane transport	1	59.2×	0.023	SLC12A5
Transport of small molecules	1	25.1×	0.040	SLC12A5

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
hypotonic response	1	8426.0×	0.001	SLC12A5
thermosensory behavior	1	8426.0×	0.001	SLC12A5
postsynaptic neurotransmitter receptor diffusion trapping	1	2106.5×	0.002	SLC12A5
intracellular chloride ion homeostasis	1	1685.2×	0.002	SLC12A5
chloride ion homeostasis	1	1532.0×	0.002	SLC12A5
intracellular pH reduction	1	1203.7×	0.002	SLC12A5
dendritic spine development	1	1203.7×	0.002	SLC12A5
potassium ion homeostasis	1	766.0×	0.003	SLC12A5
cell volume homeostasis	1	601.9×	0.003	SLC12A5
potassium ion import across plasma membrane	1	366.4×	0.004	SLC12A5
regulation of postsynapse assembly	1	343.9×	0.004	SLC12A5
learning	1	280.9×	0.005	SLC12A5
chloride transmembrane transport	1	237.3×	0.006	SLC12A5
monoatomic ion transport	1	156.0×	0.008	SLC12A5
multicellular organism growth	1	137.0×	0.008	SLC12A5
chemical synaptic transmission	1	77.3×	0.014	SLC12A5
response to xenobiotic stimulus	1	69.1×	0.014	SLC12A5

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
SLC12A5	0	0
SLC12A5-AS1	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
SLC12A5	6	Functional:4, Binding:2

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SLC12A5, SLC12A5-AS1

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)
SLC12A5	6	—
SLC12A5-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.