Neuronal ceroid lipofuscinosis

Summary

Neuronal ceroid lipofuscinosis (MONDO:0016295) is a disease (an umbrella term covering 14 Mondo subtypes) caused by variants in CLN6, CTSD, MFSD8, and 1 other genes, with 27 cohort genes and 7 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal genes: CLN6 (GenCC Definitive), CTSD (GenCC Definitive), MFSD8 (GenCC Definitive), TPP1 (GenCC Definitive)
• Umbrella term: 14 Mondo subtypes
• Cohort genes: 27
• ClinVar variants: 3,765
• Clinical trials: 7

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2	Europe	Validated
Annual incidence	1-9 / 1 000 000	0.98	Italy	Validated
Point prevalence	1-9 / 1 000 000	0.12	Italy	Validated
Prevalence at birth	1-9 / 1 000 000	0.56	Italy	Validated
Prevalence at birth	1-9 / 100 000	4	Norway	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronal ceroid lipofuscinosis
Mondo ID	MONDO:0016295
OMIM	256730
Orphanet	216
DOID	DOID:14503
ICD-10-CM	E75.4
ICD-11	1568332253
NCIT	C61257
SNOMED CT	42012007
UMLS	C0027877
MedGen	10326
GARD	0010739
Is cancer (heuristic)	no

Also known as: ceroid lipofuscinoses · NCL · neuronal ceroid lipofuscinosis

Data availability: 3,765 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 14 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

Related subtypes (6): triglyceride storage disease, xanthomatosis, neutral lipid storage disease, sphingolipidosis, cerebral lipidosis with dementia, lysosomal acid lipase deficiency

Subtypes (14): neuronal ceroid lipofuscinosis 3, ceroid lipofuscinosis, neuronal, 6B (Kufs type), neuronal ceroid lipofuscinosis 2, neuronal ceroid lipofuscinosis 1, neuronal ceroid lipofuscinosis 5, neuronal ceroid lipofuscinosis 8, 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

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:

312 likely benign, 156 uncertain significance, 41 benign/likely benign, 35 conflicting classifications of pathogenicity, 22 pathogenic, 15 benign, 12 pathogenic/likely pathogenic, 7 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012399	NM_001042432.2(CLN3):c.460+1G>A	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067645	NM_001042432.2(CLN3):c.962+2T>G	CLN3	Pathogenic	criteria provided, single submitter
1070933	NM_001042432.2(CLN3):c.392del (p.Ser131fs)	CLN3	Pathogenic	criteria provided, single submitter
1072038	NM_001042432.2(CLN3):c.43G>T (p.Glu15Ter)	CLN3	Pathogenic	criteria provided, single submitter
1072910	NM_001042432.2(CLN3):c.592del (p.Ser198fs)	CLN3	Pathogenic	criteria provided, single submitter
1073957	NC_000016.9:g.(?_28484798)_28497560del	CLN3	Pathogenic	criteria provided, single submitter
1073958	NC_000016.9:g.(?28493426)(28493993_?)del	CLN3	Pathogenic	criteria provided, single submitter
1073959	NC_000016.9:g.(?28502803)(28503080_?)del	CLN3	Pathogenic	criteria provided, single submitter
1075948	NM_001042432.2(CLN3):c.992_993del (p.Phe331fs)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076288	NM_001042432.2(CLN3):c.1198-2A>C	CLN3	Pathogenic	criteria provided, single submitter
1213977	NM_001042432.2(CLN3):c.512C>T (p.Ser171Phe)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1378760	NM_001042432.2(CLN3):c.639del (p.Leu214fs)	CLN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1387336	NM_001042432.2(CLN3):c.105del (p.His34_Trp35insTer)	CLN3	Pathogenic	criteria provided, single submitter
1069801	NM_006493.4(CLN5):c.84_96dup (p.Leu33fs)	CLN5	Pathogenic	criteria provided, single submitter
1071340	NM_006493.4(CLN5):c.827_828del (p.Phe276fs)	CLN5	Pathogenic	criteria provided, single submitter
1072711	NM_006493.4(CLN5):c.990G>A (p.Trp330Ter)	CLN5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073281	NM_006493.4(CLN5):c.812del (p.Asn271fs)	CLN5	Pathogenic	criteria provided, multiple submitters, no conflicts
1075607	NM_006493.4(CLN5):c.580C>T (p.Gln194Ter)	CLN5	Pathogenic	criteria provided, multiple submitters, no conflicts
1075843	NM_006493.4(CLN5):c.207_213del (p.Pro68_Tyr69insTer)	CLN5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
128784	NM_006493.4(CLN5):c.525del (p.His174_Trp175insTer)	CLN5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1351290	NM_006493.4(CLN5):c.251_252del (p.Pro84fs)	CLN5	Pathogenic	criteria provided, single submitter
1017289	NM_017882.3(CLN6):c.3G>A (p.Met1Ile)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068527	NM_017882.3(CLN6):c.583_596del (p.Gly195fs)	CLN6	Pathogenic	criteria provided, single submitter
1071216	NM_017882.3(CLN6):c.121del (p.Ala41fs)	CLN6	Pathogenic	criteria provided, single submitter
1072427	NM_017882.3(CLN6):c.768C>G (p.Asp256Glu)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072428	NM_017882.3(CLN6):c.712_713delinsAC (p.Phe238Thr)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075854	NM_017882.3(CLN6):c.196dup (p.Met66fs)	CLN6	Pathogenic	criteria provided, single submitter
1180629	NM_017882.3(CLN6):c.396dup (p.Val133fs)	CLN6	Pathogenic	criteria provided, multiple submitters, no conflicts
1363826	NM_017882.3(CLN6):c.397_398del (p.Val133fs)	CLN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069263	NM_018941.4(CLN8):c.130C>T (p.Gln44Ter)	CLN8	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 46 · Orphanet: 38 · 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
ACD	Definitive	Autosomal recessive	neuronal ceroid lipofuscinosis	15
CLN6	Definitive	Autosomal recessive	neuronal ceroid lipofuscinosis	10
CTSD	Definitive	Autosomal recessive	neuronal ceroid lipofuscinosis	5
MFSD8	Definitive	Autosomal recessive	neuronal ceroid lipofuscinosis	7
TPP1	Definitive	Autosomal recessive	neuronal ceroid lipofuscinosis	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TPP1	Orphanet:284324	Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia
TPP1	Orphanet:699751	Infantile CLN2 disease
TPP1	Orphanet:699761	Late infantile CLN2 disease
TPP1	Orphanet:699769	Juvenile CLN2 disease
CLN6	Orphanet:700467	Late infantile CLN6 disease
CLN6	Orphanet:700472	Juvenile CLN6 disease
CLN6	Orphanet:700477	Adult CLN6 disease
ACD	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
ACD	Orphanet:397692	Hereditary isolated aplastic anemia
ACD	Orphanet:618	Familial melanoma
CTSD	Orphanet:700487	Congenital CLN10 disease
CTSD	Orphanet:700492	Late infantile CLN10 disease
CTSD	Orphanet:700497	Juvenile CLN10 disease
MFSD8	Orphanet:1872	Cone rod dystrophy
MFSD8	Orphanet:228366	CLN7 disease
CLRN1	Orphanet:231183	Usher syndrome type 3
CLRN1	Orphanet:791	Retinitis pigmentosa
ARHGEF10	Orphanet:140481	Autosomal dominant slowed nerve conduction velocity
DNAJC5	Orphanet:228343	CLN4 disease
CLN3	Orphanet:699780	Juvenile CLN3 disease
CLN3	Orphanet:699796	Protracted juvenile CLN3 disease
CLN5	Orphanet:699802	Late infantile CLN5 disease
CLN5	Orphanet:699807	Juvenile CLN5 disease
CLN5	Orphanet:699812	Adult CLN5 disease
CLN8	Orphanet:1947	Northern epilepsy
CLN8	Orphanet:700484	Late infantile CLN8 disease
KCTD7	Orphanet:263516	Progressive myoclonic epilepsy type 3
KCTD7	Orphanet:699708	CLN14 disease
MYCBP2	Orphanet:528084	Non-specific syndromic intellectual disability
CTSF	Orphanet:352709	CLN13 disease
MEFV	Orphanet:117	Behçet disease
MEFV	Orphanet:3243	Sweet syndrome
MEFV	Orphanet:329967	Intermittent hydrarthrosis
MEFV	Orphanet:342	Familial Mediterranean fever
PPT1	Orphanet:699718	Infantile CLN1 disease
PPT1	Orphanet:699734	Late infantile CLN1 disease
PPT1	Orphanet:699739	Juvenile CLN1 disease
PPT1	Orphanet:699745	Adult CLN1 disease

Cohort genes → proteins

27 cohort genes, 26 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	27

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TPP1	HGNC:2073	ENSG00000166340	O14773	Tripeptidyl-peptidase 1	gencc,clinvar
CLN6	HGNC:2077	ENSG00000128973	Q9NWW5	Ceroid-lipofuscinosis neuronal protein 6	gencc,clinvar
ACD	HGNC:25070	ENSG00000102977	Q96AP0	Adrenocortical dysplasia protein homolog	gencc,clinvar
CTSD	HGNC:2529	ENSG00000117984	P07339	Cathepsin D	gencc,clinvar
MFSD8	HGNC:28486	ENSG00000164073	Q8NHS3	Major facilitator superfamily domain-containing protein 8	gencc,clinvar
MRPL23	HGNC:10322	ENSG00000214026	Q16540	Large ribosomal subunit protein uL23m	clinvar
SRMS	HGNC:11298	ENSG00000125508	Q9H3Y6	Tyrosine-protein kinase Srms	clinvar
CLRN1	HGNC:12605	ENSG00000163646	P58418	Clarin-1	clinvar
ARHGEF10	HGNC:14103	ENSG00000104728	O15013	Rho guanine nucleotide exchange factor 10	clinvar
ABHD16B	HGNC:16128	ENSG00000183260	Q9H3Z7	ABHD16B	clinvar
DNAJC5	HGNC:16235	ENSG00000101152	Q9H3Z4	DnaJ homolog subfamily C member 5	clinvar
MYDGF	HGNC:16948	ENSG00000074842	Q969H8	Myeloid-derived growth factor	clinvar
IL27	HGNC:19157	ENSG00000197272	Q8NEV9	Interleukin-27 subunit alpha	clinvar
CLN3	HGNC:2074	ENSG00000188603	Q13286	Battenin	clinvar
CLN5	HGNC:2076	ENSG00000102805	O75503	Bis(monoacylglycero)phosphate synthase CLN5	clinvar
CLN8	HGNC:2079	ENSG00000182372	Q9UBY8	Protein CLN8	clinvar
KCTD7	HGNC:21957	ENSG00000243335	Q96MP8	BTB/POZ domain-containing protein KCTD7	clinvar
MYCBP2	HGNC:23386	ENSG00000005810	O75592	E3 ubiquitin-protein ligase MYCBP2	clinvar
CTSF	HGNC:2531	ENSG00000174080	Q9UBX1	Cathepsin F	clinvar
ABHD18	HGNC:26111	ENSG00000164074	Q0P651	Protein ABHD18	clinvar
GSG1L	HGNC:28283	ENSG00000169181	Q6UXU4	Germ cell-specific gene 1-like protein	clinvar
FEM1B	HGNC:3649	ENSG00000169018	Q9UK73	Protein fem-1 homolog B	clinvar
PRADX	HGNC:40168	ENSG00000235027		PRC2 and DDX5 associated lncRNA	clinvar
ILK	HGNC:6040	ENSG00000166333	Q13418	Scaffold protein ILK	clinvar
MEFV	HGNC:6998	ENSG00000103313	O15553	Pyrin	clinvar
MUC2	HGNC:7512	ENSG00000198788	Q02817	Mucin-2	clinvar
PPT1	HGNC:9325	ENSG00000131238	P50897	Palmitoyl-protein thioesterase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TPP1	Tripeptidyl-peptidase 1	Lysosomal serine protease with tripeptidyl-peptidase I activity.
ACD	Adrenocortical dysplasia protein homolog	Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection.
CTSD	Cathepsin D	Acid protease active in intracellular protein breakdown.
MFSD8	Major facilitator superfamily domain-containing protein 8	Outward-rectifying chloride channel involved in endolysosomal chloride homeostasis, membrane fusion and function.
SRMS	Tyrosine-protein kinase Srms	Non-receptor tyrosine-protein kinase which phosphorylates DOK1 on tyrosine residues.
CLRN1	Clarin-1	May have a role in the excitatory ribbon synapse junctions between hair cells and cochlear ganglion cells and presumably also in analogous synapses within the retina.
ARHGEF10	Rho guanine nucleotide exchange factor 10	May play a role in developmental myelination of peripheral nerves.
ABHD16B	ABHD16B	Hydrolyzes the sn-1 position of glycerophospholipids with high specificity towards phosphatidylserine (PS), PS-PLA1 enzyme.
DNAJC5	DnaJ homolog subfamily C member 5	Acts as a general chaperone in regulated exocytosis.
MYDGF	Myeloid-derived growth factor	Bone marrow-derived monocyte and paracrine-acting protein that promotes cardiac myocyte survival and adaptive angiogenesis for cardiac protection and/or repair after myocardial infarction (MI).
IL27	Interleukin-27 subunit alpha	Associates with EBI3 to form the IL-27 interleukin, a heterodimeric cytokine which functions in innate immunity.
CLN3	Battenin	Mediates microtubule-dependent, anterograde transport connecting the Golgi network, endosomes, autophagosomes, lysosomes and plasma membrane, and participates in several cellular processes such as regulation of lysosomal pH, lysosome prote…
CLN5	Bis(monoacylglycero)phosphate synthase CLN5	Catalyzes the synthesis of bis(monoacylglycero)phosphate (BMP) via transacylation of 2 molecules of lysophosphatidylglycerol (LPG).
CLN8	Protein CLN8	Could play a role in cell proliferation during neuronal differentiation and in protection against cell death.
KCTD7	BTB/POZ domain-containing protein KCTD7	May be involved in the control of excitability of cortical neurons.
MYCBP2	E3 ubiquitin-protein ligase MYCBP2	Atypical E3 ubiquitin-protein ligase which specifically mediates ubiquitination of threonine and serine residues on target proteins, instead of ubiquitinating lysine residues.
CTSF	Cathepsin F	Thiol protease which is believed to participate in intracellular degradation and turnover of proteins.
GSG1L	Germ cell-specific gene 1-like protein	As a component of the inner core of AMPAR complex, modifies AMPA receptor (AMPAR) gating.
FEM1B	Protein fem-1 homolog B	Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to…
ILK	Scaffold protein ILK	Scaffold protein which mediates protein-protein interactions during a range of cellular events including focal adhesion assembly, cell adhesion and cell migration.
MEFV	Pyrin	Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma.
MUC2	Mucin-2	Coats the epithelia of the intestines and other mucus membrane-containing organs to provide a protective, lubricating barrier against particles and infectious agents at mucosal surfaces.
PPT1	Palmitoyl-protein thioesterase 1	Has thioesterase activity against fatty acid thioesters with 14 -18 carbons, including palmitoyl-CoA, S-palmitoyl-N-acetylcysteamine, and palmitoylated proteins.

Protein-family classification

Druggable: 8 · Difficult: 4 · Unknown: 15 · Druggable fraction: 0.3

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
Transporter	2	5.8×	0.164
Protease	3	4.1×	0.164
Kinase	2	2.0×	0.594
Scaffold/PPI	2	1.3×	0.819
Other/Unknown	15	1.0×	0.826
Transcription factor	2	0.6×	0.905
Enzyme (other)	1	0.4×	0.905

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TPP1	Protease	yes	3.4.14.9	Peptidase_S8/S53_dom, S53_propep, Sedolisin_dom
CLN6	Other/Unknown	no		CLN6
ACD	Other/Unknown	no		TPP1/Est3, ACD
CTSD	Protease	yes	3.4.23.5	Aspartic_peptidase_A1, Aspartic_peptidase_AS, Aspartic_peptidase_N
MFSD8	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
MRPL23	Other/Unknown	no		Nucleotide-bd_a/b_plait_sf, Ribosomal_uL23/eL15/eS24_sf, Ribosomal_uL23-like
SRMS	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
CLRN1	Other/Unknown	no		Clarin
ARHGEF10	Scaffold/PPI	no		DH_dom, WD40/YVTN_repeat-like_dom_sf, DBL_dom_sf
ABHD16B	Other/Unknown	no		AB_hydrolase_1, AB_hydrolase_fold
DNAJC5	Other/Unknown	no		DnaJ_domain, DnaJ_domain_CS, J_dom_sf
MYDGF	Other/Unknown	no		MYDGF
IL27	Other/Unknown	no		4_helix_cytokine-like_core, IL-27_alpha
CLN3	Transporter	yes		Battenin_disease_Cln3, Battenin_disease_Cln3_subgr, MFS_trans_sf
CLN5	Other/Unknown	no		CLN5
CLN8	Other/Unknown	no		TLC-dom, TLCD
KCTD7	Other/Unknown	no		BTB/POZ_dom, T1-type_BTB, SKP1/BTB/POZ_sf
MYCBP2	Transcription factor	no	2.3.2.33	Reg_chr_condens, Znf_RING, APC_su10/DOC_dom
CTSF	Protease	yes	3.4.22.41	Pept_cys_AS, Peptidase_C1A_C, Peptidase_C1A
ABHD18	Other/Unknown	no		ABHD18, AB_hydrolase_fold
GSG1L	Other/Unknown	no		GSG-1, PMP-22/EMP/MP20-like
FEM1B	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf
PRADX	Other/Unknown	no
ILK	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ankyrin_rpt
MEFV	Transcription factor	no		Znf_B-box, B30.2/SPRY, SPRY_dom
MUC2	Other/Unknown	no		VWF_dom, VWF_type-D, TIL_dom
PPT1	Enzyme (other)	yes	3.1.2.2	Palm_thioest, AB_hydrolase_fold

Expression context

Cohort genes with no expression data: 0.

21 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)	27
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	4
leukocyte	3
mucosa of transverse colon	3
bone marrow	2
cerebellar cortex	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
right adrenal gland	2
right adrenal gland cortex	2
adrenal tissue	2
pancreatic ductal cell	2
sural nerve	2
left testis	2
right testis	2
stromal cell of endometrium	2
C1 segment of cervical spinal cord	2
buccal mucosa cell	2
mononuclear cell	2
dorsal motor nucleus of vagus nerve	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TPP1	298	ubiquitous	marker	pigmented layer of retina, retina, dorsal motor nucleus of vagus nerve
CLN6	139	ubiquitous	marker	monocyte, leukocyte, bone marrow
ACD	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
CTSD	290	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
MFSD8	256	ubiquitous	marker	oviduct epithelium, adrenal tissue, calcaneal tendon
MRPL23	134	ubiquitous	marker	olfactory segment of nasal mucosa, apex of heart, right uterine tube
SRMS	115		yes	mucosa of transverse colon, pancreatic ductal cell, spleen
CLRN1	61	tissue_specific	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
ARHGEF10	134	ubiquitous	yes	sural nerve, tibial nerve, right lung
ABHD16B	106		yes	right testis, left testis, testis
DNAJC5	254	ubiquitous	marker	cardiac muscle of right atrium, right frontal lobe, Brodmann (1909) area 9
MYDGF	292	ubiquitous	marker	stromal cell of endometrium, body of pancreas, adenohypophysis
IL27	129	tissue_specific	yes	right lobe of liver, monocyte, leukocyte
CLN3	134	ubiquitous	marker	mucosa of transverse colon, placenta, granulocyte
CLN5	271	ubiquitous	marker	left lobe of thyroid gland, right lobe of thyroid gland, thyroid gland
CLN8	134	ubiquitous	marker	corpus callosum, C1 segment of cervical spinal cord, stromal cell of endometrium
KCTD7	261	ubiquitous	yes	cortical plate, ganglionic eminence, C1 segment of cervical spinal cord
MYCBP2	294	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, hair follicle
CTSF	293	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ABHD18	263	ubiquitous	marker	buccal mucosa cell, jejunal mucosa, jejunum
GSG1L	144	tissue_specific	yes	sural nerve, pancreatic ductal cell, right atrium auricular region
FEM1B	296	ubiquitous	marker	endothelial cell, left testis, right testis
PRADX	128		marker	blood, bone marrow, bone marrow cell
ILK	287	ubiquitous	marker	body of uterus, popliteal artery, tibial artery
MEFV	153	broad	marker	buccal mucosa cell, monocyte, mononuclear cell
MUC2	96	tissue_specific	marker	mucosa of transverse colon, rectum, small intestine Peyer’s patch
PPT1	294	ubiquitous	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 57.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CTSD	4,280
DNAJC5	3,802
MRPL23	2,519
PPT1	2,444
MYCBP2	2,267
MEFV	2,217
MUC2	2,069
FEM1B	2,008
TPP1	1,739
CLN3	1,613

Intra-cohort edges

A	B	Sources
ABHD16B	ABHD18	string_interaction
ABHD18	MFSD8	string_interaction
ARHGEF10	CLN8	string_interaction
CLN3	CLN5	intact, string_interaction
CLN3	CLN6	string_interaction
CLN3	CLN8	string_interaction
CLN3	CTSD	string_interaction
CLN3	CTSF	string_interaction
CLN3	DNAJC5	string_interaction
CLN3	KCTD7	string_interaction
CLN3	MFSD8	string_interaction
CLN3	PPT1	string_interaction
CLN3	TPP1	string_interaction
CLN5	CLN6	string_interaction
CLN5	CLN8	string_interaction
CLN5	CTSD	string_interaction
CLN5	CTSF	string_interaction
CLN5	DNAJC5	string_interaction
CLN5	KCTD7	string_interaction
CLN5	MFSD8	string_interaction
CLN5	PPT1	string_interaction
CLN5	TPP1	string_interaction
CLN6	CLN8	string_interaction
CLN6	CTSD	string_interaction
CLN6	CTSF	string_interaction
CLN6	DNAJC5	string_interaction
CLN6	KCTD7	string_interaction
CLN6	MFSD8	string_interaction
CLN6	PPT1	string_interaction
CLN6	TPP1	string_interaction
CLN8	CTSD	string_interaction
CLN8	CTSF	string_interaction
CLN8	DNAJC5	string_interaction
CLN8	KCTD7	string_interaction
CLN8	MFSD8	string_interaction
CLN8	PPT1	string_interaction
CLN8	TPP1	string_interaction
CTSD	CTSF	string_interaction
CTSD	DNAJC5	string_interaction
CTSD	MFSD8	string_interaction
CTSD	PPT1	biogrid_interaction, string_interaction
CTSD	TPP1	string_interaction
CTSF	DNAJC5	string_interaction
CTSF	KCTD7	string_interaction
CTSF	MFSD8	string_interaction
CTSF	PPT1	string_interaction
CTSF	TPP1	string_interaction
DNAJC5	KCTD7	string_interaction
DNAJC5	MFSD8	string_interaction
DNAJC5	PPT1	string_interaction

Structural data

PDB: 15 · AlphaFold-only: 11 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPL23	Q16540	86
FEM1B	Q9UK73	31
ACD	Q96AP0	19
ILK	Q13418	17
MUC2	Q02817	12
MEFV	O15553	11
CTSD	P07339	9
IL27	Q8NEV9	4
MYDGF	Q969H8	3
TPP1	O14773	2
DNAJC5	Q9H3Z4	2
MYCBP2	O75592	2
CLN5	O75503	1
CTSF	Q9UBX1	1
PPT1	P50897	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLRN1	P58418	90.74
CLN8	Q9UBY8	90.47
ABHD16B	Q9H3Z7	86.64
CLN6	Q9NWW5	85.86
SRMS	Q9H3Y6	83.99
MFSD8	Q8NHS3	83.20
CLN3	Q13286	81.81
KCTD7	Q96MP8	81.67
ABHD18	Q0P651	80.82
GSG1L	Q6UXU4	72.23
ARHGEF10	O15013	65.56

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 93. Enrichment computed across 27 evidence-associated genes (16 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 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Localization of the PINCH-ILK-PARVIN complex to focal adhesions	1	178.4×	0.105	ILK
PTK6 Down-Regulation	1	178.4×	0.105	SRMS
Depurination	1	102.0×	0.105	ACD
Glycosphingolipid transport	1	89.2×	0.105	CLN3
Inflammasomes	1	71.4×	0.105	MEFV
Cell recruitment (pro-inflammatory response)	1	71.4×	0.105	MEFV
Interleukin-27 signaling	1	64.9×	0.105	IL27
Depyrimidination	1	59.5×	0.105	ACD
Base-Excision Repair, AP Site Formation	1	54.9×	0.105	ACD
Signaling by Insulin receptor	1	54.9×	0.105	CTSD
Telomere C-strand synthesis initiation	1	51.0×	0.105	ACD
Processive synthesis on the C-strand of the telomere	1	47.6×	0.105	ACD
Telomere C-strand (Lagging Strand) Synthesis	1	47.6×	0.105	ACD
Base Excision Repair	1	44.6×	0.105	ACD
Cell-extracellular matrix interactions	1	42.0×	0.105	ILK
The NLRP3 inflammasome	1	42.0×	0.105	MEFV
Removal of the Flap Intermediate from the C-strand	1	39.6×	0.105	ACD
Metabolism of Angiotensinogen to Angiotensins	1	39.6×	0.105	CTSD
GABA synthesis, release, reuptake and degradation	1	39.6×	0.105	DNAJC5
Extension of Telomeres	1	37.6×	0.105	ACD
Signaling by PTK6	1	34.0×	0.105	SRMS
Signaling by Non-Receptor Tyrosine Kinases	1	34.0×	0.105	SRMS
IRE1alpha activates chaperones	1	32.4×	0.105	MYDGF
XBP1(S) activates chaperone genes	2	26.9×	0.105	TPP1, MYDGF
MHC class II antigen presentation	2	11.2×	0.105	CTSD, CTSF
Adaptive Immune System	3	5.6×	0.105	CTSD, KCTD7, CTSF
Immune System	4	3.2×	0.105	CTSD, KCTD7, CTSF, MEFV
Telomere Extension By Telomerase	1	28.6×	0.112	ACD
Fatty acyl-CoA biosynthesis	1	27.4×	0.112	PPT1
Polymerase switching on the C-strand of the telomere	1	26.4×	0.112	ACD

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 25 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lysosome organization	6	73.5×	4e-08	TPP1, CLN6, MFSD8, CLN3, CLN5, CLN8
lysosomal lumen acidification	4	107.8×	5e-06	CLN6, CLN3, CLN5, PPT1
protein catabolic process	5	47.5×	5e-06	TPP1, CLN6, CLN5, CLN8, PPT1
lysosomal protein catabolic process	3	126.4×	1e-04	TPP1, MFSD8, CLN3
negative regulation of neuron apoptotic process	5	22.2×	1e-04	MFSD8, DNAJC5, CLN3, CLN8, PPT1
visual perception	5	15.9×	6e-04	CLN6, CLRN1, CLN5, CLN8, PPT1
associative learning	3	57.8×	7e-04	CLN3, CLN8, PPT1
positive regulation of pinocytosis	2	269.6×	7e-04	CLN3, PPT1
neuromuscular process controlling balance	3	39.6×	0.002	TPP1, CLN3, CLN8
protein localization to chromosome, telomeric region	2	122.6×	0.003	TPP1, ACD
regulation of short-term neuronal synaptic plasticity	2	89.9×	0.005	CLN3, GSG1L
myelination in peripheral nervous system	2	71.0×	0.008	ARHGEF10, ILK
negative regulation of proteolysis	2	53.9×	0.012	CLN3, CLN8
regulation of cytoskeleton organization	2	51.9×	0.012	CLN3, MYCBP2
antigen processing and presentation of exogenous peptide antigen via MHC class II	2	43.5×	0.017	CTSD, CTSF
neuromuscular process	2	42.1×	0.017	MFSD8, MYCBP2
regulation of T-helper 1 cell differentiation	1	674.1×	0.018	IL27
maintenance of location	1	674.1×	0.018	MFSD8
obsolete phagosome-lysosome docking	1	674.1×	0.018	CLN3
regulation of cellular response to osmotic stress	1	674.1×	0.018	CLN3
regulation of arginine biosynthetic process	1	674.1×	0.018	CLN3
positive regulation of GTP binding	1	674.1×	0.018	CLN5
glycolipid metabolic process	1	337.0×	0.023	MFSD8
segmentation	1	337.0×	0.023	ACD
renal potassium excretion	1	337.0×	0.023	CLN3
regulation of ubiquitin-protein transferase activity	1	337.0×	0.023	FEM1B
glutamate reuptake	1	337.0×	0.023	CLN8
inclusion body assembly	1	337.0×	0.023	MFSD8
retinal rod cell apoptotic process	1	337.0×	0.023	CLN8
pyroptosome complex assembly	1	337.0×	0.023	MEFV

Therapeutics

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 4 · Undrugged: 23

Druggability breadth: 11 of 27 evidence-associated genes (41%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CTSD	AMPRENAVIR
SRMS	FEDRATINIB
CTSF	BOCEPREVIR
ILK	NILOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SRMS	19	4
CTSD	8	4
ILK	4	4
CTSF	3	4
TPP1	0	0
CLN6	0	0
ACD	0	0
MFSD8	0	0
MRPL23	0	0
CLRN1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMPRENAVIR	4	CTSD
TIPRANAVIR	4	CTSD
FEDRATINIB	4	SRMS
SORAFENIB	4	SRMS
VANDETANIB	4	SRMS
BOSUTINIB	4	SRMS
PAZOPANIB	4	SRMS
DASATINIB	4	SRMS
BOCEPREVIR	4	CTSF
NILOTINIB	4	ILK
ERLOTINIB	4	ILK
LINIFANIB	3	SRMS
CANERTINIB	3	SRMS
ALVOCIDIB	3	SRMS
LESTAURTINIB	3	SRMS
ODANACATIB	3	CTSF
CRENOLANIB	3	ILK
MOLIBRESIB	2	CTSD
URSOLIC ACID	2	CTSD
PEPSTATIN	2	CTSD
BALICATIB	2	CTSD
PIPERINE	2	CTSD
FORETINIB	2	SRMS
SU-014813	2	SRMS
REBASTINIB	2	SRMS
ILORASERTIB	2	SRMS
DEFOSBARASERTIB	2	SRMS
OSI-632	2	SRMS
R-406	2	SRMS
ATUZAGINSTAT	2	CTSF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CTSD	352	Binding:331, ADMET:15, Toxicity:3, Functional:3
SRMS	179	Binding:178, Functional:1
ILK	71	Binding:71
FEM1B	29	Binding:29
CTSF	18	Binding:17, Toxicity:1
PPT1	5	Binding:5
TPP1	1	Binding:1
CLN6	1	Binding:1
DNAJC5	1	Binding:1
MYCBP2	1	Binding:1
MEFV	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TPP1	3.4.14.9	tripeptidyl-peptidase I
CTSD	3.4.23.5	cathepsin D
SRMS	2.7.10.2	non-specific protein-tyrosine kinase
MYCBP2	2.3.2.33	RCR-type E3 ubiquitin transferase
CTSF	3.4.22.41	cathepsin F
ILK	2.7.10.2	non-specific protein-tyrosine kinase
PPT1	3.1.2.2, 3.1.2.22	palmitoyl-CoA hydrolase, palmitoyl[protein] hydrolase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CTSD	352
SRMS	179

Pharmacogenomics

Cohort genes with a PharmGKB record: 26; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 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.

Compound	Max phase	Cohort target (bioactivity)
AMPRENAVIR	4	CTSD
TIPRANAVIR	4	CTSD
FEDRATINIB	4	SRMS
SORAFENIB	4	SRMS
VANDETANIB	4	SRMS
BOSUTINIB	4	SRMS
PAZOPANIB	4	SRMS
DASATINIB	4	SRMS
BOCEPREVIR	4	CTSF
NILOTINIB	4	ILK
ERLOTINIB	4	ILK
LINIFANIB	3	SRMS
CANERTINIB	3	SRMS
ALVOCIDIB	3	SRMS
LESTAURTINIB	3	SRMS
ODANACATIB	3	CTSF
CRENOLANIB	3	ILK
MOLIBRESIB	2	CTSD
URSOLIC ACID	2	CTSD
PEPSTATIN	2	CTSD
BALICATIB	2	CTSD
PIPERINE	2	CTSD
FORETINIB	2	SRMS
SU-014813	2	SRMS
REBASTINIB	2	SRMS
ILORASERTIB	2	SRMS
DEFOSBARASERTIB	2	SRMS
OSI-632	2	SRMS
R-406	2	SRMS
ATUZAGINSTAT	2	CTSF

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	CTSD, SRMS, CTSF, ILK
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	TPP1, PPT1
D	Druggable family + AlphaFold only, no drug	2	MFSD8, CLN3
E	Difficult family or no structure, no drug	19	CLN6, ACD, MRPL23, CLRN1, ARHGEF10, ABHD16B, DNAJC5, MYDGF, IL27, CLN5 (+9 more)

Undrugged target profiles

23 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TPP1	1	—
CLN6	1	—
ACD	0	—
MFSD8	0	—
MRPL23	0	—
CLRN1	0	—
ARHGEF10	0	—
ABHD16B	0	—
DNAJC5	1	—
MYDGF	0	—
IL27	0	—
CLN3	0	—
CLN5	0	—
CLN8	0	—
KCTD7	0	—
MYCBP2	1	—
ABHD18	0	—
GSG1L	0	—
FEM1B	29	—
PRADX	0	—
MEFV	1	—
MUC2	0	—
PPT1	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE1	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07582484	PHASE1/PHASE2	NOT_YET_RECRUITING	Gene Therapy Trial for CLN6 Batten Disease
NCT00337636	PHASE1	COMPLETED	Study of HuCNS-SC Cells in Patients With Infantile or Late Infantile Neuronal Ceroid Lipofuscinosis (NCL)
NCT01238315	PHASE1	WITHDRAWN	Safety and Efficacy Study of HuCNS-SC in Subjects With Neuronal Ceroid Lipofuscinosis
NCT01873924	Not specified	RECRUITING	Clinical and Neuropsychological Investigations in Batten Disease
NCT04613089	Not specified	RECRUITING	Natural History and Longitudinal Clinical Assessments in NCL / Batten Disease, the International DEM-CHILD Database
NCT06844877	Not specified	RECRUITING	Italian NCL Registry: a Registry for NCL as an Integration Tool for Future Therapeutic Strategies
NCT01966757	Not specified	COMPLETED	Neuronal Ceroid Lipofuscinosis and Associated Sleep Abnormalities