SYN1-Related Neurodevelopmental Disorder

Mendelian MONDO:0010339 Pathograph 6 Show in embeddings browser Neurodevelopmental Disorder

An X-linked neurodevelopmental disorder caused by loss-of-function variants in SYN1, which encodes synapsin-1, a neuron-specific presynaptic phosphoprotein that tethers synaptic vesicles into the reserve pool and regulates neurotransmitter release and synaptogenesis. Loss of synapsin-1 function reduces the size and trafficking of synaptic vesicle pools, disturbing synaptic homeostasis. Affected males (and some carrier females) present with epilepsy — characteristically focal (partial) — and autism spectrum disorder, with variable learning disabilities and behavioral problems. It represents the vesicle-clustering / reserve-pool arm of the synaptic vesicle cycle, upstream of the docking, priming, and fusion steps disrupted in the other synaptic vesicle cycle disorders.

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1
Inheritance
2
Pathophys.
2
Phenotypes
6
Pathograph
1
Genes
1
Variants
3
Medical Actions
1
Differentials
1
References
👪

Inheritance

1
X-linked HP:0001417
SYN1 is an X-linked gene; hemizygous males are typically affected, with variable expression in carrier females.
X-linked inheritance
Show evidence (1 reference)
PMID:21441247 SUPPORT Human Clinical
"Here we report a Q555X mutation in synapsin 1 (SYN1), an X-linked gene encoding for a neuron-specific phosphoprotein implicated in the regulation of neurotransmitter release and synaptogenesis."
Establishes the X-linked inheritance and the synapsin-1 gene product.
⚙

Pathophysiology

2
Synapsin-1 Loss of Function and Impaired Vesicle Clustering
Synapsin-1 is a neuron-specific phosphoprotein that reversibly tethers synaptic vesicles to the actin cytoskeleton, clustering them into the reserve pool and regulating their mobilization for release. Loss-of-function variants (a Q555X nonsense variant and proline-rich D-domain missense variants) impair this function: in synapsin-1 knockout neurons the disease variants fail to rescue the reduced size and trafficking of synaptic vesicle pools, disturbing synaptic homeostasis.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
synaptic vesicle cycle GO:0099504 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal synaptic vesicle cycle (GO:0099504). GO:0099504 is a biological process from the Gene Ontology. ⚠ ABNORMAL
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Disturbed Neurotransmitter Release and Synaptic Homeostasis
Show evidence (1 reference)
PMID:21441247 SUPPORT In Vitro
"all the D-domain mutants failed in rescuing the impairment in the size and trafficking of synaptic vesicle pools, whereas the wild-type human SynI fully reverted the KO phenotype."
Demonstrates that the disease variants impair synapsin-1's clustering/ reserve-pool function on synaptic vesicle pools.
Disturbed Neurotransmitter Release and Synaptic Homeostasis
Reduced reserve-pool vesicle availability and impaired mobilization dysregulate neurotransmitter release and disturb synaptic homeostasis. This imbalance in cortical synaptic transmission is proposed to underlie both the epilepsy and the autism spectrum phenotype of SYN1 disease.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
neurotransmitter secretion GO:0007269 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal neurotransmitter secretion (GO:0007269). GO:0007269 is a biological process from the Gene Ontology. ⚠ ABNORMAL chemical synaptic transmission GO:0007268 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chemical synaptic transmission (GO:0007268). GO:0007268 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Epilepsy
Autism Spectrum Disorder
Show evidence (1 reference)
PMID:21441247 SUPPORT Human Clinical
"These results demonstrate that SYN1 is a novel predisposing gene to ASDs, in addition to epilepsy, and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies the pathogenesis of both diseases."
Links the synaptic-homeostasis disturbance to both the epilepsy and the autism phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for SYN1-Related Neurodevelopmental Disorder Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

2
Epilepsy Clinical HP:0007359 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal-onset seizure (HP:0007359). HP:0007359 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21441247 SUPPORT Human Clinical
"SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function."
Identifies partial (focal) epilepsy as a core phenotype of SYN1 disease.
Autism Spectrum Disorder Clinical HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21441247 SUPPORT Human Clinical
"This nonsense mutation was found in all affected individuals from a large French-Canadian family segregating epilepsy and ASDs."
Documents autism spectrum disorder co-segregating with epilepsy in the SYN1 family.
🧬

Genetic Associations

1
SYN1 (Loss-of-Function Mutations)
Gene: SYN1 hgnc:11494 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SYN1 (hgnc:11494). hgnc:11494 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
X-linked
Show evidence (1 reference)
PMID:21441247 SUPPORT Human Clinical
"Additional mutations in SYN1 (A51G, A550T and T567A) were found in 1.0 and 3.5% of French-Canadian individuals with autism and epilepsy, respectively."
Defines the additional D-domain variant spectrum beyond the founding Q555X variant.
Variants (1)
p.Gln555* (Q555X) Pathogenic
nonsense
Nonsense variant segregating in a large French-Canadian family with epilepsy and autism; impairs MAPK/Erk phosphorylation and neurite outgrowth.
💊

Medical Actions

3
Antiseizure Medication
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: levetiracetam CHEBI:6437 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levetiracetam (CHEBI:6437). CHEBI:6437 is a therapeutic agent from Chemical Entities of Biological Interest.
Focal epilepsy is managed with antiseizure medications.
Supportive and Behavioral Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Developmental, educational, and behavioral support address the autism and learning/behavioral components.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling addresses X-linked inheritance and recurrence risk, including variable expression in carrier females.
🔬

Diagnosis

1
SYN1 Molecular Diagnosis
Diagnosis is established by identifying a hemizygous (males) or heterozygous (females) pathogenic SYN1 loss-of-function variant in an individual with epilepsy and/or autism spectrum disorder.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: A pathogenic SYN1 loss-of-function variant establishes the diagnosis.
Show evidence (1 reference)
PMID:21441247 SUPPORT Human Clinical
"Here we report a Q555X mutation in synapsin 1 (SYN1), an X-linked gene encoding for a neuron-specific phosphoprotein implicated in the regulation of neurotransmitter release and synaptogenesis."
Molecular identification of a SYN1 variant established the disorder.
📊

Prevalence

1
Worldwide
Unknown Ultra Rare
Rare X-linked disorder of synaptic vesicle clustering; precise population prevalence not established.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from SYN1-Related Neurodevelopmental Disorder:

Other synaptic vesicle cycle disorders
Overlapping Features Other synaptic vesicle cycle disorders (STXBP1, UNC13A, SNAP25, DNM1, SYT1) present with epilepsy and neurodevelopmental impairment; SYN1 disease is distinguished by X-linked inheritance and the prominent autism/epilepsy combination without a severe neonatal epileptic encephalopathy.
Distinguishing Features
  • An X-linked SYN1 loss-of-function variant with focal epilepsy and autism favors this disorder.
  • A de novo variant in another vesicle-cycle gene favors that diagnosis.
{ }

Source YAML

click to show 
name: SYN1-Related Neurodevelopmental Disorder
creation_date: "2026-07-06T00:00:00Z"
description: >-
  An X-linked neurodevelopmental disorder caused by loss-of-function variants in
  SYN1, which encodes synapsin-1, a neuron-specific presynaptic phosphoprotein that
  tethers synaptic vesicles into the reserve pool and regulates neurotransmitter
  release and synaptogenesis. Loss of synapsin-1 function reduces the size and
  trafficking of synaptic vesicle pools, disturbing synaptic homeostasis. Affected
  males (and some carrier females) present with epilepsy — characteristically focal
  (partial) — and autism spectrum disorder, with variable learning disabilities and
  behavioral problems. It represents the vesicle-clustering / reserve-pool arm of
  the synaptic vesicle cycle, upstream of the docking, priming, and fusion steps
  disrupted in the other synaptic vesicle cycle disorders.
category: Mendelian
parents:
- Neurodevelopmental Disorder
disease_term:
  preferred_term: SYN1-related X-linked epilepsy with variable learning disabilities and behavior disorders
  term:
    id: MONDO:0010339
    label: epilepsy, X-linked 1, with variable learning disabilities and behavior disorders
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: ULTRA_RARE
  notes: >-
    Rare X-linked disorder of synaptic vesicle clustering; precise population prevalence not established.
references:
- reference: PMID:21441247
  title: "SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function."
inheritance:
- name: X-linked
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  description: >-
    SYN1 is an X-linked gene; hemizygous males are typically affected, with
    variable expression in carrier females.
  evidence:
  - reference: PMID:21441247
    reference_title: "SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a Q555X mutation in synapsin 1 (SYN1), an X-linked gene
      encoding for a neuron-specific phosphoprotein implicated in the regulation of
      neurotransmitter release and synaptogenesis.
    explanation: >-
      Establishes the X-linked inheritance and the synapsin-1 gene product.
pathophysiology:
- name: Synapsin-1 Loss of Function and Impaired Vesicle Clustering
  conforms_to: "synaptic_vesicle_cycle#Synaptic Vesicle Cycle Protein Deficiency"
  description: >-
    Synapsin-1 is a neuron-specific phosphoprotein that reversibly tethers synaptic
    vesicles to the actin cytoskeleton, clustering them into the reserve pool and
    regulating their mobilization for release. Loss-of-function variants (a Q555X
    nonsense variant and proline-rich D-domain missense variants) impair this
    function: in synapsin-1 knockout neurons the disease variants fail to rescue the
    reduced size and trafficking of synaptic vesicle pools, disturbing synaptic
    homeostasis.
  role: trigger
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: synaptic vesicle cycle
    term:
      id: GO:0099504
      label: synaptic vesicle cycle
    modifier: ABNORMAL
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:21441247
    reference_title: "SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      all the D-domain mutants failed in rescuing the impairment in the size and
      trafficking of synaptic vesicle pools, whereas the wild-type human SynI fully
      reverted the KO phenotype.
    explanation: >-
      Demonstrates that the disease variants impair synapsin-1's clustering/
      reserve-pool function on synaptic vesicle pools.
  downstream:
  - target: Disturbed Neurotransmitter Release and Synaptic Homeostasis
    causal_link_type: DIRECT
- name: Disturbed Neurotransmitter Release and Synaptic Homeostasis
  conforms_to: "synaptic_vesicle_cycle#Neurotransmitter Release Failure and Synaptic Transmission Deficit"
  description: >-
    Reduced reserve-pool vesicle availability and impaired mobilization dysregulate
    neurotransmitter release and disturb synaptic homeostasis. This imbalance in
    cortical synaptic transmission is proposed to underlie both the epilepsy and the
    autism spectrum phenotype of SYN1 disease.
  role: effector
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neurotransmitter secretion
    term:
      id: GO:0007269
      label: neurotransmitter secretion
    modifier: ABNORMAL
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: ABNORMAL
  evidence:
  - reference: PMID:21441247
    reference_title: "SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results demonstrate that SYN1 is a novel predisposing gene to ASDs, in
      addition to epilepsy, and strengthen the hypothesis that a disturbance of
      synaptic homeostasis underlies the pathogenesis of both diseases.
    explanation: >-
      Links the synaptic-homeostasis disturbance to both the epilepsy and the
      autism phenotype.
  downstream:
  - target: Epilepsy
    causal_link_type: DIRECT
  - target: Autism Spectrum Disorder
    causal_link_type: DIRECT
phenotypes:
- name: Epilepsy
  category: Clinical
  description: >-
    Epilepsy, characteristically focal (partial), segregating with SYN1 variants.
  diagnostic: true
  phenotype_term:
    preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: PMID:21441247
    reference_title: "SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired
      synaptic function.
    explanation: >-
      Identifies partial (focal) epilepsy as a core phenotype of SYN1 disease.
- name: Autism Spectrum Disorder
  category: Clinical
  description: >-
    Autism spectrum disorder co-occurs with epilepsy in affected individuals.
  diagnostic: true
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:21441247
    reference_title: "SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This nonsense mutation was found in all affected individuals from a large
      French-Canadian family segregating epilepsy and ASDs.
    explanation: >-
      Documents autism spectrum disorder co-segregating with epilepsy in the
      SYN1 family.
genetic:
- name: SYN1
  gene_term:
    preferred_term: SYN1
    term:
      id: hgnc:11494
      label: SYN1
  association: Loss-of-Function Mutations
  presence: Positive
  variant_origin: GERMLINE
  inheritance:
  - name: X-linked
    inheritance_term:
      preferred_term: X-linked inheritance
      term:
        id: HP:0001417
        label: X-linked inheritance
  notes: >-
    A Q555X nonsense variant and proline-rich D-domain missense variants (A51G,
    A550T, T567A) have been reported; the D-domain is a substrate of multiple
    protein kinases regulating synapsin function.
  variants:
  - name: "p.Gln555* (Q555X)"
    description: >-
      Nonsense variant segregating in a large French-Canadian family with epilepsy
      and autism; impairs MAPK/Erk phosphorylation and neurite outgrowth.
    type: nonsense
    clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:21441247
    reference_title: "SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional mutations in SYN1 (A51G, A550T and T567A) were found in 1.0 and
      3.5% of French-Canadian individuals with autism and epilepsy, respectively.
    explanation: >-
      Defines the additional D-domain variant spectrum beyond the founding Q555X
      variant.
diagnosis:
- name: SYN1 Molecular Diagnosis
  description: >-
    Diagnosis is established by identifying a hemizygous (males) or heterozygous
    (females) pathogenic SYN1 loss-of-function variant in an individual with
    epilepsy and/or autism spectrum disorder.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: SYN1
        term:
          id: hgnc:11494
          label: SYN1
  results: A pathogenic SYN1 loss-of-function variant establishes the diagnosis.
  evidence:
  - reference: PMID:21441247
    reference_title: "SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a Q555X mutation in synapsin 1 (SYN1), an X-linked gene
      encoding for a neuron-specific phosphoprotein implicated in the regulation of
      neurotransmitter release and synaptogenesis.
    explanation: >-
      Molecular identification of a SYN1 variant established the disorder.
differential_diagnoses:
- name: Other synaptic vesicle cycle disorders
  description: >-
    Other synaptic vesicle cycle disorders (STXBP1, UNC13A, SNAP25, DNM1, SYT1)
    present with epilepsy and neurodevelopmental impairment; SYN1 disease is
    distinguished by X-linked inheritance and the prominent autism/epilepsy
    combination without a severe neonatal epileptic encephalopathy.
  distinguishing_features:
  - An X-linked SYN1 loss-of-function variant with focal epilepsy and autism favors this disorder.
  - A de novo variant in another vesicle-cycle gene favors that diagnosis.
treatments:
- name: Antiseizure Medication
  description: >-
    Focal epilepsy is managed with antiseizure medications.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
- name: Supportive and Behavioral Care
  description: >-
    Developmental, educational, and behavioral support address the autism and
    learning/behavioral components.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic Counseling
  description: >-
    Genetic counseling addresses X-linked inheritance and recurrence risk,
    including variable expression in carrier females.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
📚

References & Deep Research

References

1
PMID:21441247
SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function.
No top-level findings curated for this source.