Developmental and epileptic encephalopathy, 53

Summary

Developmental and epileptic encephalopathy, 53 (MONDO:0033362) is a disease caused by SYNJ1 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: SYNJ1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 1,381

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 53
Mondo ID	MONDO:0033362
OMIM	617389
DOID	DOID:0080464
UMLS	C4479313
MedGen	1374886
GARD	0016224
Is cancer (heuristic)	no

Also known as: DEE53 · developmental and epileptic encephalopathy 53 · EIEE53 · epileptic encephalopathy, early infantile, 53

Data availability: 1,381 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › Mendelian neurodevelopmental disorder › genetic developmental and epileptic encephalopathy › developmental and epileptic encephalopathy, 53

Related subtypes (104): developmental and epileptic encephalopathy, 9, developmental and epileptic encephalopathy, 8, developmental and epileptic encephalopathy, 2, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, developmental and epileptic encephalopathy, 1, developmental and epileptic encephalopathy, 3, developmental and epileptic encephalopathy, 4, microcephaly, seizures, and developmental delay, developmental and epileptic encephalopathy, 5, developmental and epileptic encephalopathy, 7, developmental and epileptic encephalopathy, 11, neonatal-onset encephalopathy with rigidity and seizures, developmental and epileptic encephalopathy, 14, developmental and epileptic encephalopathy, 15, developmental and epileptic encephalopathy, 17, developmental and epileptic encephalopathy, 18, developmental and epileptic encephalopathy, 19, developmental and epileptic encephalopathy, 23, developmental and epileptic encephalopathy, 27, developmental and epileptic encephalopathy, 30, developmental and epileptic encephalopathy, 50, developmental and epileptic encephalopathy, 35, developmental and epileptic encephalopathy, 37, developmental and epileptic encephalopathy, 38, developmental and epileptic encephalopathy, 40, developmental and epileptic encephalopathy, 48, developmental and epileptic encephalopathy, 49, developmental and epileptic encephalopathy, 51, Lennox-Gastaut syndrome, developmental and epileptic encephalopathy 91, developmental and epileptic encephalopathy 92, developmental and epileptic encephalopathy 93, developmental and epileptic encephalopathy 96, developmental and epileptic encephalopathy, 90, developmental and epileptic encephalopathy, 85, with or without midline brain defects, developmental and epileptic encephalopathy, 67, developmental and epileptic encephalopathy, 86, developmental and epileptic encephalopathy, 87, developmental and epileptic encephalopathy, 88, developmental and epileptic encephalopathy 6B, developmental and epileptic encephalopathy 97, developmental and epileptic encephalopathy 98, developmental and epileptic encephalopathy 99, developmental and epileptic encephalopathy 100, developmental and epileptic encephalopathy 101, developmental and epileptic encephalopathy 89, developmental and epileptic encephalopathy 102, developmental and epileptic encephalopathy 103, developmental and epileptic encephalopathy 104, developmental and epileptic encephalopathy 105 with hypopituitarism, developmental and epileptic encephalopathy 106, developmental and epileptic encephalopathy 107, developmental and epileptic encephalopathy, 68, developmental and epileptic encephalopathy, 69, developmental and epileptic encephalopathy, 70, developmental and epileptic encephalopathy, 71, developmental and epileptic encephalopathy, 72, developmental and epileptic encephalopathy, 74, developmental and epileptic encephalopathy, 75, developmental and epileptic encephalopathy, 76, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 78, developmental and epileptic encephalopathy, 79, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 81, developmental and epileptic encephalopathy, 82, developmental and epileptic encephalopathy, 83, developmental and epileptic encephalopathy, 84, developmental and epileptic encephalopathy, 52, developmental and epileptic encephalopathy, 54, developmental and epileptic encephalopathy, 55, developmental and epileptic encephalopathy, 56, developmental and epileptic encephalopathy, 57, developmental and epileptic encephalopathy, 58, developmental and epileptic encephalopathy, 59, developmental and epileptic encephalopathy, 60, developmental and epileptic encephalopathy, 61, developmental and epileptic encephalopathy, 62, developmental and epileptic encephalopathy, 63, developmental and epileptic encephalopathy, 64, developmental and epileptic encephalopathy, 65, developmental and epileptic encephalopathy, 73, developmental and epileptic encephalopathy, 66, developmental and epileptic encephalopathy, 6A, non-neonatal early infantile epileptic encephalopathy, Dravet syndrome, neonatal-onset developmental and epileptic encephalopathy, hemiplegic migraine-developmental and epileptic encephalopathy spectrum, DNM1-encephalopathy and neurodevelopmental disorder, TMEM63B-related developmental and epileptic encephalopathy with anemia, developmental and epileptic encephalopathy 108, developmental and epileptic encephalopathy 109, developmental and epileptic encephalopathy 110, developmental and epileptic encephalopathy 111, developmental and epileptic encephalopathy 112, developmental and epileptic encephalopathy 113, developmental and epileptic encephalopathy 114, developmental and epileptic encephalopathy 115, developmental and epileptic encephalopathy 116, developmental and epileptic encephalopathy 118, developmental and epileptic encephalopathy 120, developmental and epileptic encephalopathy 121, developmental and epileptic encephalopathy 119

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:

294 uncertain significance, 270 likely benign, 13 benign, 12 pathogenic, 7 conflicting classifications of pathogenicity, 3 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069960	NM_003895.4(SYNJ1):c.12_13dup (p.Trp5fs)	SYNJ1	Pathogenic	criteria provided, single submitter
1070684	NM_203446.3(SYNJ1):c.3438dup (p.Ala1147fs)	SYNJ1	Pathogenic	criteria provided, single submitter
1074545	NM_203446.3(SYNJ1):c.1093dup (p.Tyr365fs)	SYNJ1	Pathogenic	criteria provided, single submitter
1075587	NM_203446.3(SYNJ1):c.1279_1280dup (p.Met428fs)	SYNJ1	Pathogenic	criteria provided, single submitter
1076901	NM_203446.3(SYNJ1):c.3865C>T (p.Arg1289Ter)	SYNJ1	Pathogenic	criteria provided, single submitter
1361698	NM_203446.3(SYNJ1):c.295del (p.Thr99fs)	SYNJ1	Pathogenic	criteria provided, single submitter
1422351	NM_203446.3(SYNJ1):c.345del (p.Ile116fs)	SYNJ1	Pathogenic	criteria provided, single submitter
1456091	NM_203446.3(SYNJ1):c.748C>T (p.Arg250Ter)	SYNJ1	Pathogenic	criteria provided, single submitter
1457606	NM_203446.3(SYNJ1):c.-12G>T	SYNJ1	Pathogenic	criteria provided, single submitter
1457746	NM_203446.3(SYNJ1):c.1696_1699del (p.Pro566fs)	SYNJ1	Pathogenic	criteria provided, single submitter
1458746	NC_000021.8:g.(?34072128)(34074377_?)del	SYNJ1	Pathogenic	criteria provided, single submitter
1954917	NM_203446.3(SYNJ1):c.2125C>T (p.Arg709Ter)	SYNJ1	Pathogenic	criteria provided, single submitter
1490816	NM_203446.3(SYNJ1):c.3430+1G>A	SYNJ1	Likely pathogenic	criteria provided, single submitter
1509533	NC_000021.8:g.(?34029319)(34031816_?)del	SYNJ1	Likely pathogenic	criteria provided, single submitter
1806858	NM_203446.3(SYNJ1):c.2461+2T>C	SYNJ1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1034741	NM_203446.3(SYNJ1):c.3007G>A (p.Ala1003Thr)	SYNJ1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1042251	NM_203446.3(SYNJ1):c.1868A>G (p.Asn623Ser)	SYNJ1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1092383	NM_203446.3(SYNJ1):c.1953-10T>C	SYNJ1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1119322	NM_203446.3(SYNJ1):c.38T>C (p.Leu13Ser)	SYNJ1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1136325	NM_203446.3(SYNJ1):c.2587G>A (p.Val863Ile)	SYNJ1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1147907	NM_203446.3(SYNJ1):c.*443G>A	SYNJ1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1374520	NM_203446.3(SYNJ1):c.3196A>G (p.Ile1066Val)	SYNJ1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1035906	NC_000021.8:g.(?32439271)(37133458_?)dup	ATP5PO	Uncertain significance	criteria provided, single submitter
1000406	NM_203446.3(SYNJ1):c.3391+6A>C	SYNJ1	Uncertain significance	criteria provided, single submitter
1000814	NM_203446.3(SYNJ1):c.2050T>G (p.Cys684Gly)	SYNJ1	Uncertain significance	criteria provided, single submitter
1000830	NM_203446.3(SYNJ1):c.809G>T (p.Arg270Leu)	SYNJ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1002142	NM_203446.3(SYNJ1):c.3560G>A (p.Gly1187Glu)	SYNJ1	Uncertain significance	criteria provided, single submitter
1002258	NM_203446.3(SYNJ1):c.842C>T (p.Ala281Val)	SYNJ1	Uncertain significance	criteria provided, single submitter
1003992	NM_203446.3(SYNJ1):c.344G>A (p.Arg115His)	SYNJ1	Uncertain significance	criteria provided, single submitter
1004293	NM_203446.3(SYNJ1):c.1601G>A (p.Arg534Gln)	SYNJ1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 4 · 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
SYNJ1	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 53	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SYNJ1	Orphanet:2828	Young-onset Parkinson disease
SYNJ1	Orphanet:391411	Atypical juvenile parkinsonism
SYNJ1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CFAP298	Orphanet:244	Primary ciliary dyskinesia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SYNJ1	HGNC:11503	ENSG00000159082	O43426	Synaptojanin-1	gencc,clinvar
CFAP298	HGNC:1301	ENSG00000159079	P57076	Cilia- and flagella-associated protein 298	clinvar
ATP5PO	HGNC:850	ENSG00000241837	P48047	ATP synthase peripheral stalk subunit OSCP, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SYNJ1	Synaptojanin-1	Phosphatase that acts on various phosphoinositides, including phosphatidylinositol 4-phosphate, phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate.
CFAP298	Cilia- and flagella-associated protein 298	Plays a role in motile cilium function, possibly by acting on outer dynein arm assembly.
ATP5PO	ATP synthase peripheral stalk subunit OSCP, mitochondrial	Subunit OSCP, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SYNJ1	Other/Unknown	no		IPPc, RRM_dom, SAC_dom
CFAP298	Other/Unknown	no		CFAP298
ATP5PO	Other/Unknown	no		ATPase_OSCP/dsu, ATPase_OSCP/d_CS, ATP_synth_OSCP/delta_N_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
lateral nuclear group of thalamus	1
pons	1
left testis	1
olfactory segment of nasal mucosa	1
right uterine tube	1
apex of heart	1
heart left ventricle	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SYNJ1	278	ubiquitous	yes	Brodmann (1909) area 23, lateral nuclear group of thalamus, pons
CFAP298	173	ubiquitous	marker	right uterine tube, olfactory segment of nasal mucosa, left testis
ATP5PO	149	ubiquitous	marker	heart left ventricle, apex of heart, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP5PO	3,811
SYNJ1	2,177
CFAP298	596

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP5PO	P48047	9
SYNJ1	O43426	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CFAP298	P57076	86.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of IP2, IP, and Ins in the cytosol	1	380.7×	0.017	SYNJ1
Formation of ATP by chemiosmotic coupling	1	285.5×	0.017	ATP5PO
Inositol phosphate metabolism	1	237.9×	0.017	SYNJ1
Synthesis of IP3 and IP4 in the cytosol	1	211.5×	0.017	SYNJ1
PI Metabolism	1	178.4×	0.017	SYNJ1
Cristae formation	1	173.0×	0.017	ATP5PO
Metabolism	2	11.6×	0.019	SYNJ1, ATP5PO
Synthesis of PIPs at the plasma membrane	1	105.7×	0.020	SYNJ1
Phospholipid metabolism	1	100.2×	0.020	SYNJ1
Mitochondrial biogenesis	1	84.0×	0.021	ATP5PO
Mitochondrial protein degradation	1	57.1×	0.029	ATP5PO
Aerobic respiration and respiratory electron transport	1	44.3×	0.032	ATP5PO
Clathrin-mediated endocytosis	1	42.6×	0.032	SYNJ1
Organelle biogenesis and maintenance	1	33.0×	0.039	ATP5PO
Membrane Trafficking	1	18.5×	0.064	SYNJ1
Vesicle-mediated transport	1	17.4×	0.064	SYNJ1
Metabolism of lipids	1	15.8×	0.066	SYNJ1
Metabolism of proteins	1	6.2×	0.155	ATP5PO

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of endosome organization	1	5617.3×	0.004	SYNJ1
synaptic vesicle uncoating	1	1872.4×	0.005	SYNJ1
regulation of cilium movement	1	1404.3×	0.005	CFAP298
ATP biosynthetic process	1	330.4×	0.008	ATP5PO
inositol phosphate metabolic process	1	330.4×	0.008	SYNJ1
phosphatidylinositol metabolic process	1	295.6×	0.008	SYNJ1
synaptic vesicle transport	1	280.9×	0.008	SYNJ1
proton motive force-driven ATP synthesis	1	267.5×	0.008	ATP5PO
synaptic vesicle priming	1	267.5×	0.008	SYNJ1
phosphatidylinositol dephosphorylation	1	216.1×	0.009	SYNJ1
cellular response to cytokine stimulus	1	181.2×	0.010	ATP5PO
membrane organization	1	170.2×	0.010	SYNJ1
synaptic vesicle endocytosis	1	144.0×	0.010	SYNJ1
neurotransmitter transport	1	140.4×	0.010	SYNJ1
phosphatidylinositol biosynthetic process	1	122.1×	0.011	SYNJ1
proton transmembrane transport	1	104.0×	0.012	ATP5PO
cellular response to cAMP	1	96.8×	0.012	ATP5PO
learning	1	93.6×	0.012	SYNJ1
proton motive force-driven mitochondrial ATP synthesis	1	87.8×	0.012	ATP5PO
cilium assembly	1	24.5×	0.040	CFAP298

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
SYNJ1	PYRVINIUM

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SYNJ1	1	4
CFAP298	0	0
ATP5PO	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PYRVINIUM	4	SYNJ1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SYNJ1	2	Binding:2
ATP5PO	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
PYRVINIUM	4	SYNJ1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SYNJ1
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	CFAP298, ATP5PO

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)
CFAP298	0	—
ATP5PO	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.