GeneBe

SYNJ1

protein-coding

synaptojanin 1, the group of Phosphoinositide phosphatases

Gene summary

This gene encodes a phosphoinositide phosphatase that regulates levels of membrane phosphatidylinositol-4,5-bisphosphate. As such, expression of this enzyme may affect synaptic transmission and membrane trafficking. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

MANE transcript

NM_203446.3

Inheritance

AR, AD

ClinVar variants

P:53U:532B:323

Top phenotype

Developmental and epileptic encephalopathy 53; Parkinson disease 20, early-onset

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chr21:32,628,759-32,728,040

External References & Databases

Ensembl (ENSG00000159082)NCBI Gene (8867)OMIM (604297)HGNC:11503GenCCUniProt (O43426)AlphaFoldClinVar (SYNJ1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~99.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

early-onset Parkinson disease 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014233

Submitter: PanelApp Australia

early-onset Parkinson disease 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014233

Submitter: Genomics England PanelApp

developmental and epileptic encephalopathy, 53MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0033362

Submitter: Ambry Genetics

early-onset Parkinson disease 20MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014233

Submitter: Ambry Genetics

early-onset Parkinson disease 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014233

Submitter: Labcorp Genetics (formerly Invitae)

young-onset Parkinson diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017279

Submitter: Orphanet

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

atypical juvenile parkinsonismSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018321

Submitter: Orphanet

developmental and epileptic encephalopathy, 53STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033362

Submitter: Labcorp Genetics (formerly Invitae)

genetic developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100062

Submitter: ClinGen

SYNJ1 was first reported in relation to autosomal recessive Developmental Epileptic Encephalopathy (DEE) in 2015 (Dyment et al. 2015 PMID: 25316601). Besides DEE, SYNJ1 has been associated with autosomal recessive Parkinson disease, early onset. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in phenotypes of these diseases. Therefore, the following disease entities have been split into two disease entities, Developmental and epileptic encephalopathy (OMIM:617389) and Parkinson disease, early onset (OMIM:615530). The split curation for autosomal recessive Parkinson disease, early onset may be curated by Parkinson disease GCEP. Eight SYNJ1 variants that have been reported in seven probands in five publications have been included in this curation. Typical phenotypes of these probands were neonatal onset seizures, hypotonia, severe to profound global developmental delay, and quadriplegia. Of the seven reported families, five had biallelic loss-of-function variants, and the default point of 1.5 was awarded for each allele, resulting in 15 points. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be LOF. This gene-disease association is also supported by an animal model (PMID: 10535736). The SYNJ1 knockout mice with seizures, failure to thrive, and ataxia, which manifest immediately after birth was given 2 points. In summary, SYNJ1 is definitively associated with autosomal recessive DEE. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

developmental and epileptic encephalopathy, 53STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033362

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 53; Parkinson disease 20, early-onsetAR

Manifestation: Neurologic

Intervention: Neurologic

Rationale: For Parkinson disease 20, response to levodopa has been described

Refs: 23804563; 23804577; 27435091Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SYNJ1 variants in ClinVar

9 Conditions Cataloged
Developmental and epileptic encephalopathy, 53Total: 1092
Early-onset Parkinson disease 20Total: 1091
not providedTotal: 196
Inborn genetic diseasesTotal: 117
not specifiedTotal: 75
SYNJ1-related disorderTotal: 28
Developmental and epileptic encephalopathy, 1Total: 5
Young-onset Parkinson diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_203446.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
7
clinvar
292
clinvar
2
clinvar
 301
missense
2
clinvar
2
clinvar
517
clinvar
26
clinvar
2
clinvar
 549
nonsense
11
clinvar
5
clinvar
2
clinvar
 18
start loss
1
clinvar
 1
frameshift
17
clinvar
5
clinvar
1
clinvar
 23
splice donor/acceptor (+/-2bp)
1
clinvar
10
clinvar
4
clinvar
1
clinvar
 16
Total31225323194908

Highest pathogenic variant AF is 0.000011629148

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 51 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_203446.3RefSeqNP_982271.331MANE Select
ENST00000674351.1EnsemblENSP00000501530.131MANE Select
NM_001160302.2RefSeqNP_001153774.130Standard
NM_001160306.2RefSeqNP_001153778.127Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
synj1Danio rerio

Structure: neuromast hair cell

Quality: amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Inositol phosphate metabolism - Homo sapiens (human)
  • Phosphatidylinositol signaling system - Homo sapiens (human)
  • Phosphatidylinositol Phosphate Metabolism
  • Joubert syndrome
  • EGF-EGFR Signaling Pathway

Biological Process

  • phosphatidylinositol biosynthetic process
  • neurotransmitter transport
  • brain development
  • learning
  • synaptic vesicle priming

Molecular Function

  • RNA binding
  • phosphatidylinositol-3-phosphatase activity
  • phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity
  • SH3 domain binding
  • phosphatidylinositol phosphate 5-phosphatase activity

Cellular Component

  • cytosol
  • microtubule
  • vesicle membrane
  • membrane coat
  • clathrin coat of coated pit

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000433931
Coding exons
32
Length
99291
Individuals with no LoFs
125687
Homozygous LoFs
0
Heterozygous LoFs
61
Defined
125748
p
0.000243
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.256678520.7830.000044610473
Missense (PolyPhen)214356.610.600094369
Synonymous0.4092953040.9700.00001633181
Loss of Function6.611984.50.2250.00000480994

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000560.00055rare
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000220.00022rare
Finnish0.0000950.000092rare
European (Non-Finnish)0.000190.00019rare
South Asian0.000590.00059rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Phosphatase that acts on various phosphoinositides, including phosphatidylinositol 4-phosphate, phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate (PubMed:27435091). Has a role in clathrin-mediated endocytosis (By similarity). Hydrolyzes PIP2 bound to actin regulatory proteins resulting in the rearrangement of actin filaments downstream of tyrosine kinase and ASH/GRB2 (By similarity). {ECO:0000250|UniProtKB:O18964, ECO:0000250|UniProtKB:Q62910, ECO:0000269|PubMed:27435091}.;
Disease
DISEASE: Parkinson disease 20, early-onset (PARK20) [MIM:615530]: An early-onset form of Parkinson disease, a complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. PARK20 is characterized by young adult-onset of parkinsonism. Additional features may include seizures, cognitive decline, abnormal eye movements, and dystonia. {ECO:0000269|PubMed:23804563, ECO:0000269|PubMed:23804577, ECO:0000269|PubMed:27496670}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 53 (EIEE53) [MIM:617389]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE53 inheritance is autosomal recessive. {ECO:0000269|PubMed:27435091}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.121

Intolerance Scores

LoFtool
0.0251
RVIS EVS
0.5
RVIS percentile EVS
79.67

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.988

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerHighMediumHigh
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