Neuronal ceroid lipofuscinosis 8

Summary

Neuronal ceroid lipofuscinosis 8 (MONDO:0010830) is a disease caused by CLN8 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CLN8 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 172

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		21	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronal ceroid lipofuscinosis 8
Mondo ID	MONDO:0010830
MeSH	C537952
OMIM	600143
Orphanet	228354
DOID	DOID:0110723
SNOMED CT	703526007
UMLS	C1838570
MedGen	374004
GARD	0017152
Is cancer (heuristic)	no

Also known as: ceroid lipofuscinosis, neuronal, 8 · ceroid lipofuscinosis, neuronal, type 8 · CLN8 · CLN8 neuronal ceroid lipofuscinosis · neuronal ceroid lipofuscinosis 8 · neuronal ceroid lipofuscinosis caused by mutation in CLN8 · neuronal ceroid lipofuscinosis type 8

Data availability: 172 ClinVar variants · 6 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › lysosomal lipid storage disorder › neuronal ceroid lipofuscinosis › neuronal ceroid lipofuscinosis 8

Related subtypes (13): neuronal ceroid lipofuscinosis 3, ceroid lipofuscinosis, neuronal, 6B (Kufs type), neuronal ceroid lipofuscinosis 2, neuronal ceroid lipofuscinosis 1, neuronal ceroid lipofuscinosis 5, ceroid lipofuscinosis, neuronal, 6A, neuronal ceroid lipofuscinosis 10, neuronal ceroid lipofuscinosis 7, progressive myoclonic epilepsy type 3, adult neuronal ceroid lipofuscinosis, infantile neuronal ceroid lipofuscinosis, juvenile neuronal ceroid lipofuscinosis, congenital neuronal ceroid lipofuscinosis

Subtypes (2): neuronal ceroid lipofuscinosis 8 northern epilepsy variant, late infantile neuronal ceroid lipofuscinosis 8

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

172 retrieved; paginated sample, class counts are floors:

86 uncertain significance, 21 likely pathogenic, 20 conflicting classifications of pathogenicity, 15 pathogenic/likely pathogenic, 12 pathogenic, 11 likely benign, 4 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1389933	NM_018941.4(CLN8):c.29C>G (p.Ser10Ter)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188917	NM_018941.4(CLN8):c.709G>A (p.Gly237Arg)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
205194	NM_018941.4(CLN8):c.499G>T (p.Glu167Ter)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242453	NM_018941.4(CLN8):c.208C>T (p.Arg70Cys)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2627378	NM_018941.4(CLN8):c.447C>A (p.Cys149Ter)	CLN8	Pathogenic	criteria provided, single submitter
2627618	NM_018941.4(CLN8):c.424dup (p.Ala142fs)	CLN8	Pathogenic	criteria provided, single submitter
2802	NM_018941.4(CLN8):c.70C>G (p.Arg24Gly)	CLN8	Pathogenic	criteria provided, multiple submitters, no conflicts
2803	NM_018941.4(CLN8):c.789G>C (p.Trp263Cys)	CLN8	Pathogenic	criteria provided, multiple submitters, no conflicts
2804	NM_018941.4(CLN8):c.610C>T (p.Arg204Cys)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2806	NM_018941.4(CLN8):c.88G>C (p.Ala30Pro)	CLN8	Pathogenic	no assertion criteria provided
3595450	NM_018941.4(CLN8):c.1del (p.Met1*)	CLN8	Pathogenic	criteria provided, single submitter
370553	NM_018941.4(CLN8):c.263del (p.Asp88fs)	CLN8	Pathogenic	criteria provided, single submitter
3895973	NC_000008.10:g.(?1711954)(1734737_?)del	CLN8	Pathogenic	criteria provided, single submitter
487522	NM_018941.4(CLN8):c.1A>G (p.Met1Val)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
555198	NM_018941.4(CLN8):c.283A>T (p.Lys95Ter)	CLN8	Pathogenic	criteria provided, single submitter
556335	NM_018941.4(CLN8):c.312G>A (p.Trp104Ter)	CLN8	Pathogenic	criteria provided, single submitter
556399	NM_018941.4(CLN8):c.226C>T (p.Gln76Ter)	CLN8	Pathogenic	criteria provided, single submitter
558034	NM_018941.4(CLN8):c.398T>A (p.Leu133Ter)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
558594	NM_018941.4(CLN8):c.763C>T (p.Gln255Ter)	CLN8	Pathogenic	criteria provided, multiple submitters, no conflicts
56703	NM_018941.4(CLN8):c.181_183del (p.Lys61del)	CLN8	Pathogenic/Likely pathogenic	no assertion criteria provided
56704	NM_018941.4(CLN8):c.209G>A (p.Arg70His)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56710	NM_018941.4(CLN8):c.473A>G (p.Tyr158Cys)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56713	NM_018941.4(CLN8):c.562_563del (p.Leu188fs)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56718	NM_018941.4(CLN8):c.66del (p.Ile23fs)	CLN8	Pathogenic/Likely pathogenic	no assertion criteria provided
56720	NM_018941.4(CLN8):c.88del (p.Ala30fs)	CLN8	Pathogenic/Likely pathogenic	no assertion criteria provided
654163	NM_018941.4(CLN8):c.295C>T (p.Gln99Ter)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
952744	NM_018941.4(CLN8):c.593_596dup (p.Met200fs)	CLN8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217887	NM_018941.3(CLN8):c.[208C>T;792C>G]		Likely pathogenic	no assertion criteria provided
424769	NM_018941.3(CLN8):c.[212C>T];[562_563delCT]		Likely pathogenic	criteria provided, single submitter
1809612	NM_018941.4(CLN8):c.544-1G>T	CLN8	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
CLN8	Definitive	Autosomal recessive	neuronal ceroid lipofuscinosis 8	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLN8	Orphanet:1947	Northern epilepsy
CLN8	Orphanet:700484	Late infantile CLN8 disease

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
CLN8	HGNC:2079	ENSG00000182372	Q9UBY8	Protein CLN8	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLN8	Protein CLN8	Could play a role in cell proliferation during neuronal differentiation and in protection against cell death.

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)
CLN8	Other/Unknown	no		TLC-dom, TLCD

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
C1 segment of cervical spinal cord	1
corpus callosum	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLN8	134	ubiquitous	marker	corpus callosum, C1 segment of cervical spinal cord, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLN8	1,122

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLN8	Q9UBY8	90.47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
glutamate reuptake	1	8426.0×	0.002	CLN8
retinal rod cell apoptotic process	1	8426.0×	0.002	CLN8
somatic motor neuron differentiation	1	5617.3×	0.002	CLN8
musculoskeletal movement	1	2808.7×	0.002	CLN8
mitochondrial membrane organization	1	2407.4×	0.002	CLN8
neurofilament cytoskeleton organization	1	1685.2×	0.003	CLN8
neuromuscular process controlling posture	1	1053.2×	0.003	CLN8
lipid biosynthetic process	1	991.3×	0.003	CLN8
ceramide metabolic process	1	802.5×	0.004	CLN8
regulation of cell size	1	766.0×	0.004	CLN8
negative regulation of proteolysis	1	674.1×	0.004	CLN8
adult walking behavior	1	495.6×	0.004	CLN8
associative learning	1	481.5×	0.004	CLN8
ceramide biosynthetic process	1	421.3×	0.005	CLN8
photoreceptor cell maintenance	1	358.6×	0.005	CLN8
phospholipid metabolic process	1	343.9×	0.005	CLN8
lipid homeostasis	1	337.0×	0.005	CLN8
neuromuscular process controlling balance	1	330.4×	0.005	CLN8
lysosome organization	1	306.4×	0.005	CLN8
social behavior	1	271.8×	0.005	CLN8
lipid transport	1	263.3×	0.005	CLN8
retina development in camera-type eye	1	255.3×	0.005	CLN8
protein catabolic process	1	237.3×	0.005	CLN8
cholesterol metabolic process	1	195.9×	0.006	CLN8
negative regulation of neuron apoptotic process	1	110.9×	0.010	CLN8
visual perception	1	79.5×	0.013	CLN8
nervous system development	1	45.9×	0.022	CLN8

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
CLN8	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	CLN8

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)
CLN8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.