Neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities

Summary

Neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities (MONDO:0030947) is a disease caused by CLCN6 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CLCN6 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities
Mondo ID	MONDO:0030947
OMIM	619173
Orphanet	610573
DOID	DOID:0061189
UMLS	C5543020
MedGen	1781967
GARD	0018023
Is cancer (heuristic)	no

Also known as: CONRIBA · neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities

Data availability: 23 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities

Related subtypes (81): Huntington disease and related disorders, agenesis of the corpus callosum with peripheral neuropathy, striatonigral degeneration, angioid streaks of choroid, amyotrophic lateral sclerosis-parkinsonism-dementia complex, inherited Creutzfeldt-Jakob disease, mitochondrial DNA depletion syndrome 4a, cerebellar ataxia-hypogonadism syndrome, myoclonic cerebellar dyssynergia, cerebral sclerosis similar to Pelizaeus-Merzbacher disease, Chediak-Higashi syndrome, encephalopathy due to beta-mercaptolactate-cysteine disulfiduria, PEHO syndrome, deafness dystonia syndrome, Kennedy disease, fatal familial insomnia, Huntington disease-like 1, neuronal intranuclear inclusion disease, ataxia-telangiectasia-like disorder, radiation sensitivity/chromosome instability syndrome, autosomal dominant, Huntington disease-like 2, microphthalmia-brain atrophy syndrome, neurodegenerative syndrome due to cerebral folate transport deficiency, hereditary sensory neuropathy-deafness-dementia syndrome, infantile cerebellar-retinal degeneration, Alzheimer disease 17, hypotonia, infantile, with psychomotor retardation and characteristic facies, Alzheimer disease 18, diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome, severe neurodegenerative syndrome with lipodystrophy, developmental and epileptic encephalopathy, 35, combined oxidative phosphorylation deficiency 29, neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, neuronal ceroid lipofuscinosis, frontotemporal dementia with motor neuron disease, frontotemporal dementia, GM2 gangliosidosis, attenuated Chédiak-Higashi syndrome, autosomal recessive cerebral atrophy, neurodegeneration with brain iron accumulation, fatal post-viral neurodegenerative disorder, ferro-cerebro-cutaneous syndrome, PRKAR1B-related neurodegenerative dementia with intermediate filaments, ITM2B amyloidosis, corticobasal syndrome, infantile-onset axonal motor and sensory neuropathy-optic atrophy-neurodegenerative syndrome, recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, posterior cortical atrophy, progressive supranuclear palsy, leukodystrophy, hereditary spastic paraplegia, facial onset sensory and motor neuronopathy, X-linked neurodegenerative syndrome, Bertini type, X-linked neurodegenerative syndrome, Hamel type, boylan dew greco syndrome, hereditary motor neuron disease, neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, frontotemporal dementia and/or amyotrophic lateral sclerosis, neurodegeneration with ataxia and late-onset optic atrophy, neurodegeneration, childhood-onset, with cerebellar atrophy, neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, neurodegeneration, infantile-onset, biotin-responsive, hereditary optic atrophy, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome, familial Alzheimer disease, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, hereditary cerebellar ataxia, DCTN1-related neurodegeneration, early-childhood-onset neurodegeneration with retinitis pigmentosa, sensorineural hearing loss, and demyelinating peripheral neuropathy, TUBB4A-related neurologic disorder, neurodegeneration, childhood-onset, with progressive microcephaly, neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, neurodegeneration and seizures due to copper transport defect, neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairment, neurodegenerative disorder with cerebellar and caudate atrophy, APP-related brain and vascular amyloidosis

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

23 retrieved; paginated sample, class counts are floors:

17 uncertain significance, 3 likely benign, 1 benign, 1 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
3338632	NM_001286.5(CLCN6):c.599A>C (p.Glu200Ala)	CLCN6	Pathogenic	no assertion criteria provided
974617	NM_001286.5(CLCN6):c.1658A>G (p.Tyr553Cys)	CLCN6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1474642	NM_001286.5(CLCN6):c.2488A>T (p.Met830Leu)	CLCN6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1699264	NM_001286.5(CLCN6):c.769C>A (p.Pro257Thr)	CLCN6	Uncertain significance	criteria provided, single submitter
1709114	NM_001286.5(CLCN6):c.1534G>A (p.Gly512Arg)	CLCN6	Uncertain significance	criteria provided, single submitter
1805218	NM_001286.5(CLCN6):c.1404C>G (p.Phe468Leu)	CLCN6	Uncertain significance	criteria provided, single submitter
2032597	NM_001286.5(CLCN6):c.697C>T (p.Arg233Ter)	CLCN6	Uncertain significance	criteria provided, multiple submitters, no conflicts
2431570	NM_001286.5(CLCN6):c.1696T>C (p.Trp566Arg)	CLCN6	Uncertain significance	criteria provided, single submitter
2440136	NM_001286.5(CLCN6):c.677A>G (p.Gln226Arg)	CLCN6	Uncertain significance	criteria provided, multiple submitters, no conflicts
2440137	NM_001286.5(CLCN6):c.1059T>A (p.Cys353Ter)	CLCN6	Uncertain significance	criteria provided, single submitter
2779467	NM_001286.5(CLCN6):c.320A>G (p.Gln107Arg)	CLCN6	Uncertain significance	criteria provided, multiple submitters, no conflicts
3014325	NM_001286.5(CLCN6):c.2243C>T (p.Ser748Leu)	CLCN6	Uncertain significance	criteria provided, multiple submitters, no conflicts
3392522	NM_001286.5(CLCN6):c.638G>A (p.Gly213Asp)	CLCN6	Uncertain significance	criteria provided, single submitter
3731512	NM_001286.5(CLCN6):c.855G>A (p.Met285Ile)	CLCN6	Uncertain significance	criteria provided, single submitter
4078309	NM_001286.5(CLCN6):c.78del (p.Glu27fs)	CLCN6	Uncertain significance	criteria provided, single submitter
4277505	NM_001286.5(CLCN6):c.1831T>C (p.Tyr611His)	CLCN6	Uncertain significance	criteria provided, single submitter
4277506	NM_001286.5(CLCN6):c.2321A>G (p.Tyr774Cys)	CLCN6	Uncertain significance	criteria provided, single submitter
4532253	NM_001286.5(CLCN6):c.1319C>T (p.Thr440Ile)	CLCN6	Uncertain significance	criteria provided, single submitter
4814073	NM_001286.5(CLCN6):c.1747C>T (p.Arg583Ter)	CLCN6	Uncertain significance	criteria provided, single submitter
1643105	NM_001286.5(CLCN6):c.593A>G (p.Glu198Gly)	CLCN6	Benign	criteria provided, multiple submitters, no conflicts
3065631	NM_001286.5(CLCN6):c.280G>T (p.Val94Leu)	CLCN6	Likely benign	criteria provided, single submitter
4795835	NM_001286.5(CLCN6):c.698G>T (p.Arg233Leu)	CLCN6	Likely benign	criteria provided, single submitter
4819423	NM_001286.5(CLCN6):c.1372+4A>G	CLCN6	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
CLCN6	Strong	Autosomal dominant	neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLCN6	Orphanet:610573	CLCN6-related childhood-onset progressive neurodegeneration-peripheral neuropathy 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
CLCN6	HGNC:2024	ENSG00000011021	P51797	H(+)/Cl(-) exchange transporter 6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLCN6	H(+)/Cl(-) exchange transporter 6	Voltage-gated channel mediating the exchange of chloride ions against protons.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLCN6	Other/Unknown	no		CBS_dom, ClC, Cl_channel-6

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
left testis	1
right atrium auricular region	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLCN6	239	ubiquitous	marker	right testis, left testis, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLCN6	1,042

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLCN6	P51797	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Signaling by BRAF and RAF1 fusions	1	170.4×	0.007	CLCN6
Stimuli-sensing channels	1	135.9×	0.007	CLCN6

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
cell volume homeostasis	1	601.9×	0.005	CLCN6
chloride transport	1	455.5×	0.005	CLCN6
response to mechanical stimulus	1	300.9×	0.006	CLCN6
monoatomic ion transmembrane transport	1	208.1×	0.006	CLCN6
signal transduction	1	16.1×	0.062	CLCN6

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CLCN6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	CLCN6

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)
CLCN6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.