ceroid lipofuscinosis, neuronal, 4 (Kufs type)

Summary

ceroid lipofuscinosis, neuronal, 4 (Kufs type) (MONDO:0008083) is a disease caused by DNAJC5 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DNAJC5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 158

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		16	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	ceroid lipofuscinosis, neuronal, 4 (Kufs type)
Mondo ID	MONDO:0008083
OMIM	162350
Orphanet	228343
DOID	DOID:0110720
NCIT	C128116
UMLS	C1834207
MedGen	320287
GARD	0001222
Is cancer (heuristic)	no

Also known as: adult neuronal ceroid lipofuscinosis 4B · autosomal dominant Kufs disease · ceroid lipofuscinosis, neuronal, 4 (Kufs type) · ceroid lipofuscinosis, neuronal, 4 (Kufs type), autosomal dominant · ceroid lipofuscinosis, neuronal, 4B, autosomal dominant · CLN4 · CLN4B · Kuf’s disease type B · Kuf’s disease, autosomal dominant · neuronal ceroid lipofuscinosis type 4B · neuronal ceroid lipofuscinosis, parry type

Data availability: 158 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

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 › adult neuronal ceroid lipofuscinosis › ceroid lipofuscinosis, neuronal, 4 (Kufs type)

Related subtypes (4): neuronal ceroid lipofuscinosis 11, neuronal ceroid lipofuscinosis 13, adult neuronal ceroid lipofuscinosis 1, adult neuronal ceroid lipofuscinosis 5

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

158 retrieved; paginated sample, class counts are floors:

83 uncertain significance, 37 benign, 21 benign/likely benign, 9 conflicting classifications of pathogenicity, 4 pathogenic, 4 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1178346	NM_025219.3(DNAJC5):c.347T>G (p.Leu116Arg)	DNAJC5	Pathogenic	criteria provided, single submitter
30893	NM_025219.3(DNAJC5):c.343CTC[1] (p.Leu116del)	DNAJC5	Pathogenic	criteria provided, multiple submitters, no conflicts
30894	NM_025219.3(DNAJC5):c.344T>G (p.Leu115Arg)	DNAJC5	Pathogenic	criteria provided, multiple submitters, no conflicts
689476	NM_025219.3(DNAJC5):c.370_399dup (p.Cys124_Cys133dup)	DNAJC5	Pathogenic	criteria provided, single submitter
205367	NM_025219.3(DNAJC5):c.153G>T (p.Pro51=)	DNAJC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
339356	NM_025219.3(DNAJC5):c.122A>G (p.Lys41Arg)	DNAJC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
339357	NM_025219.3(DNAJC5):c.438G>A (p.Thr146=)	DNAJC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
339358	NM_025219.3(DNAJC5):c.444C>T (p.Phe148=)	DNAJC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
339359	NM_025219.3(DNAJC5):c.504C>T (p.Asp168=)	DNAJC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
431814	NM_025219.3(DNAJC5):c.524C>T (p.Pro175Leu)	DNAJC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895066	NM_025219.3(DNAJC5):c.*853C>A	DNAJC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896432	NM_025219.3(DNAJC5):c.162G>A (p.Ala54=)	DNAJC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898060	NM_025219.3(DNAJC5):c.*158A>T	DNAJC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1046215	NM_025219.3(DNAJC5):c.340G>A (p.Gly114Ser)	DNAJC5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1401106	NM_025219.3(DNAJC5):c.565C>T (p.His189Tyr)	DNAJC5	Uncertain significance	criteria provided, multiple submitters, no conflicts
2159688	NM_025219.3(DNAJC5):c.563C>T (p.Ser188Phe)	DNAJC5	Uncertain significance	criteria provided, multiple submitters, no conflicts
2440941	NM_025219.3(DNAJC5):c.493+1dup	DNAJC5	Uncertain significance	criteria provided, single submitter
2440942	NM_025219.3(DNAJC5):c.482C>G (p.Ser161Cys)	DNAJC5	Uncertain significance	criteria provided, multiple submitters, no conflicts
339344	NM_025219.3(DNAJC5):c.-194C>T	DNAJC5	Uncertain significance	criteria provided, single submitter
339346	NM_025219.3(DNAJC5):c.-186C>T	DNAJC5	Uncertain significance	criteria provided, single submitter
339347	NM_025219.3(DNAJC5):c.-185G>T	DNAJC5	Uncertain significance	criteria provided, single submitter
339352	NM_025219.3(DNAJC5):c.-109A>G	DNAJC5	Uncertain significance	criteria provided, multiple submitters, no conflicts
339353	NM_025219.3(DNAJC5):c.-95G>C	DNAJC5	Uncertain significance	criteria provided, single submitter
339354	NM_025219.3(DNAJC5):c.-89C>G	DNAJC5	Uncertain significance	criteria provided, single submitter
339360	NM_025219.3(DNAJC5):c.*80A>G	DNAJC5	Uncertain significance	criteria provided, single submitter
339361	NM_025219.3(DNAJC5):c.*135C>T	DNAJC5	Uncertain significance	criteria provided, single submitter
339363	NM_025219.3(DNAJC5):c.*243G>A	DNAJC5	Uncertain significance	criteria provided, single submitter
339364	NM_025219.3(DNAJC5):c.*273C>G	DNAJC5	Uncertain significance	criteria provided, single submitter
339365	NM_025219.3(DNAJC5):c.*276C>T	DNAJC5	Uncertain significance	criteria provided, single submitter
339366	NM_025219.3(DNAJC5):c.*286G>A	DNAJC5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
DNAJC5	Strong	Autosomal dominant	ceroid lipofuscinosis, neuronal, 4 (Kufs type)	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNAJC5	Orphanet:228343	CLN4 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
DNAJC5	HGNC:16235	ENSG00000101152	Q9H3Z4	DnaJ homolog subfamily C member 5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNAJC5	DnaJ homolog subfamily C member 5	Acts as a general chaperone in regulated exocytosis.

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)
DNAJC5	Other/Unknown	no		DnaJ_domain, DnaJ_domain_CS, J_dom_sf

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
Brodmann (1909) area 9	1
cardiac muscle of right atrium	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNAJC5	254	ubiquitous	marker	cardiac muscle of right atrium, right frontal lobe, Brodmann (1909) area 9

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNAJC5	3,802

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNAJC5	Q9H3Z4	2

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
GABA synthesis, release, reuptake and degradation	1	634.4×	0.005	DNAJC5
Sensory processing of sound by inner hair cells of the cochlea	1	163.1×	0.009	DNAJC5
Neutrophil degranulation	1	23.1×	0.043	DNAJC5

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 synaptic vesicle cycle	1	1123.5×	0.003	DNAJC5
regulated exocytosis	1	887.0×	0.003	DNAJC5
synaptic vesicle exocytosis	1	766.0×	0.003	DNAJC5
neuron apoptotic process	1	185.2×	0.009	DNAJC5
exocytosis	1	151.8×	0.009	DNAJC5
negative regulation of neuron apoptotic process	1	110.9×	0.010	DNAJC5
protein folding	1	103.4×	0.010	DNAJC5

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
DNAJC5	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
DNAJC5	1	Binding: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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DNAJC5

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)
DNAJC5	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.