early-onset Parkinson disease 20

Summary

early-onset Parkinson disease 20 (MONDO:0014233) is a disease caused by SYNJ1 (GenCC Strong), with 5 cohort genes.

At a glance

• Causal gene: SYNJ1 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 1,383

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	early-onset Parkinson disease 20
Mondo ID	MONDO:0014233
OMIM	615530
DOID	DOID:0060898
UMLS	C3809824
MedGen	816154
GARD	0018462
Is cancer (heuristic)	no

Also known as: early-onset Parkinson disease type 20 · PARK20 · Parkinson disease 20, early-onset · Parkinson disease caused by mutation in SYNJ1 · SYNJ1 Parkinson disease

Data availability: 1,383 ClinVar variants · 4 GenCC gene-disease records · 5 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › basal ganglia disorder › parkinsonian disorder › Parkinson disease › young-onset Parkinson disease › early-onset Parkinson disease 20

Related subtypes (8): juvenile-onset Parkinson disease, Parkinson disease 12, autosomal recessive juvenile Parkinson disease 2, Parkinson disease 3, autosomal dominant, autosomal recessive early-onset Parkinson disease 6, autosomal recessive early-onset Parkinson disease 7, Parkinson disease 10, autosomal recessive early-onset Parkinson disease 23

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:

293 uncertain significance, 270 likely benign, 13 benign, 12 pathogenic, 8 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
129994	NM_002693.3(POLG):c.3131T>C (p.Val1044Ala)	POLG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 15 · 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	early-onset Parkinson disease 20	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
SPG11	Orphanet:2822	Autosomal recessive spastic paraplegia type 11
SPG11	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
SPG11	Orphanet:466775	Autosomal recessive Charcot-Marie-Tooth disease type 2X
CFAP298	Orphanet:244	Primary ciliary dyskinesia
POLG	Orphanet:254881	Spinocerebellar ataxia with epilepsy
POLG	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
POLG	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
POLG	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy
POLG	Orphanet:402082	Progressive myoclonic epilepsy type 5
POLG	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
POLG	Orphanet:726	Alpers-Huttenlocher syndrome
POLG	Orphanet:94125	Recessive mitochondrial ataxia syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SYNJ1	HGNC:11503	ENSG00000159082	O43426	Synaptojanin-1	gencc,clinvar
SPG11	HGNC:11226	ENSG00000104133	Q96JI7	Spatacsin	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
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	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.
SPG11	Spatacsin	May play a role in neurite plasticity by maintaining cytoskeleton stability and regulating synaptic vesicle transport.
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…
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 5 · 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	5	1.8×	0.054

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SYNJ1	Other/Unknown	no		IPPc, RRM_dom, SAC_dom
SPG11	Other/Unknown	no		Spatacsin, Spatacsin_C_dom
CFAP298	Other/Unknown	no		CFAP298
ATP5PO	Other/Unknown	no		ATPase_OSCP/dsu, ATPase_OSCP/d_CS, ATP_synth_OSCP/delta_N_sf
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
Brodmann (1909) area 23	1
lateral nuclear group of thalamus	1
pons	1
bronchial epithelial cell	1
calcaneal tendon	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
small intestine Peyer’s patch	1
tibial nerve	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
SPG11	295	ubiquitous	marker	bronchial epithelial cell, granulocyte, calcaneal tendon
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
POLG	295	ubiquitous	marker	granulocyte, small intestine Peyer’s patch, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP5PO	3,811
POLG	3,400
SYNJ1	2,177
SPG11	1,691
CFAP298	596

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG	P54098	36
ATP5PO	P48047	9
SYNJ1	O43426	5
SPG11	Q96JI7	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CFAP298	P57076	86.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Strand-asynchronous mitochondrial DNA replication	1	380.7×	0.023	POLG
Synthesis of IP2, IP, and Ins in the cytosol	1	253.8×	0.023	SYNJ1
Formation of ATP by chemiosmotic coupling	1	190.3×	0.023	ATP5PO
Inositol phosphate metabolism	1	158.6×	0.023	SYNJ1
Synthesis of IP3 and IP4 in the cytosol	1	141.0×	0.023	SYNJ1
PI Metabolism	1	119.0×	0.023	SYNJ1
Cristae formation	1	115.3×	0.023	ATP5PO
Synthesis of PIPs at the plasma membrane	1	70.5×	0.031	SYNJ1
Phospholipid metabolism	1	66.8×	0.031	SYNJ1
Mitochondrial biogenesis	1	56.0×	0.034	ATP5PO
Metabolism	2	7.7×	0.036	SYNJ1, ATP5PO
Mitochondrial protein degradation	1	38.1×	0.041	ATP5PO
Aerobic respiration and respiratory electron transport	1	29.5×	0.047	ATP5PO
Clathrin-mediated endocytosis	1	28.4×	0.047	SYNJ1
Organelle biogenesis and maintenance	1	22.0×	0.057	ATP5PO
Membrane Trafficking	1	12.4×	0.094	SYNJ1
Vesicle-mediated transport	1	11.6×	0.094	SYNJ1
Metabolism of lipids	1	10.5×	0.097	SYNJ1
Metabolism of proteins	1	4.1×	0.223	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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
synaptic vesicle transport	2	337.0×	6e-04	SYNJ1, SPG11
phagosome-lysosome fusion involved in apoptotic cell clearance	1	3370.4×	0.005	SPG11
positive regulation of endosome organization	1	3370.4×	0.005	SYNJ1
synaptic vesicle uncoating	1	1123.5×	0.007	SYNJ1
DNA replication proofreading	1	1123.5×	0.007	POLG
localization within membrane	1	1123.5×	0.007	SPG11
regulation of cilium movement	1	842.6×	0.007	CFAP298
axo-dendritic transport	1	842.6×	0.007	SPG11
autophagosome organization	1	674.1×	0.008	SPG11
walking behavior	1	561.7×	0.008	SPG11
corticospinal tract morphogenesis	1	481.5×	0.009	SPG11
mitochondrial DNA replication	1	306.4×	0.012	POLG
base-excision repair, gap-filling	1	224.7×	0.013	POLG
motor neuron apoptotic process	1	224.7×	0.013	SPG11
DNA metabolic process	1	210.7×	0.013	POLG
regulation of store-operated calcium entry	1	210.7×	0.013	SPG11
ATP biosynthetic process	1	198.3×	0.013	ATP5PO
inositol phosphate metabolic process	1	198.3×	0.013	SYNJ1
phosphatidylinositol metabolic process	1	177.4×	0.013	SYNJ1
vesicle transport along microtubule	1	177.4×	0.013	SPG11
proton motive force-driven ATP synthesis	1	160.5×	0.013	ATP5PO
synaptic vesicle priming	1	160.5×	0.013	SYNJ1
phosphatidylinositol dephosphorylation	1	129.6×	0.015	SYNJ1
DNA-templated DNA replication	1	112.3×	0.015	POLG
motor behavior	1	112.3×	0.015	SPG11
skeletal muscle fiber development	1	108.7×	0.015	SPG11
cellular response to cytokine stimulus	1	108.7×	0.015	ATP5PO
neuromuscular junction development	1	105.3×	0.015	SPG11
cholesterol efflux	1	105.3×	0.015	SPG11
membrane organization	1	102.1×	0.015	SYNJ1

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 5 evidence-associated genes (80%) 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
POLG	ADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SYNJ1	1	4
POLG	1	4
SPG11	0	0
CFAP298	0	0
ATP5PO	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PYRVINIUM	4	SYNJ1
ADEFOVIR DIPIVOXIL	4	POLG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
POLG	33	Binding:30, ADMET:2, Functional:1
SYNJ1	2	Binding:2
SPG11	1	Binding:1
ATP5PO	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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
ADEFOVIR DIPIVOXIL	4	POLG

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SYNJ1, POLG
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	3	SPG11, CFAP298, ATP5PO

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SPG11	1	—
CFAP298	0	—
ATP5PO	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.