Neurodevelopmental disorder with seizures and brain abnormalities

Summary

Neurodevelopmental disorder with seizures and brain abnormalities (MONDO:0859188) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodevelopmental disorder with seizures and brain abnormalities
Mondo ID	MONDO:0859188
OMIM	619517
UMLS	C5561979
MedGen	1794189
Is cancer (heuristic)	no

Data availability: 5 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › neurodevelopmental disorder with seizures and brain abnormalities

Related subtypes (20): intellectual disability, microcephaly, Williams syndrome, Aicardi syndrome, Hao-Fountain syndrome, toluene embryopathy, alternating hemiplegia, atypical Rett syndrome, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, complex neurodevelopmental disorder, Mendelian neurodevelopmental disorder, TCF7L2-related neurodevelopmental disorder, Yoon-Bellen neurodevelopmental syndrome, neurodevelopmental disorder with microcephaly, hypotonia, and absent language, neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss, neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, neurodevelopmental disorder with parkinsonism or other movement abnormalities, neurodevelopmental disorder with seizures and impaired intellectual and language development, Ebstein-Bezieau neurodevelopmental syndrome, Luo-Agrawal neurodevelopmental syndrome

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

5 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1192292	NM_001829.4(CLCN3):c.336_339del (p.Lys112fs)	CLCN3	Pathogenic	no assertion criteria provided
3383301	NR_199791.1(RNU2-2):n.35A>G	RNU2-2	Pathogenic	criteria provided, multiple submitters, no conflicts
3590451	NM_001829.4(CLCN3):c.508G>C (p.Glu170Gln)	CLCN3	Uncertain significance	criteria provided, single submitter
3590452	NM_001829.4(CLCN3):c.1963G>T (p.Ala655Ser)	CLCN3	Uncertain significance	criteria provided, single submitter
3590453	NM_001829.4(CLCN3):c.2084T>C (p.Ile695Thr)	CLCN3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
CLCN3	Strong	Autosomal dominant	complex neurodevelopmental disorder	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLCN3	Orphanet:528084	Non-specific syndromic intellectual disability

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
CLCN3	HGNC:2021	ENSG00000109572	P51790	H(+)/Cl(-) exchange transporter 3	gencc,clinvar
RNU2-2	HGNC:10152	ENSG00000222328		RNA, U2 small nuclear 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLCN3	H(+)/Cl(-) exchange transporter 3	Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons.

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)
CLCN3	Other/Unknown	no		CBS_dom, ClC, ClC3
RNU2-2	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic mucosa	1
endothelial cell	1
mucosa of sigmoid colon	1
adrenal tissue	1
corpus callosum	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLCN3	291	ubiquitous	marker	mucosa of sigmoid colon, endothelial cell, colonic mucosa
RNU2-2	127	broad	yes	adrenal tissue, corpus callosum, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLCN3	1,632
RNU2-2	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLCN3	P51790	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Stimuli-sensing channels	1	135.9×	0.007	CLCN3

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
negative regulation of cell volume	1	3370.4×	0.002	CLCN3
regulation of pH	1	1404.3×	0.002	CLCN3
endosomal lumen acidification	1	1203.7×	0.002	CLCN3
positive regulation of reactive oxygen species biosynthetic process	1	1123.5×	0.002	CLCN3
synaptic vesicle lumen acidification	1	936.2×	0.002	CLCN3
phagocytosis, engulfment	1	674.1×	0.003	CLCN3
synaptic transmission, GABAergic	1	495.6×	0.003	CLCN3
synaptic transmission, glutamatergic	1	358.6×	0.003	CLCN3
photoreceptor cell maintenance	1	358.6×	0.003	CLCN3
adult locomotory behavior	1	300.9×	0.004	CLCN3
chloride transmembrane transport	1	237.3×	0.004	CLCN3

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
CLCN3	0	0
RNU2-2	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
CLCN3	18	Binding:18

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	CLCN3, RNU2-2

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)
CLCN3	18	—
RNU2-2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.