SYT1-Associated Neurodevelopmental Disorder

Mendelian MONDO:0033864 Pathograph 8 Show in embeddings browser Neurodevelopmental Disorder

A neurodevelopmental disorder (Baker-Gordon syndrome) caused by de novo heterozygous missense variants in SYT1, which encodes synaptotagmin-1, the presynaptic vesicular calcium sensor for fast, synchronous, calcium-triggered neurotransmitter release. Pathogenic variants cluster in the calcium-binding C2B domain and act by a dominant-negative mechanism, slowing and desynchronizing synaptic vesicle fusion. The clinical syndrome comprises infantile hypotonia, congenital ophthalmic (oculomotor) abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and moderate-to-profound developmental delay, with a distinctive, universal EEG signature of intermittent low-frequency high-amplitude oscillations. Notably, epileptic seizures are characteristically absent — distinguishing it from the epileptic encephalopathies among the synaptic vesicle cycle disorders. It represents the calcium-sensor / fusion arm of the synaptic vesicle cycle.

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1
Inheritance
3
Pathophys.
7
Phenotypes
8
Pathograph
1
Genes
1
Variants
2
Medical Actions
1
Differentials
2
References
👪

Inheritance

1
Autosomal Dominant (De Novo) HP:0000006
The disorder arises from de novo heterozygous SYT1 missense variants acting by a dominant-negative mechanism.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:30107533 SUPPORT Human Clinical
"This paper describes 11 patients with de novo heterozygous missense mutations in SYT1."
Establishes the de novo dominant genetic basis across a patient case series.
⚙

Pathophysiology

3
Dominant-Negative Synaptotagmin-1 C2B Dysfunction
De novo missense variants in SYT1 alter highly conserved residues clustered in the calcium-binding C2B domain of synaptotagmin-1 (e.g. M303K, D304G, D366E, I368T, N371K). Synaptotagmin-1 is the vesicular calcium sensor that couples action-potential calcium influx to synchronous vesicle fusion; the variants act dominant-negatively, with mutant sensor incorporated at nerve terminals impairing wild-type function.
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
Impaired Calcium-Triggered Synchronous Vesicle Fusion
Show evidence (2 references)
PMID:30107533 SUPPORT Human Clinical
"All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K)."
Establishes the C2B calcium-binding-domain clustering of the disease variants.
PMID:25705886 SUPPORT Human Clinical
"Trio analysis of whole-exome sequence identified a de novo SYT1 missense variant (I368T)."
The founding case established a de novo C2B-domain SYT1 missense variant.
Impaired Calcium-Triggered Synchronous Vesicle Fusion
Synaptotagmin-1 is the calcium sensor that triggers fast, synchronous SNARE-mediated vesicle fusion. The dominant-negative C2B variants slow vesicle fusion kinetics and desynchronize evoked neurotransmitter release, degrading the temporal precision of synaptic transmission; the variants also perturb the coupled endocytic retrieval of the sensor. This is the key conformance target of the module — the calcium-sensor/fusion arm.
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.
calcium-dependent activation of synaptic vesicle fusion GO:0099502 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased calcium-dependent activation of synaptic vesicle fusion (GO:0099502). GO:0099502 is a biological process from the Gene Ontology. ↓ DECREASED synaptic vesicle exocytosis GO:0016079 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased synaptic vesicle exocytosis (GO:0016079). GO:0016079 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Disrupted Neurotransmission and Impaired Neurodevelopment
Show evidence (2 references)
PMID:30107533 SUPPORT Human Clinical
"Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis."
Establishes synaptotagmin-1 as the calcium sensor for synchronous fusion, the step impaired by the disease variants.
PMID:25705886 SUPPORT In Vitro
"The presence of the mutant SYT1 slowed synaptic vesicle fusion kinetics, a finding that agrees with the previously demonstrated role for I368 in calcium-dependent membrane penetration."
In vitro neuronal expression shows the disease variant slows calcium-triggered vesicle fusion.
Disrupted Neurotransmission and Impaired Neurodevelopment
Desynchronized, kinetically impaired neurotransmitter release degrades the dynamic fidelity of synaptic transmission, limiting activity-dependent postnatal brain organization. Clinically this produces a hyperkinetic movement disorder, developmental delay/intellectual disability, and a distinctive universal EEG disturbance (intermittent low-frequency high-amplitude oscillations); the severity of the synaptic-kinetic disturbance tracks phenotype severity. Epileptic seizures are characteristically absent.
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
Hyperkinetic Movement Disorder
Neurodevelopmental Delay
EEG Abnormality
Show evidence (1 reference)
PMID:30107533 SUPPORT Human Clinical
"The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals' phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development."
Directly links the degree of synaptic-vesicle-kinetic disturbance to neurodevelopmental phenotype severity.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for SYT1-Associated 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

7
Eye 1
Ophthalmic Abnormality Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30107533 SUPPORT Human Clinical
"Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound."
Documents congenital ophthalmic abnormalities; strabismus (esotropia) was seen in the founding case.
Musculoskeletal 1
Infantile Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30107533 SUPPORT Human Clinical
"Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound."
Documents infantile hypotonia as a core feature.
Nervous System 3
Neurodevelopmental Delay HP:0012758 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurodevelopmental delay (HP:0012758). HP:0012758 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30107533 SUPPORT Human Clinical
"developmental delay varying in severity from moderate to profound."
Documents developmental delay across a moderate-to-profound range.
Sleep Disturbance HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30107533 SUPPORT Human Clinical
"Behavioural characteristics include sleep disturbance and episodic agitation."
Documents sleep disturbance as a behavioural feature.
EEG Abnormality HP:0002353 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EEG abnormality (HP:0002353). HP:0002353 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30107533 SUPPORT Human Clinical
"Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations."
Documents the characteristic universal EEG signature with normal structural MRI.
PMID:25705886 SUPPORT Human Clinical
"Structural MRI was normal, but EEG showed extensive neurophysiological disturbances that included the unusual features of low-frequency oscillatory bursts and enhanced paired-pulse depression of visual evoked potentials."
The founding case documented the low-frequency oscillatory EEG signature with normal MRI.
Other 2
Hyperkinetic Movement Disorder Hyperkinetic movements HP:0002487 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperkinetic movements (HP:0002487). HP:0002487 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30107533 SUPPORT Human Clinical
"Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound."
Documents childhood-onset hyperkinetic movement disorders as a core feature.
PMID:25705886 SUPPORT Human Clinical
"The individual harboring this variant presented with an early onset dyskinetic movement disorder, severe motor delay, and profound cognitive impairment."
The founding case documented an early-onset dyskinetic movement disorder.
Motor Stereotypy HP:0000733 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor stereotypy (HP:0000733). HP:0000733 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30107533 SUPPORT Human Clinical
"childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound."
Documents motor stereotypies as a feature.
🧬

Genetic Associations

1
SYT1 (Dominant-Negative Mutations)
Gene: SYT1 hgnc:11509 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SYT1 (hgnc:11509). hgnc:11509 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Autosomal Dominant (De Novo)
Show evidence (2 references)
PMID:30107533 SUPPORT Human Clinical
"All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K)."
Defines the recurrent C2B-domain variant spectrum.
PMID:25705886 SUPPORT Human Clinical
"Trio analysis of whole-exome sequence identified a de novo SYT1 missense variant (I368T)."
Identification of the founding de novo I368T variant.
Variants (1)
p.Ile368Thr (I368T) Pathogenic
missense
The founding de novo C2B-domain variant, shown in vitro to slow calcium-triggered vesicle fusion by a dominant-negative mechanism.
💊

Medical Actions

2
Supportive and Developmental 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
Management is supportive: developmental therapies, management of the hyperkinetic movement disorder, and treatment of sleep disturbance. No disease-specific therapy corrects the synaptotagmin-1 defect.
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 the de novo dominant mechanism and generally low recurrence risk, with attention to the possibility of parental mosaicism.
🔬

Diagnosis

2
SYT1 Molecular Diagnosis
Diagnosis is established by identifying a de novo heterozygous SYT1 missense variant in the C2B domain in a child with the characteristic syndrome (hypotonia, hyperkinetic movement disorder, ophthalmic abnormalities, developmental delay, and the distinctive EEG signature without seizures).
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: A de novo C2B-domain SYT1 missense variant establishes the diagnosis.
Show evidence (1 reference)
PMID:30107533 SUPPORT Human Clinical
"de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics."
Supports molecular diagnosis combined with the clinical and EEG signature.
EEG Signature Assessment
EEG documents the characteristic intermittent low-frequency high-amplitude oscillations, a supportive diagnostic feature in the absence of overt seizures.
electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Results: Intermittent low-frequency high-amplitude oscillations support the diagnosis.
Show evidence (1 reference)
PMID:30107533 SUPPORT Human Clinical
"Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations."
The universal EEG signature is a supportive diagnostic feature.
📈

Progression

1
Infancy to Childhood
Infantile hypotonia is followed by emergence of a childhood-onset hyperkinetic movement disorder, with developmental delay ranging from moderate to profound; phenotype severity tracks the degree of synaptic-vesicle-kinetic disturbance.
Show evidence (1 reference)
PMID:30107533 SUPPORT Human Clinical
"Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1."
Documents variable severity linked to the specific SYT1 variant.
📊

Prevalence

1
Worldwide
Unknown Ultra Rare
Ultra-rare neurodevelopmental disorder (Baker-Gordon syndrome); precise population prevalence not established.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from SYT1-Associated Neurodevelopmental Disorder:

Epileptic synaptic vesicle cycle disorders (STXBP1, UNC13A, DNM1)
Overlapping Features Other synaptic vesicle cycle disorders (STXBP1, UNC13A, DNM1) present with developmental impairment and movement features but are epileptic encephalopathies; the characteristic absence of seizures and the prominent hyperkinetic movement disorder with distinctive EEG favor SYT1 disease.
Distinguishing Features
  • A de novo C2B-domain SYT1 variant with a hyperkinetic movement disorder and no seizures favors this disorder.
  • Prominent early-onset epilepsy favors an epileptic vesicle-cycle disorder (STXBP1, UNC13A, DNM1).
Show evidence (1 reference)
PMID:30107533 SUPPORT Human Clinical
"Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features."
The absence of seizures is a key discriminator from the epileptic vesicle-cycle encephalopathies.
{ }

Source YAML

click to show 
name: SYT1-Associated Neurodevelopmental Disorder
creation_date: "2026-07-06T00:00:00Z"
description: >-
  A neurodevelopmental disorder (Baker-Gordon syndrome) caused by de novo
  heterozygous missense variants in SYT1, which encodes synaptotagmin-1, the
  presynaptic vesicular calcium sensor for fast, synchronous, calcium-triggered
  neurotransmitter release. Pathogenic variants cluster in the calcium-binding C2B
  domain and act by a dominant-negative mechanism, slowing and desynchronizing
  synaptic vesicle fusion. The clinical syndrome comprises infantile hypotonia,
  congenital ophthalmic (oculomotor) abnormalities, childhood-onset hyperkinetic
  movement disorders, motor stereotypies, and moderate-to-profound developmental
  delay, with a distinctive, universal EEG signature of intermittent low-frequency
  high-amplitude oscillations. Notably, epileptic seizures are characteristically
  absent — distinguishing it from the epileptic encephalopathies among the synaptic
  vesicle cycle disorders. It represents the calcium-sensor / fusion arm of the
  synaptic vesicle cycle.
category: Mendelian
parents:
- Neurodevelopmental Disorder
disease_term:
  preferred_term: Baker-Gordon syndrome
  term:
    id: MONDO:0033864
    label: infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare neurodevelopmental disorder (Baker-Gordon syndrome); precise population prevalence not established.
references:
- reference: PMID:30107533
  title: "SYT1-associated neurodevelopmental disorder: a case series."
- reference: PMID:25705886
  title: "Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling."
inheritance:
- name: Autosomal Dominant (De Novo)
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    The disorder arises from de novo heterozygous SYT1 missense variants acting by
    a dominant-negative mechanism.
  evidence:
  - reference: PMID:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This paper describes 11 patients with de novo heterozygous missense mutations
      in SYT1.
    explanation: >-
      Establishes the de novo dominant genetic basis across a patient case series.
pathophysiology:
- name: Dominant-Negative Synaptotagmin-1 C2B Dysfunction
  conforms_to: "synaptic_vesicle_cycle#Synaptic Vesicle Cycle Protein Deficiency"
  description: >-
    De novo missense variants in SYT1 alter highly conserved residues clustered in
    the calcium-binding C2B domain of synaptotagmin-1 (e.g. M303K, D304G, D366E,
    I368T, N371K). Synaptotagmin-1 is the vesicular calcium sensor that couples
    action-potential calcium influx to synchronous vesicle fusion; the variants act
    dominant-negatively, with mutant sensor incorporated at nerve terminals
    impairing wild-type function.
  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:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All mutations alter highly conserved residues, and cluster in two regions of
      the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366
      (D366E), Ile368 (I368T) and Asn371 (N371K).
    explanation: >-
      Establishes the C2B calcium-binding-domain clustering of the disease variants.
  - reference: PMID:25705886
    reference_title: "Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Trio analysis of whole-exome sequence identified a de novo SYT1 missense
      variant (I368T).
    explanation: >-
      The founding case established a de novo C2B-domain SYT1 missense variant.
  downstream:
  - target: Impaired Calcium-Triggered Synchronous Vesicle Fusion
    causal_link_type: DIRECT
- name: Impaired Calcium-Triggered Synchronous Vesicle Fusion
  conforms_to: "synaptic_vesicle_cycle#Impaired Calcium-Triggered SNARE-Mediated Vesicle Fusion"
  description: >-
    Synaptotagmin-1 is the calcium sensor that triggers fast, synchronous
    SNARE-mediated vesicle fusion. The dominant-negative C2B variants slow vesicle
    fusion kinetics and desynchronize evoked neurotransmitter release, degrading the
    temporal precision of synaptic transmission; the variants also perturb the
    coupled endocytic retrieval of the sensor. This is the key conformance target
    of the module — the calcium-sensor/fusion arm.
  role: central_effector
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: calcium-dependent activation of synaptic vesicle fusion
    term:
      id: GO:0099502
      label: calcium-dependent activation of synaptic vesicle fusion
    modifier: DECREASED
  - preferred_term: synaptic vesicle exocytosis
    term:
      id: GO:0016079
      label: synaptic vesicle exocytosis
    modifier: DECREASED
  evidence:
  - reference: PMID:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous,
      calcium-dependent neurotransmitter release and also modulates synaptic
      vesicle endocytosis.
    explanation: >-
      Establishes synaptotagmin-1 as the calcium sensor for synchronous fusion, the
      step impaired by the disease variants.
  - reference: PMID:25705886
    reference_title: "Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The presence of the mutant SYT1 slowed synaptic vesicle fusion kinetics, a
      finding that agrees with the previously demonstrated role for I368 in
      calcium-dependent membrane penetration.
    explanation: >-
      In vitro neuronal expression shows the disease variant slows calcium-triggered
      vesicle fusion.
  downstream:
  - target: Disrupted Neurotransmission and Impaired Neurodevelopment
    causal_link_type: DIRECT
- name: Disrupted Neurotransmission and Impaired Neurodevelopment
  conforms_to: "synaptic_vesicle_cycle#Neurotransmitter Release Failure and Synaptic Transmission Deficit"
  description: >-
    Desynchronized, kinetically impaired neurotransmitter release degrades the
    dynamic fidelity of synaptic transmission, limiting activity-dependent postnatal
    brain organization. Clinically this produces a hyperkinetic movement disorder,
    developmental delay/intellectual disability, and a distinctive universal EEG
    disturbance (intermittent low-frequency high-amplitude oscillations); the
    severity of the synaptic-kinetic disturbance tracks phenotype severity.
    Epileptic seizures are characteristically absent.
  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:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The extent of disturbance to synaptic vesicle kinetics is mirrored by the
      severity of the affected individuals' phenotypes, suggesting that the
      efficiency of SYT1-mediated neurotransmitter release is critical to cognitive
      development.
    explanation: >-
      Directly links the degree of synaptic-vesicle-kinetic disturbance to
      neurodevelopmental phenotype severity.
  downstream:
  - target: Hyperkinetic Movement Disorder
    causal_link_type: DIRECT
  - target: Neurodevelopmental Delay
    causal_link_type: DIRECT
  - target: EEG Abnormality
    causal_link_type: DIRECT
phenotypes:
- name: Hyperkinetic Movement Disorder
  category: Clinical
  description: >-
    Childhood-onset hyperkinetic movement disorder (dyskinesia including chorea and
    dystonia), a cardinal feature of the syndrome.
  diagnostic: true
  phenotype_term:
    preferred_term: Hyperkinetic movements
    term:
      id: HP:0002487
      label: Hyperkinetic movements
  evidence:
  - reference: PMID:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phenotypic features include infantile hypotonia, congenital ophthalmic
      abnormalities, childhood-onset hyperkinetic movement disorders, motor
      stereotypies, and developmental delay varying in severity from moderate to
      profound.
    explanation: >-
      Documents childhood-onset hyperkinetic movement disorders as a core feature.
  - reference: PMID:25705886
    reference_title: "Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individual harboring this variant presented with an early onset
      dyskinetic movement disorder, severe motor delay, and profound cognitive
      impairment.
    explanation: >-
      The founding case documented an early-onset dyskinetic movement disorder.
- name: Infantile Hypotonia
  category: Clinical
  description: >-
    Infantile hypotonia is a consistent early feature.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phenotypic features include infantile hypotonia, congenital ophthalmic
      abnormalities, childhood-onset hyperkinetic movement disorders, motor
      stereotypies, and developmental delay varying in severity from moderate to
      profound.
    explanation: >-
      Documents infantile hypotonia as a core feature.
- name: Ophthalmic Abnormality
  category: Clinical
  description: >-
    Congenital ophthalmic (oculomotor) abnormalities, such as strabismus, are part
    of the recognizable syndrome.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phenotypic features include infantile hypotonia, congenital ophthalmic
      abnormalities, childhood-onset hyperkinetic movement disorders, motor
      stereotypies, and developmental delay varying in severity from moderate to
      profound.
    explanation: >-
      Documents congenital ophthalmic abnormalities; strabismus (esotropia) was
      seen in the founding case.
- name: Motor Stereotypy
  category: Clinical
  description: >-
    Motor stereotypies are a recognized feature.
  phenotype_term:
    preferred_term: Motor stereotypy
    term:
      id: HP:0000733
      label: Motor stereotypy
  evidence:
  - reference: PMID:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      childhood-onset hyperkinetic movement disorders, motor stereotypies, and
      developmental delay varying in severity from moderate to profound.
    explanation: >-
      Documents motor stereotypies as a feature.
- name: Neurodevelopmental Delay
  category: Clinical
  description: >-
    Developmental delay/intellectual disability varying in severity from moderate to
    profound.
  diagnostic: true
  phenotype_term:
    preferred_term: Neurodevelopmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: PMID:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developmental delay varying in severity from moderate to profound.
    explanation: >-
      Documents developmental delay across a moderate-to-profound range.
- name: Sleep Disturbance
  category: Clinical
  description: >-
    Behavioural features include sleep disturbance and episodic agitation.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Behavioural characteristics include sleep disturbance and episodic agitation.
    explanation: >-
      Documents sleep disturbance as a behavioural feature.
- name: EEG Abnormality
  category: Clinical
  description: >-
    A universal EEG disturbance characterized by intermittent low-frequency
    high-amplitude oscillations, in the setting of a structurally normal MRI.
  diagnostic: true
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  evidence:
  - reference: PMID:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Structural MRI is unremarkable but EEG disturbance is universal,
      characterized by intermittent low frequency high amplitude oscillations.
    explanation: >-
      Documents the characteristic universal EEG signature with normal structural
      MRI.
  - reference: PMID:25705886
    reference_title: "Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Structural MRI was normal, but EEG showed extensive neurophysiological
      disturbances that included the unusual features of low-frequency oscillatory
      bursts and enhanced paired-pulse depression of visual evoked potentials.
    explanation: >-
      The founding case documented the low-frequency oscillatory EEG signature with
      normal MRI.
genetic:
- name: SYT1
  gene_term:
    preferred_term: SYT1
    term:
      id: hgnc:11509
      label: SYT1
  association: Dominant-Negative Mutations
  presence: Positive
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal Dominant (De Novo)
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    De novo heterozygous missense variants clustering in the calcium-binding C2B
    domain (e.g. M303K, D304G, D366E, I368T, N371K) act by a dominant-negative
    mechanism on the synaptotagmin-1 calcium sensor.
  variants:
  - name: "p.Ile368Thr (I368T)"
    description: >-
      The founding de novo C2B-domain variant, shown in vitro to slow
      calcium-triggered vesicle fusion by a dominant-negative mechanism.
    type: missense
    clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All mutations alter highly conserved residues, and cluster in two regions of
      the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366
      (D366E), Ile368 (I368T) and Asn371 (N371K).
    explanation: >-
      Defines the recurrent C2B-domain variant spectrum.
  - reference: PMID:25705886
    reference_title: "Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Trio analysis of whole-exome sequence identified a de novo SYT1 missense
      variant (I368T).
    explanation: >-
      Identification of the founding de novo I368T variant.
diagnosis:
- name: SYT1 Molecular Diagnosis
  description: >-
    Diagnosis is established by identifying a de novo heterozygous SYT1 missense
    variant in the C2B domain in a child with the characteristic syndrome
    (hypotonia, hyperkinetic movement disorder, ophthalmic abnormalities,
    developmental delay, and the distinctive EEG signature without seizures).
  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: SYT1
        term:
          id: hgnc:11509
          label: SYT1
  results: A de novo C2B-domain SYT1 missense variant establishes the diagnosis.
  evidence:
  - reference: PMID:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      de novo dominant SYT1 missense mutations are associated with a recognizable
      neurodevelopmental syndrome, and further cases can now be diagnosed based on
      clinical features, electrophysiological signature and mutation
      characteristics.
    explanation: >-
      Supports molecular diagnosis combined with the clinical and EEG signature.
- name: EEG Signature Assessment
  description: >-
    EEG documents the characteristic intermittent low-frequency high-amplitude
    oscillations, a supportive diagnostic feature in the absence of overt seizures.
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  results: Intermittent low-frequency high-amplitude oscillations support the diagnosis.
  evidence:
  - reference: PMID:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Structural MRI is unremarkable but EEG disturbance is universal,
      characterized by intermittent low frequency high amplitude oscillations.
    explanation: >-
      The universal EEG signature is a supportive diagnostic feature.
differential_diagnoses:
- name: Epileptic synaptic vesicle cycle disorders (STXBP1, UNC13A, DNM1)
  description: >-
    Other synaptic vesicle cycle disorders (STXBP1, UNC13A, DNM1) present with
    developmental impairment and movement features but are epileptic
    encephalopathies; the characteristic absence of seizures and the prominent
    hyperkinetic movement disorder with distinctive EEG favor SYT1 disease.
  distinguishing_features:
  - A de novo C2B-domain SYT1 variant with a hyperkinetic movement disorder and no seizures favors this disorder.
  - Prominent early-onset epilepsy favors an epileptic vesicle-cycle disorder (STXBP1, UNC13A, DNM1).
  evidence:
  - reference: PMID:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Absence of epileptic seizures and normal orbitofrontal head circumference are
      important negative features.
    explanation: >-
      The absence of seizures is a key discriminator from the epileptic vesicle-cycle
      encephalopathies.
progression:
- phase: Infancy to Childhood
  notes: >-
    Infantile hypotonia is followed by emergence of a childhood-onset hyperkinetic
    movement disorder, with developmental delay ranging from moderate to profound;
    phenotype severity tracks the degree of synaptic-vesicle-kinetic disturbance.
  evidence:
  - reference: PMID:30107533
    reference_title: "SYT1-associated neurodevelopmental disorder: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variation in phenotype severity may reflect mutation-specific impact on the
      diverse physiological functions of SYT1.
    explanation: >-
      Documents variable severity linked to the specific SYT1 variant.
treatments:
- name: Supportive and Developmental Care
  description: >-
    Management is supportive: developmental therapies, management of the
    hyperkinetic movement disorder, and treatment of sleep disturbance. No
    disease-specific therapy corrects the synaptotagmin-1 defect.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic Counseling
  description: >-
    Genetic counseling addresses the de novo dominant mechanism and generally low
    recurrence risk, with attention to the possibility of parental mosaicism.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
📚

References & Deep Research

References

2
PMID:30107533
SYT1-associated neurodevelopmental disorder: a case series.
No top-level findings curated for this source.
PMID:25705886
Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling.
No top-level findings curated for this source.