VAMP2-Related Neurodevelopmental Disorder

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Inheritance

1

Autosomal Dominant (De Novo) HP:0000006

The disorder arises from de novo heterozygous VAMP2 variants.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:30929742 SUPPORT Human Clinical

"Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features."

Establishes the de novo dominant genetic basis and core phenotype.

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Mechanistic Hypotheses

2

Dominant-negative interference by SNARE-motif missense variants

dominant_negative_snare_interference CANONICAL

Evidence balance 3 support

SNARE-motif missense variants encode a stable protein that is incorporated into SNARE complexes but assembles or zippers defectively, poisoning complexes that also contain wild-type VAMP2. The decisive experiment is the 50:50 wild-type:mutant liposome, whose fusion profile matched pure mutant rather than falling halfway — reduced dose alone cannot produce that. This is the better-evidenced arm and accounts for dominant inheritance. PMID:32906212 associates the two dominant-negatively acting missense variants it tested, p.Gly73Trp and p.Arg56Leu, with a more severe phenotype including epilepsy — but epilepsy does not track the C-terminal cluster itself: the p.Ser75Pro carrier had no seizures while a p.Val43del carrier did, so severity and epilepsy are curated separately from cluster membership.

Pathograph links

VAMP2 v-SNARE Defect -> Dominant-Negative Interference with Wild-Type VAMP2 DIRECT Route taken by SNARE-motif missense variants, which produce a stable protein that is incorporated into SNARE complexes.

Dominant-Negative Interference with Wild-Type VAMP2 -> Impaired SNARE-Mediated Vesicle Fusion DIRECT

Show evidence (3 references)

PMID:30929742 SUPPORT In Vitro

"This implies that p.Ser75Pro mutant dominantly interferes with WT"

The authors' conclusion from the mixed-liposome experiment. Note this variant's carrier had no epileptic seizures, which is why this hypothesis is not curated as explaining an epilepsy phenotype.

PMID:30929742 SUPPORT Human Clinical

"Individual 1 did not present with epileptic seizures"

Bounds this hypothesis: the carrier of the variant whose dominant-negative effect is the decisive experiment had no seizures.

PMID:32906212 SUPPORT In Vitro

"exert a dominant-negative effect on action potential-triggered SV fusion and neurotransmitter release in vitro"

Independent replication in neurons for additional missense variants (p.Gly73Trp, p.Arg56Leu), which are the variants the source ties to the more severe epilepsy-bearing phenotype — not the C-terminal cluster as such.

Haploinsufficiency from truncating loss-of-function variants

truncating_haploinsufficiency ALTERNATIVE

Evidence balance 2 support

Truncating variants act by reduced gene dose rather than by poisoning the complex: nonsense-mediated decay removes the mutant transcript and the truncated protein does not interfere with wild-type VAMP2 in cellular assays. Curated as ALTERNATIVE rather than a competing account of the same variants — the two arms are proposed for different allelic classes, and the phenotypic correlate is real (the truncating carrier was milder and had no epilepsy). It is the weaker arm on three counts: nonsense-mediated decay is predicted, not measured; the absent dominant-negative effect may be an artifact of a construct lacking the transmembrane domain and was not directly tested; and mouse Vamp2 heterozygous loss of function is reported to cause only a mild phenotype, which a pure gene-dose mechanism has to explain away.

Pathograph links

VAMP2 v-SNARE Defect -> VAMP2 Haploinsufficiency DIRECT Route proposed for truncating variants, where nonsense-mediated decay of the mutant transcript leaves a single functional allele.

VAMP2 Haploinsufficiency -> Impaired SNARE-Mediated Vesicle Fusion DIRECT

Show evidence (2 references)

PMID:32906212 SUPPORT INDIRECT In Vitro

"does not cause dominant-negative effects, suggesting that haploinsufficiency underlies the disease mechanism for the R56X variant patient"

The in vitro basis of the haploinsufficiency proposal. Graded INDIRECT because the authors state the dominant-negative effect was not directly tested.

PMID:32906212 SUPPORT In Vitro

"Although not directly tested, this variant could also result in a dominant negative effect."

The authors' explicit caveat that the haploinsufficiency attribution is not exclusive — kept on the hypothesis it qualifies.

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Discussions and Knowledge Gaps

2

Why is p.Glu78Ala pathogenic in patients when its reconstituted fusion profile is indistinguishable from wild-type and it remains fully Munc18-1-activatable — does it act through a regulatory protein absent from the assay (synaptotagmin-1, complexin, Munc13), and does the same apply to the untested p.Phe77Ser?

KNOWLEDGE GAP OPEN gap_vamp2_glu78ala_no_fusion_defect

Attached to

pathophysiology#Impaired SNARE-Mediated Vesicle Fusion

The entry asserts impaired SNARE-mediated fusion as its central effector, but the assay supporting that node returned a clear defect for only one of the two variants it could test. A third could not be purified. Treating "disease variants impair fusion" as settled across the allelic series would overstate the evidence, and the alternative the authors themselves propose — disrupted binding to regulatory elements such as Munc18-1 or synaptotagmin — predicts different therapeutic leverage. Until this is resolved, the fusion node is curated as variant-specific.

Proposed experiments

Reconstituted fusion with the full regulatory complement

exp_vamp2_glu78ala_full_regulatory_fusion

Repeat the lipid-mixing assay for p.Glu78Ala with synaptotagmin-1, complexin, and Munc13 included, under calcium triggering, and compare with wild-type.

Supporting outcome

A calcium-triggered release defect appearing only when regulatory proteins are present would support the regulatory-interaction mechanism.

Refuting outcome

A normal profile even with the full regulatory complement would leave p.Glu78Ala pathogenicity unexplained by any fusion-step mechanism.

Show evidence (1 reference)

PMID:30929742 SUPPORT In Vitro

"The pathophysiological phenotype for the p.Glu78Ala variant might be due to impaired interactions with regulatory proteins that were not included in the in vitro assay."

The authors' own statement of the gap and of the leading candidate explanation.

How far does the homozygous Vamp2-null mouse, which dies immediately after birth, inform a human disorder caused by heterozygous missense and truncating variants in surviving children with a graded genotype-phenotype correlation?

HUMAN MODEL MISMATCH OPEN mismatch_vamp2_null_mouse_vs_human_heterozygote

Attached to

pathophysiology#Impaired SNARE-Mediated Vesicle Fusion pathophysiology#VAMP2 Haploinsufficiency pathophysiology#Impaired Synaptic Vesicle Endocytosis and Recycling

The knockout supplies the strongest causal evidence that VAMP2 is required for fast calcium-triggered fusion and for fast endocytosis, and the entry relies on it for both. But it models neither human allelic class: it removes the protein entirely, so it cannot exhibit dominant-negative interference, which requires mutant protein to be present, and it is homozygous and perinatally lethal, whereas affected humans are heterozygous and survive into adolescence with variable severity. The mismatch cuts against the haploinsufficiency arm specifically: mouse Vamp2 heterozygous loss of function is reported to cause only a mild phenotype, whereas the humans proposed to have a haploinsufficiency mechanism have a neurodevelopmental disorder. No knock-in of a human SNARE-motif variant has been reported, so the dominant-negative arm has never been tested in vivo at all. Separately, the one direct test of endocytosis in human variant-expressing neurons was negative, while the endocytic requirement is well established in the null mouse — so the recycling node's species evidence and its human evidence disagree.

Proposed experiments

Knock-in mouse carrying a human SNARE-motif variant

exp_vamp2_snare_motif_knockin_mouse

Generate and characterize knock-in mice carrying a human SNARE-motif missense variant (e.g. p.Ser75Pro) and a truncating variant, benchmarked against the already-reported heterozygous null, comparing survival, evoked release, endocytosis, and behaviour.

Supporting outcome

A missense knock-in more severely affected than the reported mild heterozygous null phenotype would confirm dominant-negative action in vivo and validate the two-arm model.

Refuting outcome

A missense knock-in no worse than the heterozygous null would argue that reduced dose accounts for both allelic classes and that the dominant-negative arm is an in vitro artifact.

Show evidence (3 references)

PMID:30929742 SUPPORT Model Organism

"mice present severely decreased rates of both spontaneous and Ca2+-triggered synaptic-vesicle fusion, and these mice die immediately after birth."

Establishes both the model's informativeness and the perinatal lethality that limits its translational reach.

PMID:32906212 SUPPORT Model Organism

"while VAMP2 heterozygosity loss of function in mice causes only a mild phenotype"

The heterozygous mouse — the genotype that actually matches the human truncating carriers — is only mildly affected, which is the substance of the mismatch for the haploinsufficiency arm.

PMID:32906212 SUPPORT In Vitro

"The post-stimulus fluorescence decay of syp-pH, representing endocytosis, is not significantly altered by any of the VAMP2 variants compared to WT"

The human-versus-mouse disagreement on the endocytic arm, recorded here because it is the same translational-validity question.

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Pathophysiology

6

VAMP2 v-SNARE Defect

De novo variants affect conserved residues of the VAMP2 SNARE motif (residues 31-91) — the region whose zippering with syntaxin-1 and SNAP-25 provides the energy for membrane fusion. Three allelic classes are reported — a scheme that is the literature's and not exhaustive, since a de novo start-loss variant (c.1A>G, p.Met1?) fits none of them: non-synonymous variants within the motif, of which the three index-cohort variants (p.Ser75Pro, p.Phe77Ser, p.Glu78Ala) cluster in its C-terminal portion, with p.Gly73Trp reported adjacent to that cluster and p.Arg56Leu, p.Arg66Pro and p.Ala67Pro lying further N-terminally; in-frame single-amino-acid deletions at more N-terminal residues (p.Val43del, p.Ile45del); and truncating loss-of-function variants (p.Arg56*, p.Tyr113Glnfs*12). VAMP2 is the vesicle-associated (v-)SNARE essential for vesicular exocytosis and activity-dependent neurotransmitter release, so these variants act directly on the fusion machinery. The downstream route differs by allelic class: SNARE-motif missense variants act dominant-negatively, whereas truncating variants are proposed to act through haploinsufficiency.

Dominant-negative interference by SNARE-motif missense variants Haploinsufficiency from truncating loss-of-function variants

neuron CL:0000540

synaptic vesicle cycle GO:0099504 ⚠ ABNORMAL

brain UBERON:0000955

Downstream

Dominant-Negative Interference with Wild-Type VAMP2 Route taken by SNARE-motif missense variants, which produce a stable protein that is incorporated into SNARE complexes.

Impaired Synaptic Vesicle Endocytosis and Recycling A parallel arm, not a consequence of the fusion defect. VAMP2 is separately required for fast endocytic retrieval, so loss of the protein degrades both halves of the vesicle cycle independently. Drawn from the trigger rather than from the fusion node because the cited evidence establishes shared dependence on one protein, not that impaired fusion causes impaired retrieval — and because the module places endocytosis upstream of fusion, so a fusion-to-endocytosis edge would invert it.

VAMP2 Haploinsufficiency Route proposed for truncating variants, where nonsense-mediated decay of the mutant transcript leaves a single functional allele.

Show evidence (3 references)

PMID:30929742 SUPPORT Other

"VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2)."

Identifies VAMP2/synaptobrevin-2 as the vesicular SNARE whose defect defines this disorder. Definitional background rather than a study result, hence OTHER.

PMID:30929742 SUPPORT Human Clinical

"In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif."

Defines the variant spectrum of the index cohort and localizes the lesion to the fusion machinery. Note this abstract sentence lumps all five variants as C-terminal; the discussion is more precise, and the genetic section records that the two deletions sit at residues 43 and 45.

PMID:37901860 SUPPORT Human Clinical

"To date, only three types of allelic variants (loss of function, in-frame deletions, and missense variants) in the VAMP2 gene have been previously reported in 11 patients with learning difficulties."

Establishes that the allelic series comprises three classes, including truncating loss-of-function variants beyond the original missense and in-frame-deletion spectrum.

Dominant-Negative Interference with Wild-Type VAMP2

SNARE-motif missense variants produce a protein that is still incorporated into the SNARE complex but assembles or zippers defectively, so the mutant poisons complexes that also contain wild-type VAMP2. In the reconstituted fusion assay, liposomes carrying a 50:50 mixture of wild-type and p.Ser75Pro VAMP2 fused no better than liposomes carrying mutant protein alone — the signature of dominant-negative action, and a direct explanation for dominant inheritance of a heterozygous variant. Cellular assays extend this to p.Gly73Trp and p.Arg56Leu, which reduce action-potential-triggered vesicle fusion and are associated with the more severe, epilepsy-bearing phenotype.

Dominant-negative interference by SNARE-motif missense variants

neuron CL:0000540

Experimental models

Variant-expressing cultured neurons with synaptophysin-pHluorin imaging PRIMARY CELL CULTURE Distinguishes SNARE-motif missense variants, which suppress action-potential-triggered fusion in the presence of endogenous wild-type VAMP2, from the nonsense variant, which does not.

Downstream

Impaired SNARE-Mediated Vesicle Fusion

Show evidence (2 references)

PMID:30929742 SUPPORT In Vitro

"in the case of p.Ser75Pro, the fusion profile for the mixed v-liposomes (50:50 WT:mutant) was identical to the fusion profile for the homogenous samples containing only the mutant proteins"

The mixed-liposome experiment is the direct demonstration of dominant-negative interference, deliberately designed to emulate the heterozygous state.

PMID:32906212 SUPPORT In Vitro

"exert a dominant-negative effect on action potential-triggered SV fusion and neurotransmitter release in vitro"

Independent replication of dominant-negative action for further SNARE-motif missense variants, in neurons rather than liposomes.

VAMP2 Haploinsufficiency

Truncating variants (p.Arg56*, p.Tyr113Glnfs*12) are predicted to trigger nonsense-mediated decay, leaving a single functional VAMP2 allele. Unlike the missense variants, the truncated protein did not interfere with wild-type VAMP2 in cellular assays, so reduced gene dose rather than poisoning of the complex is the proposed mechanism. VAMP2 is strongly constrained in population databases, consistent with intolerance to loss of function. Two caveats keep this arm weaker than the dominant-negative one: nonsense-mediated decay is predicted rather than measured, and the authors attribute the absent dominant-negative effect possibly to their construct lacking the transmembrane domain, noting it was not directly tested.

Haploinsufficiency from truncating loss-of-function variants

neuron CL:0000540

Downstream

Impaired SNARE-Mediated Vesicle Fusion

Show evidence (3 references)

PMID:30929742 SUPPORT Human Clinical

"In the ExAC database (last accessed January 30, 2018), which contains exomes from 60,706 unrelated individuals, there are no listed loss-of-function variants in VAMP2"

Population-database constraint indicating VAMP2 loss of function is not tolerated in unaffected individuals — the background against which haploinsufficiency is plausible. The ExAC framing is quoted in full because the bare clause would otherwise read as a claim that no VAMP2 LoF variants exist, which this entry contradicts by curating two in affected children.

PMID:32906212 SUPPORT Other

"predicting a premature truncation and haploinsufficiency from nonsense mediated decay."

The proposed haploinsufficiency mechanism for the truncating allele. This is a prediction from the variant's position, not a measurement of transcript level, which is why the evidence source is OTHER.

PMID:32906212 SUPPORT Human Clinical

"Sympathetic skin responses were very low amplitude, with relative preservation of response latencies, providing confirmation that VAMP2 haploinsufficiency caused symptoms."

The only in-human functional measurement bearing on this arm — reduced autonomic nerve responses in the truncating-variant carrier. The paper's "providing confirmation" is an n-of-1 overclaim: one patient, no controls, and an assay that cannot distinguish reduced gene dose from any other cause of impaired transmission, so the item carries the measurement and not the confirmation.

Impaired SNARE-Mediated Vesicle Fusion

VAMP2 is one of the three core neuronal SNAREs whose zippering, triggered by the calcium sensor synaptotagmin-1, fuses the synaptic vesicle with the presynaptic membrane. The fusion defect is variant-specific rather than uniform across the allelic series: in the reconstituted lipid-mixing assay p.Ser75Pro reduced fusion to roughly 25% of wild-type and could not be activated by Munc18-1 (a >90% loss-of-function under Munc18-activated conditions), whereas p.Glu78Ala was indistinguishable from wild-type and p.Phe77Ser could not be purified for testing. In cultured neurons, two of three variants tested reduced both the rate of exocytosis and the size of the released recycling pool. The authors therefore frame impaired fusion as one of the possible mechanisms and explicitly invoke mutation-specific mechanisms; for variants without a reconstituted fusion defect, disrupted interaction with regulatory proteins absent from the assay is the proposed alternative. This is the module's key conformance target — the fusion-machinery arm.

neuron CL:0000540

calcium-dependent activation of synaptic vesicle fusion GO:0099502 ↓ DECREASED synaptic vesicle exocytosis GO:0016079 ↓ DECREASED

Experimental models

Reconstituted SNARE liposome lipid-mixing (fusion) assay OTHER Isolates the SNARE fusion step from all other presynaptic biology, which is what makes it decisive for p.Ser75Pro and uninformative for variants whose defect lies in regulatory-protein interaction.

Animal models

Synaptobrevin-2 (Vamp2) knockout mouse Mouse (Mus musculus) partially recapitulates Establishes the direction and the disproportionate sensitivity of calcium-triggered release to loss of VAMP2, which is the mechanism this node asserts.

Downstream

Disrupted Neurotransmission and Impaired Neurodevelopment

Show evidence (7 references)

PMID:30929742 SUPPORT In Vitro

"Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms."

The authors' own hedged framing: reconstituted fusion impairment is one of the possible mechanisms, not the established sole mechanism.

PMID:30929742 SUPPORT In Vitro

"The reduction in the fusion associated with p.Ser75Pro was estimated to be approximately 25% that in the WT"

Quantifies the fusion defect for the one variant with a clear reconstituted phenotype.

PMID:30929742 SUPPORT In Vitro

"Consequently, we observed a significant (>90%) loss-of-function phenotype with the p.Ser75Pro variant under these conditions."

Under Munc18-activated (more physiological) conditions the p.Ser75Pro defect is far larger than the basal 25% reduction.

+ 4 more references

Impaired Synaptic Vesicle Endocytosis and Recycling

Beyond its role in fusion, VAMP2 is required for fast, stimulus-dependent synaptic vesicle endocytosis and for replenishment of the readily releasable pool. Synaptobrevin-2 knockout synapses show delayed pool replenishment, altered vesicle shape and size, and delayed uptake of endocytic tracers. **This node rests on the mouse knockout only.** When the human disease variants were tested directly, post-stimulus syp-pHluorin decay — the endocytosis readout — was not significantly altered by any of them. The reduced "recycling pool released" measure reported for two variants is an exocytosis-extent measure, not a measure of endocytic retrieval, and it belongs to the fusion arm. Whether losing one VAMP2 allele or expressing a SNARE-motif variant impairs human endocytosis is therefore untested at best and negative on the one direct measurement available.

neuron CL:0000540

synaptic vesicle endocytosis GO:0048488 ↓ DECREASED synaptic vesicle recycling GO:0036465 ↓ DECREASED

Animal models

Synaptobrevin-2 (Vamp2) knockout mouse Mouse (Mus musculus) partially recapitulates The knockout is the primary evidence that VAMP2 is required for fast endocytosis and readily-releasable-pool replenishment, not only exocytosis.

Downstream

Disrupted Neurotransmission and Impaired Neurodevelopment A recycling pool that refills too slowly limits sustained release during repetitive activity, compounding the fusion deficit.

Show evidence (3 references)

PMID:15475946 SUPPORT Model Organism

"Here we show that synaptobrevin-2 is also essential for fast synaptic-vesicle endocytosis."

Establishes the endocytic requirement for VAMP2 in knockout mouse synapses.

PMID:15475946 SUPPORT Model Organism

"the stimulus-dependent endocytosis of horseradish peroxidase and fluorescent FM1-43 were delayed"

The direct measurement of delayed endocytosis behind this node.

PMID:32906212 REFUTE In Vitro

"The post-stimulus fluorescence decay of syp-pH, representing endocytosis, is not significantly altered by any of the VAMP2 variants compared to WT"

The only direct test of endocytosis in the human disease variants was negative. Curated as REFUTE so the node cannot be read as an established human mechanism; it stands on the mouse knockout alone.

Disrupted Neurotransmission and Impaired Neurodevelopment

Impaired SNARE-mediated fusion reduces activity-dependent neurotransmitter release, disturbing cortical synaptic transmission and activity-dependent brain development. This produces axial hypotonia from birth, intellectual disability, and autistic features with motor stereotypies. Within the index cohort the three C-terminal missense carriers were additionally the ones with central visual impairment and a hyperkinetic movement disorder, but neither is curated as holding across all reported patients: a p.Ala67Pro carrier developed a hyperkinetic movement disorder, and for central visual impairment it is the preceding poor visual fixation that is documented outside the cluster. Seizures occur across allelic classes and are likewise not curated as a genotype-specific consequence.

neuron CL:0000540

neurotransmitter secretion GO:0007269 ↓ DECREASED chemical synaptic transmission GO:0007268 ⚠ ABNORMAL

Downstream

Axial Hypotonia

Intellectual Disability

Autistic Behavior

Global Developmental Delay

Motor Stereotypies No mechanistic route from impaired presynaptic release to stereotyped motor output is established; the association is clinical.

Absent Purposeful Hand Movements Clinically constant in the index cohort, but the intermediates between reduced neurotransmitter release and loss of purposeful hand use are unknown.

Absent Speech Severity tracks the allelic class, but no mechanistic route to the language phenotype specifically is established.

Inability to Walk Follows the severe end of the allelic series; intermediates between the release deficit and the motor outcome are not established.

Central Visual Impairment Cortical rather than ocular. Optic nerve and chiasm hypoplasia was seen in the one individual with an abnormal MRI, offering a candidate structural correlate, but it was not looked for systematically.

Seizures A presynaptic release deficit is a plausible route to network hyperexcitability, but the balance of excitatory versus inhibitory impairment in this disorder has not been measured. Note the aminopyridine work reports desynchronized GABA release, which would bear on this.

EEG Abnormality Recorded across the cohort including in individuals without clinical seizures, so it is curated as its own consequence rather than as a marker of the seizure node.

Attention Deficit Hyperactivity Disorder Part of the behavioural phenotype alongside autistic features; no mechanistic route from impaired presynaptic release is established.

Chorea A component movement type of the hyperkinetic movement disorder; the intermediates are the same unknown ones.

Dystonia A component movement type of the hyperkinetic movement disorder.

Myoclonus A component movement type of the hyperkinetic movement disorder, and a seizure semiology in an independently reported case.

Infantile Spasms A seizure type reported in this disorder; modelled alongside Seizures rather than beneath it because the entry curates it as its own phenotype.

Hyperkinetic Movement Disorder The intermediates are unknown. VAMP2 is most highly expressed in the putamen, which offers a candidate anatomical substrate for a hyperkinetic movement disorder, but no study connects the expression pattern to the phenotype.

Show evidence (1 reference)

PMID:30929742 SUPPORT Human Clinical

"The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function."

Frames the disorder as a genetic synaptopathy in which impaired VAMP2 function disrupts brain development.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

23

Eye 2

Nystagmus HP:0000639

Show evidence (2 references)

PMID:37901860 SUPPORT Human Clinical

"A 15-month-old girl presented with early onset hypotonia, global developmental delay, learning difficulties, microcephaly, nystagmus, strabismus, and stereotypies."

Documents nystagmus in a later reported individual.

PMID:32906212 SUPPORT Human Clinical

"Parents noticed nystagmus during infancy."

Independent report of nystagmus in the second cohort, with infantile onset.

Strabismus HP:0000486

Show evidence (1 reference)

PMID:37901860 SUPPORT Human Clinical

"A 15-month-old girl presented with early onset hypotonia, global developmental delay, learning difficulties, microcephaly, nystagmus, strabismus, and stereotypies."

Documents strabismus in a later reported individual.

Head and Neck 1

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:37901860 SUPPORT Human Clinical

"A 15-month-old girl presented with early onset hypotonia, global developmental delay, learning difficulties, microcephaly, nystagmus, strabismus, and stereotypies."

Documents microcephaly in a later reported individual.

Musculoskeletal 1

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:37901860 SUPPORT Human Clinical

"Later, she developed a sleep disorder, challenging behaviour with self-injury, and scoliosis."

Documents scoliosis as a later-developing feature.

Nervous System 12

Intellectual Disability VERY_FREQUENT HP:0001249

Show evidence (2 references)

PMID:30929742 SUPPORT Human Clinical

"axial hypotonia (which had been present since birth), intellectual disability, and autistic features."

Documents intellectual disability as a core feature.

PMID:30929742 SUPPORT Human Clinical

"who had intellectual disability (ID) with autistic features"

Frequency justification: intellectual disability in 5/5 of the index cohort. Curated VERY_FREQUENT rather than OBLIGATE because five probands is a narrow denominator, and the later cohort reports developmental delay and learning difficulty of varying degree rather than uniform severity.

Autistic Behavior VERY_FREQUENT HP:0000729

Show evidence (4 references)

PMID:30929742 SUPPORT Human Clinical

"axial hypotonia (which had been present since birth), intellectual disability, and autistic features."

Documents autistic features as a core feature.

PMID:30929742 SUPPORT Human Clinical

"All children showed autistic features, typically including flapping or flailing of the arms, as well as hand wringing or clapping."

Frequency justification: explicit "all children" statement over the index cohort. Curated VERY_FREQUENT rather than OBLIGATE because the independent second cohort includes a patient formally evaluated for autism who did not meet criteria, so autistic features are not universal.

PMID:32906212 SUPPORT Human Clinical

"reveal common features of global developmental delay, autistic tendencies, behavioral disturbances, and a higher propensity to develop epilepsy."

Independent second cohort confirming autistic features as a common feature.

+ 1 more reference

Seizures HP:0001250

Show evidence (4 references)

PMID:30929742 SUPPORT Human Clinical

"a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities."

Documents epilepsy in the more severe phenotype.

PMID:30929742 SUPPORT Human Clinical

"Individual 2 suffered from multiple focal seizures per day; these started shortly after birth"

Documents focal seizure semiology and its neonatal onset in the index cohort.

PMID:32906212 SUPPORT Human Clinical

"a higher propensity to develop epilepsy."

Independent second cohort confirming increased epilepsy propensity.

+ 1 more reference

EEG Abnormality HP:0002353

Show evidence (2 references)

PMID:30929742 SUPPORT Human Clinical

"Seizures or abnormal EEG occurred in four affected individuals."

Documents the combined seizure/EEG-abnormality burden in the index cohort.

PMID:30929742 SUPPORT Human Clinical

"Individual 1 did not present with epileptic seizures, but ictal EEG recording at the age of 15 months showed high-voltage delta activity with interspersed sharp-and-slow-wave complexes over the right central and posterior brain regions."

Shows the EEG abnormality is dissociable from clinical seizures, which is why it is curated as a phenotype in its own right.

Absent Speech FREQUENT HP:0001344

Show evidence (1 reference)

PMID:30929742 SUPPORT Human Clinical

"Severe language impairment was present in the three more severely affected children (individuals 1–3), none of whom had attained meaningful speech production, but individuals 4 and 5 were capable of saying 5–10 words"

Frequency justification: absent meaningful speech in 3 of 5 individuals (60%), supporting the FREQUENT band, and records the milder speech outcome in the deletion carriers. The denominator is five probands.

Chorea HP:0002072

Show evidence (1 reference)

PMID:30929742 SUPPORT Human Clinical

"moderate chorea (individuals 1 and 3) to a mixed-movement disorder with severe chorea and dystonic posturing (individual 2)"

Documents chorea and its severity range in the index cohort.

Dystonia HP:0001332

Show evidence (1 reference)

PMID:30929742 SUPPORT Human Clinical

"Abnormal movements ranged from dystonic posturing (mainly involving the trunk, neck, and lower limbs)"

Documents dystonic posturing and its distribution.

Myoclonus HP:0001336

Show evidence (2 references)

PMID:30929742 SUPPORT Human Clinical

"or myoclonic jerks (individual 3)"

Documents myoclonic jerks within the movement disorder.

PMID:32336483 SUPPORT Human Clinical

"he suffered from myoclonic seizures of the eyelid and tongue, which propagated to unilateral fingers, and sometimes to the bilateral legs."

Independent report of myoclonic seizure semiology.

Self-Injurious Behavior HP:0100716

Show evidence (2 references)

PMID:30929742 SUPPORT Human Clinical

"Self-injurious behaviors were evident in individual 2."

Documents self-injurious behavior in the index cohort.

PMID:37901860 SUPPORT Human Clinical

"Later, she developed a sleep disorder, challenging behaviour with self-injury, and scoliosis."

Independent confirmation of self-injurious behavior.

Global Developmental Delay VERY_FREQUENT HP:0001263

Show evidence (2 references)

PMID:30929742 SUPPORT Human Clinical

"In all affected children, family histories, pregnancies, and birth histories were unremarkable, and neurodevelopmental impairment occurred within the first year of life."

Frequency justification: explicit "in all affected children" statement over the index cohort, and dates onset to the first year. Curated VERY_FREQUENT rather than OBLIGATE because five probands is a narrow denominator.

PMID:32906212 SUPPORT Human Clinical

"reveal common features of global developmental delay"

Independent second cohort confirming global developmental delay as a common feature.

Attention Deficit Hyperactivity Disorder HP:0007018

Show evidence (2 references)

PMID:32906212 SUPPORT Human Clinical

"Later he was diagnosed with ASD and attention deficit hyperactivity disorder (ADHD)."

A formal ADHD diagnosis in a reported patient.

PMID:32906212 SUPPORT Human Clinical

"He received an autism evaluation at age 3, and did not meet criteria for autism, but displayed ADHD tendencies."

ADHD tendencies rather than a formal diagnosis in a second patient. This is the same patient whose negative autism evaluation bounds the Autistic Behavior frequency.

Sleep Disturbance HP:0002360

Show evidence (2 references)

PMID:37901860 SUPPORT Human Clinical

"Later, she developed a sleep disorder, challenging behaviour with self-injury, and scoliosis."

Documents a sleep disorder in a later reported individual.

PMID:32336483 SUPPORT Human Clinical

"He had somnolence tendency in the daytime."

Independent report of daytime somnolence.

Other 7

Axial Hypotonia VERY_FREQUENT HP:0008936

Show evidence (2 references)

PMID:30929742 SUPPORT Human Clinical

"a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features."

Documents axial hypotonia from birth as a core feature.

PMID:30929742 SUPPORT Human Clinical

"we describe five unrelated individuals who had shown hypotonia since birth"

Frequency justification: hypotonia in 5/5 of the index cohort. Curated VERY_FREQUENT rather than OBLIGATE because five probands is a narrow denominator on which to assert universality.

Context-specific annotations (1)

Onset: CONGENITAL

Show evidence (1 reference)

PMID:30929742 SUPPORT Human Clinical

"The earliest sign of neurological involvement was axial hypotonia at birth."

Establishes congenital onset for this phenotype.

Hyperkinetic Movement Disorder FREQUENT Hyperkinetic movements HP:0002487

Show evidence (3 references)

PMID:30929742 SUPPORT Human Clinical

"Abnormal movements ranged from dystonic posturing (mainly involving the trunk, neck, and lower limbs) and moderate chorea (individuals 1 and 3) to a mixed-movement disorder with severe chorea and dystonic posturing (individual 2) or myoclonic jerks (individual 3)."

Frequency justification: the movement disorder is documented in 3 of the 5 individuals in the index cohort (60%), supporting the FREQUENT band, and details its component movement types. A sixth patient is captured by the juvenile-onset context above and by the next evidence item.

PMID:32336483 SUPPORT Human Clinical

"At 8 years of age hyperkinetic movement occurred."

A hyperkinetic movement disorder in a p.Ala67Pro carrier, outside the C-terminal cluster and with juvenile rather than infantile onset. This is why neither the genotype restriction nor the infantile-onset generalization is curated as holding across all reported patients.

PMID:30929742 SUPPORT Human Clinical

"a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities."

Documents the hyperkinetic movement disorder in the more severe phenotype.

Context-specific annotations (2)

Onset: INFANTILE

Show evidence (1 reference)

PMID:30929742 SUPPORT Human Clinical

"exhibited a hyperkinetic movement disorder starting in the first year of life"

Establishes infantile onset in the index cohort.

Onset: JUVENILE; from 8.0y

Show evidence (1 reference)

PMID:32336483 SUPPORT Human Clinical

"At 8 years of age hyperkinetic movement occurred."

Documents onset well beyond infancy, so the structured onset layer matches the phenotype description rather than contradicting it.

Central Visual Impairment FREQUENT Cerebral visual impairment HP:0100704

Show evidence (3 references)

PMID:30929742 SUPPORT Human Clinical

"a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities."

Documents central visual impairment in the more severe phenotype.

PMID:30929742 SUPPORT Human Clinical

"Poor visual fixation (with only brief and occasional visual contact, lasting up to a few seconds) had been evident since the first months of life in three affected individuals (1–3); these individuals were later diagnosed with central visual impairment"

Frequency justification: central visual impairment in 3 of the 5 individuals in the index cohort (60%), supporting the FREQUENT band, and documents the preceding poor visual fixation. The denominator is the five index-cohort probands.

PMID:32336483 SUPPORT Human Clinical

"Hypotonia at early infancy, poor visual fixation, and absence of purposeful hand movements may be indicative of the diagnosis for VAMP2 variant."

Independent case report proposing poor visual fixation as a diagnostically indicative feature.

Infantile Spasms HP:0012469

Show evidence (2 references)

PMID:30929742 SUPPORT Human Clinical

"At 12 months, individual 3 presented with infantile spasms that were associated with diffuse EEG paroxysms."

Documents infantile spasms in the index cohort.

PMID:32336483 SUPPORT Human Clinical

"He presented with infantile spasms at 6 months, and electroencephalography (EEG) showed hypsarrhythmia."

Independent confirmation of infantile spasms with hypsarrhythmia.

Motor Stereotypies VERY_FREQUENT Motor stereotypy HP:0000733

Show evidence (3 references)

PMID:30929742 SUPPORT Human Clinical

"All children showed autistic features, typically including flapping or flailing of the arms, as well as hand wringing or clapping."

Frequency justification: stereotypies documented in all five index-cohort individuals, and in a sixth reported independently — 6/6 of the patients in whom they were assessed. VERY_FREQUENT rather than OBLIGATE because the denominator is narrow: the second cohort neither reports nor excludes stereotypies, and silence is not a documented absence.

PMID:30929742 SUPPORT Human Clinical

"Additional repetitive behavior patterns included body rocking and head banging."

Documents the additional stereotypy repertoire.

PMID:37901860 SUPPORT Human Clinical

"A 15-month-old girl presented with early onset hypotonia, global developmental delay, learning difficulties, microcephaly, nystagmus, strabismus, and stereotypies."

An independently reported patient with stereotypies, outside the index cohort — the sixth assessed patient behind the frequency band.

Absent Purposeful Hand Movements FREQUENT Hand apraxia HP:0032588

Show evidence (3 references)

PMID:30929742 SUPPORT Human Clinical

"A virtual absence of purposeful hand movements was present in all cases"

Frequency justification: explicit "in all cases" statement over the index cohort. Curated FREQUENT rather than VERY_FREQUENT because the index cohort is not the whole reported population — several individuals in the independent second cohort retain purposeful hand use, so the share across all reported patients falls below the 80% floor.

PMID:32906212 SUPPORT Human Clinical

"He can run, walk slowly upstairs, and scribble with a coarse grasp."

A reported patient with retained purposeful hand use. It bounds the frequency of the feature rather than contradicting the disease-phenotype association, and it is what caps the band at FREQUENT.

PMID:32336483 SUPPORT Human Clinical

"Hypotonia at early infancy, poor visual fixation, and absence of purposeful hand movements may be indicative of the diagnosis for VAMP2 variant."

Independent case report proposing this as diagnostically indicative.

Inability to Walk FREQUENT HP:0002540

Show evidence (2 references)

PMID:30929742 SUPPORT Human Clinical

"Motor development in individuals 1–3 was severely impaired, and these children had not attained the ability to walk."

Frequency justification: inability to walk in 3 of 5 individuals (60%), supporting the FREQUENT band. The denominator is five probands.

PMID:30929742 SUPPORT Human Clinical

"Individuals 4 and 5, carrying de novo single-amino-acid deletions involving residues at positions 43 and 45, presented a less severe neurological involvement, acquired the ability to walk, and were able to pronounce a few words."

Records the genotype-dependent sparing of ambulation in the deletion carriers.

🧬

Genetic Associations

1

VAMP2 (SNARE-Motif Mutations)

Gene: VAMP2 hgnc:12643 variant_origin: GERMLINE

Autosomal Dominant (De Novo)

Show evidence (3 references)

PMID:30929742 SUPPORT Human Clinical

"In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif."

Defines the de novo SNARE-motif variant spectrum of the index cohort.

PMID:30929742 SUPPORT Human Clinical

"The de novo non-synonymous variants identified in this study cluster in close proximity within the C-terminal portion of the SNARE motif"

Localizes specifically the missense variants to the C-terminal portion; the two in-frame deletions sit at residues 43 and 45, more N-terminally within the same motif.

PMID:37901860 SUPPORT Human Clinical

"To date, only three types of allelic variants (loss of function, in-frame deletions, and missense variants) in the VAMP2 gene have been previously reported in 11 patients with learning difficulties."

Establishes the three-class allelic series and the cumulative reported patient count.

Variants (12)

NM_014232(VAMP2):c.223T>C (p.Ser75Pro) Pathogenic

missense

C-terminal SNARE-motif missense variant. The only variant with a demonstrated reconstituted fusion defect: fusion reduced to ~25% of wild-type, no Munc18-1 activation (>90% loss of function under Munc18-activated conditions), and dominant interference with wild-type VAMP2 in 50:50 mixed liposomes. Predicted to lose two hydrogen bonds, one interchain with Tyr243 of STX1A and one intrachain with Gln71.

Show evidence (1 reference)

PMID:30929742 SUPPORT In Vitro

"Replacement analysis shows that the p.Ser75Pro variant will result in the loss of two hydrogen bonds, one interchain between Ser75 of VAMP2 and Tyr243 of STX1A and one intrachain between Ser75 and Gln71"

Structural basis for the p.Ser75Pro fusion defect.

NM_014232(VAMP2):c.233A>C (p.Glu78Ala) Pathogenic

missense

C-terminal SNARE-motif missense variant that disrupts the hydrogen bond between Glu78 of VAMP2 and Arg246 of STX1A, but whose reconstituted fusion profile was indistinguishable from wild-type and which remained Munc18-1-activatable. Its pathogenic mechanism is unresolved; the authors propose impaired interaction with regulatory proteins absent from the assay.

Show evidence (1 reference)

PMID:30929742 SUPPORT In Vitro

"the p.Glu78Ala variant disrupts the hydrogen bond between Glu78 of VAMP2 and Arg246 of STX1A"

Structural consequence, recorded alongside the absent functional effect in the fusion assay.

NM_014232(VAMP2):c.230T>C (p.Phe77Ser) Pathogenic

missense

C-terminal SNARE-motif missense variant introducing a hydrophilic residue into an otherwise hydrophobic region. Could not be purified, so it was never tested in the reconstituted fusion assay.

Show evidence (1 reference)

PMID:30929742 SUPPORT In Vitro

"However, all attempts to isolate the p.Phe77Ser were unsuccessful."

Records why no functional data exist for this variant.

NM_014232(VAMP2):c.128_130delTGG (p.Val43del) Pathogenic

inframe deletion

In-frame single-amino-acid deletion at a more N-terminal SNARE-motif residue, associated with the milder phenotype (walks, speaks 5-10 words, no movement disorder or visual impairment).

Show evidence (1 reference)

PMID:30929742 SUPPORT Human Clinical

"carrying a de novo single amino acid deletion at position 43"

Identifies the variant and its position within the SNARE motif.

NM_014232(VAMP2):c.135_137delCAT (p.Ile45del) Pathogenic

inframe deletion

In-frame single-amino-acid deletion at a more N-terminal SNARE-motif residue, associated with the milder phenotype.

Show evidence (1 reference)

PMID:30929742 SUPPORT Human Clinical

"an additional child (individual 5) carrying a de novo single-amino-acid deletion at position 45"

Identifies the variant and its position within the SNARE motif.

VAMP2 c.166C>T (p.Arg56*) (nonsense) Pathogenic

nonsense

Truncating variant predicted to cause nonsense-mediated decay and haploinsufficiency. In cellular assays the truncated protein did not exert dominant-negative effects, and the carrier had a milder phenotype without epilepsy. The authors caution that this null result may be an artifact of the reporter construct, which encodes only the first 55 residues and so lacks the transmembrane domain needed for membrane localization, and that a dominant-negative effect was not directly tested. This is the individual treated with off-label aminopyridine.

Show evidence (1 reference)

PMID:32906212 SUPPORT Other

"predicting a premature truncation and haploinsufficiency from nonsense mediated decay."

The predicted molecular consequence of the truncating allele — predicted from variant position, not measured, which is why the evidence source is OTHER.

VAMP2 c.167G>T (p.Arg56Leu) Pathogenic

missense

SNARE-motif missense variant affecting the same residue as the p.Arg56* truncating allele. Predicted to act dominant-negatively, and among the variants tested in the cellular exocytosis assays.

Show evidence (1 reference)

PMID:32906212 SUPPORT Human Clinical

"He carries a de novo VAMP2 variant (heterozygous de novo c.167 G>T, p.Arg56Leu)"

Identifies the variant and its de novo heterozygous status.

VAMP2 c.217G>T (p.Gly73Trp) Pathogenic

missense

SNARE-motif missense variant predicted to act dominant-negatively, and among the variants shown to reduce action-potential-triggered vesicle fusion and neurotransmitter release in neurons.

Show evidence (1 reference)

PMID:32906212 SUPPORT Human Clinical

"Whole exome testing revealed a VAMP2 variant (heterozygous de novo c.217G>T, p.Gly73Trp)."

Identifies the variant and its de novo heterozygous status.

VAMP2 c.337_341delTACTT (p.Tyr113Glnfs*12) Pathogenic

frameshift

Frameshift variant predicted to create a premature stop codon 12 residues downstream and to result in haploinsufficiency. The second truncating allele reported, alongside p.Arg56*.

Show evidence (1 reference)

PMID:32906212 SUPPORT Human Clinical

"Whole exome sequencing at 4 years of age revealed a variation in VAMP2 (heterozygous de novo c.337_341 deletion TACTT p.Tyr113Gln frameshift,"

Identifies the frameshift variant and its de novo heterozygous status.

VAMP2 c.1A>G (p.Met1?) (start loss) Pathogenic

start lost

Start-loss variant eliminating the initiator methionine, thought to result in no protein or in a truncated protein initiating at a different residue. It does not fit any of the three allelic classes the literature describes (SNARE-motif missense, in-frame deletion, truncating) and is curated here so that the class scheme is not read as exhaustive.

Show evidence (2 references)

PMID:32906212 SUPPORT Human Clinical

"Whole exome sequencing was performed and revealed a heterozygous de novo c.1 A>G, p. Met1? VAMP2 mutation."

Identifies the start-loss variant and its de novo heterozygous status.

PMID:32906212 SUPPORT Other

"This change is thought to cause elimination of initiator methionine, which could result in no protein formation, or a truncated protein with a different initiator amino acid."

The predicted consequence. Two alternative outcomes are proposed and neither was tested, which is why the evidence source is OTHER.

NM_014232.2(VAMP2):c.197G>C (p.Arg66Pro) Pathogenic

missense

SNARE-motif missense variant reported in a girl with hypotonia, global developmental delay, microcephaly, nystagmus, strabismus, and stereotypies.

Show evidence (1 reference)

PMID:37901860 SUPPORT Human Clinical

"identified a novel de novo heterozygous missense variant c.197G>C (p.Arg66Pro) in the VAMP2 gene SNARE motif region."

Identifies this later-reported SNARE-motif missense variant.

NM_014232.2(VAMP2):c.199G>C (p.Ala67Pro) Pathogenic

missense

SNARE-motif missense variant in exon 3, reported in a boy with infantile spasms and hypsarrhythmia, poor visual fixation, and absent purposeful hand movements.

Show evidence (1 reference)

PMID:32336483 SUPPORT Human Clinical

"whole-exome sequence identified a heterozygous missense variant, NM_014232.2:c.199G>C,"

Identifies this later-reported SNARE-motif missense variant.

💊

Medical Actions

5

Antiseizure Medication

Action: Pharmacotherapy NCIT:C15986

Agent: valproic acid CHEBI:39867 vigabatrin CHEBI:63638 lamotrigine CHEBI:6367

Epilepsy, when present, is managed with antiseizure medication. In the index cohort valproic acid, vigabatrin, and lamotrigine were trialed in the three individuals with seizures; benefit was noted only for valproic acid, in the individual with the mildest epilepsy phenotype, who became seizure-free with normal follow-up EEGs. No disease-specific antiseizure strategy has been established, and the evidence base is a handful of individual treatment courses rather than any trial. Adrenocorticotropic hormone for infantile spasms is curated as a separate treatment.

Target Phenotypes: Seizure HP:0001250

Show evidence (2 references)

PMID:30929742 SUPPORT Human Clinical

"Several anti-epileptic drugs, including valproic acid, vigabatrin, and lamotrigine, have been trialed in individuals 2–4"

Names the antiseizure agents actually used in the reported cohort.

PMID:30929742 SUPPORT Human Clinical

"beneficial effects of valproic acid treatment were noted in individual 4, who has been seizure-free since the age of 12 years and has had normal follow-up EEGs"

The only reported antiseizure benefit, and it is a single uncontrolled observation, so it supports the observation having been made and not a general recommendation.

Adrenocorticotropic Hormone for Infantile Spasms

Action: Pharmacotherapy NCIT:C15986

Agent: adrenocorticotropic hormone CHEBI:3892

Infantile spasms with hypsarrhythmia were treated with adrenocorticotropic hormone in an independently reported case, with complete resolution of the spasms. Curated separately from maintenance antiseizure medication because the indication, the agent class, and the course of therapy are all distinct. The interictal EEG abnormality persisted after the spasms resolved, so the response was seizure-specific rather than a normalization of the underlying encephalopathy. This is a single case, not a disease-specific recommendation.

Target Phenotypes: Infantile spasms HP:0012469

Show evidence (1 reference)

PMID:32336483 SUPPORT Human Clinical

"His infantile spasms completely disappeared by adrenocorticotropic hormone therapy, but his EEG findings continued to show high voltage slow-waves with multi-focal spikes."

Single uncontrolled case showing spasm resolution but persistent interictal EEG abnormality, which is why the EEG caveat is stated in the description.

Aminopyridine Potassium-Channel Blockade (Investigational)

Action: Pharmacotherapy NCIT:C15986

Agent: 4-aminopyridine CHEBI:34385 3,4-diaminopyridine CHEBI:135948

An investigational, mechanism-directed strategy rather than established care. Blocking presynaptic potassium channels with 4-aminopyridine or 3,4-diaminopyridine prolongs the action potential, increasing calcium entry and release probability, and so compensates for — rather than corrects — the VAMP2 fusion deficit. In neurons expressing VAMP2 variants, aminopyridine increased the rate and extent of exocytosis and total synaptic charge transfer. Clinical experience is a single patient with a nonsense variant treated off-label for two years, with improved emotional and behavioral regulation by parental report and improvement on standardized cognitive measures. This is an uncontrolled n-of-1 observation; the authors propose testing responsiveness in vitro before treating. Safety caveat that matters in this disorder specifically: 4-aminopyridine lowers the seizure threshold and the authors advise caution in patients with epilepsy — and epilepsy, infantile spasms, and EEG abnormality are all curated features here. The treated patient carried a truncating variant and had no epilepsy.

Mechanism Target:

BYPASSES Impaired SNARE-Mediated Vesicle Fusion — Aminopyridines do not repair the SNARE complex. They raise presynaptic calcium availability so that the residual fusion machinery achieves more release per action potential, compensating around the fusion deficit.

Show evidence (1 reference)

PMID:32906212 SUPPORT In Vitro

"Aminopyridine treatment increases the rate and extent of exocytosis and total synaptic charge transfer and desynchronizes GABA release."

Demonstrates the compensatory effect on the impaired exocytosis step in neurons expressing the disease variants.

Show evidence (3 references)

PMID:32906212 SUPPORT In Vitro

"we tested a potential treatment strategy, enhancing neurotransmission by prolonging action potentials with the aminopyridine family of potassium channel blockers, 4-aminopyridine and 3,4-diaminopyridine, in vitro and in vivo."

Defines the agents and the pharmacological rationale.

PMID:32906212 SUPPORT Human Clinical

"The clinical response of the patient to 2 years of off-label aminopyridine treatment includes improved emotional and behavioral regulation by parental report, and objective improvement in standardized cognitive measures."

The entire human evidence base is this single uncontrolled off-label treatment course, which is the limit of what the clinical claim can rest on.

PMID:32906212 SUPPORT Human Clinical

"4-AP should be used cautiously in patients with epilepsy given risk of lowering seizure threshold, which can limit its broad-based utility."

The authors' own safety limitation, material because epilepsy is a curated feature of this disorder and the single treated patient did not have it.

Supportive and Developmental Care

Action: Supportive Care NCIT:C15747

Multidisciplinary supportive care — developmental and behavioral therapies, management of the movement disorder, and vision support — is the mainstay. There is no disease-modifying therapy, and the care needs follow directly from the phenotype: absent speech and absent purposeful hand use, non-ambulation in the severe group, central visual impairment, and challenging or self-injurious behavior.

Show evidence (2 references)

PMID:30929742 SUPPORT Human Clinical

"Motor development in individuals 1–3 was severely impaired, and these children had not attained the ability to walk."

Documents the motor disability that defines the rehabilitative and supportive care need.

PMID:37901860 SUPPORT Human Clinical

"Later, she developed a sleep disorder, challenging behaviour with self-injury, and scoliosis."

Documents the behavioural and orthopedic problems that multidisciplinary supportive care must address.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Genetic counseling addresses the de novo dominant mechanism and generally low recurrence risk.

Show evidence (1 reference)

PMID:30929742 SUPPORT Human Clinical

"Chromatograms of individuals 1–5 and their parents confirm the de-novo occurrence of the VAMP2 variants in all cases."

Confirmed de novo occurrence in unaffected parents is the basis for counseling a low sibling recurrence risk.

🔬

Diagnosis

1

VAMP2 Molecular Diagnosis

Diagnosis is established by identifying a de novo heterozygous pathogenic VAMP2 variant (SNARE-motif deletion or non-synonymous variant) in a child with congenital axial hypotonia, intellectual disability, and autistic features.

molecular genetic testing NCIT:C19770

Results: A de novo pathogenic VAMP2 SNARE-motif variant establishes the diagnosis.

Show evidence (1 reference)

PMID:30929742 SUPPORT Human Clinical

"Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals"

Molecular identification of de novo VAMP2 variants establishes the diagnosis.

🩻

Imaging Findings

5

Delayed Myelination

Brain MRI was unrevealing in four of the five individuals of the index cohort. The exception showed a generalized delay in myelin maturation at age 2 years. Normal brain imaging does not argue against the diagnosis. The corpus callosum and cerebral white matter volume findings from the same individual, and the brain atrophy reported independently, are curated separately, since each is a distinct abnormality with its own HPO term.

Mri

Delayed myelination HP:0012448 brain UBERON:0000955

Show evidence (1 reference)

PMID:30929742 SUPPORT Human Clinical

"Brain magnetic resonance imaging (MRI) was unrevealing in all children except in individual 1, for whom mild myelination delay and a posteriorly slender corpus callosum was observed at the age of 2 years"

Records the myelination delay and, importantly, that imaging is normal in most affected individuals. The corpus callosum half of this sentence is curated on its own finding.

Brain Atrophy

Slight brain atrophy on MRI in an independently reported individual. Curated as its own finding rather than on the myelination node, since atrophy and delayed maturation are different abnormalities; reported in a single patient.

Mri

Brain atrophy HP:0012444 brain UBERON:0000955

Show evidence (1 reference)

PMID:32336483 SUPPORT Human Clinical

"Magnetic resonance imaging showed slight brain atrophy."

The single reported observation of brain atrophy in this disorder.

Reduced Cerebral White Matter Volume

Reduced posterior cerebral white matter volume in the one index-cohort individual with an abnormal MRI, reported alongside the myelination delay in the same scan. Curated separately from the myelination finding because volume loss and delayed maturation are distinct abnormalities with distinct HPO terms.

Mri

Reduced cerebral white matter volume HP:0034295 brain UBERON:0000955

Show evidence (1 reference)

PMID:30929742 SUPPORT Human Clinical

"There is some generalized delay in the maturation of myelin and a reduced volume of the cerebral white matter posteriorly."

Reports both findings from the one abnormal scan; the volume-loss half is curated here and the maturation delay on the myelination finding.

Thin Corpus Callosum

A posteriorly slender ("thin") corpus callosum in the one index-cohort individual with an abnormal MRI, and a mildly hypoplastic corpus callosum reported independently in the second cohort. Curated as its own finding rather than folded into the myelination node: it is a distinct abnormality with its own HPO term, and it is the one structural finding corroborated across two cohorts. Bound to HP:0033725 rather than HP:0002079 (Hypoplasia of the corpus callosum) because HP:0033725 is defined for thinning whose cause — hypoplasia versus atrophy after normal development — is not known, which is the case for the index cohort; only the second cohort calls it hypoplastic.

Mri

Thin corpus callosum HP:0033725 brain UBERON:0000955

Show evidence (2 references)

PMID:30929742 SUPPORT Human Clinical

"Yellow arrows show a posteriorly slender corpus callosum."

The index-cohort finding, in the single individual with an abnormal MRI.

PMID:32906212 SUPPORT Human Clinical

"MRI of the brain demonstrated a mildly hypoplastic corpus callosum."

Independent corroboration in a second cohort, which the index report had documented in only one individual.

Optic Nerve and Chiasm Hypoplasia

Hypoplastic optic nerves and chiasm in the individual with the abnormal MRI — a potential structural correlate of the central visual impairment, reported in a single individual.

Mri

Optic nerve hypoplasia HP:0000609 optic nerve UBERON:0000941

Show evidence (1 reference)

PMID:30929742 SUPPORT Human Clinical

"The optic nerves and chiasm are hypoplastic"

Documents the optic pathway hypoplasia on MRI.

📈

Progression

1

Infancy to Childhood

Neurodevelopmental impairment occurs within the first year of life, beginning with axial hypotonia at birth. In the index cohort the C-terminal missense carriers additionally developed a hyperkinetic movement disorder in the first year, and were later diagnosed with central visual impairment after poor visual fixation from the first months of life. Hyperkinetic movement has also been reported with onset at 8 years in a carrier outside that cluster. Seizure onset ranges from shortly after birth to age 5 and is not confined to the severe group.

Show evidence (1 reference)

PMID:30929742 SUPPORT Human Clinical

"axial hypotonia (which had been present since birth)"

Documents the congenital onset with axial hypotonia.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Ultra-rare monogenic neurodevelopmental disorder; precise population prevalence not established. Only a handful of individuals have been reported since the disorder was delineated in 2019. The 2023 review counts 11 patients reported *previously* — the two five-patient cohorts plus the single Japanese case — and describes a twelfth of its own.

Show evidence (1 reference)

PMID:37901860 SUPPORT Human Clinical

"To date, only three types of allelic variants (loss of function, in-frame deletions, and missense variants) in the VAMP2 gene have been previously reported in 11 patients with learning difficulties."

A cumulative reported-case count in the low tens is the basis for the ULTRA_RARE class; no population-based rate has been estimated.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from VAMP2-Related Neurodevelopmental Disorder:

Rett syndrome and Rett-like disorders

Overlapping Features The autistic features with hand stereotypies, absent purposeful hand movements, and developmental impairment resemble Rett syndrome; VAMP2 disease is distinguished by molecular testing.

Distinguishing Features

A de novo VAMP2 SNARE-motif variant favors this disorder.
MECP2 (or CDKL5/FOXG1) variants favor Rett syndrome or a Rett-like disorder.

Show evidence (2 references)

PMID:30929742 SUPPORT Human Clinical

"including variable motor stereotypies resembling Rett syndrome"

The index report itself frames the stereotypies as Rett-resembling, which is the source of the diagnostic confusion.

PMID:37901860 SUPPORT Human Clinical

"Patients presenting with features of either Rett syndrome or Angelman syndrome, in whom genetic testing is not suggestive, should be evaluated for variants in the VAMP2 gene, given the significant overlap in clinical presentation of these disorders."

Explicit recommendation to test VAMP2 in genetically unexplained Rett- or Angelman-like presentations — the practical content of this differential.

Angelman syndrome and Angelman-like disorders

Overlapping Features The developmental impairment, absent speech, movement disorder, and epilepsy overlap with Angelman syndrome. VAMP2 has been recovered by exome sequencing of a cohort assembled for an Angelman-syndrome-like phenotype with negative UBE3A/15q testing, so it belongs in that differential rather than only in the Rett one.

Distinguishing Features

A de novo VAMP2 variant favors this disorder.
UBE3A variants or a 15q11-q13 imprinting/deletion defect favor Angelman syndrome.

Show evidence (2 references)

PMID:34653234 SUPPORT Human Clinical

"The results of WES led to the identification of 10 new genes that cause an AS-like phenotype (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1, KCNQ3, SLC6A1 and LAS1L), all of them previously associated with other neurodevelopmental disorders."

Places VAMP2 among the genes recovered from an Angelman-syndrome-like diagnostic cohort.

PMID:37901860 SUPPORT Human Clinical

"highlights this condition as an important differential diagnosis of Rett/Angelman-type spectrum of disorders."

States the Angelman-spectrum differential directly.

Other SNAREopathies and synaptic vesicle cycle disorders

Overlapping Features Other SNARE-machinery and synaptic vesicle cycle disorders (SNAP25, STX1B, STXBP1, SYT1) overlap through developmental impairment, movement disorder, and epilepsy, and are distinguished by molecular testing.

Distinguishing Features

A de novo VAMP2 variant favors this disorder.
A variant in another SNARE/vesicle-cycle gene favors the corresponding SNAREopathy.

Show evidence (1 reference)

PMID:30929742 SUPPORT Other

"Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters."

Places VAMP2 within the SNARE complex shared with the other SNAREopathies. Definitional background rather than a study result, hence OTHER — matching how the same sentence is tagged on the fusion node.

🧫

Experimental Models

2

Reconstituted SNARE liposome lipid-mixing (fusion) assay OTHER

Cell-free reconstitution in which purified wild-type or variant VAMP2 is incorporated into fluorescent donor liposomes and the syntaxin-1/SNAP-25 t-SNARE complex into acceptor liposomes; fusion is read out as NBD-to-rhodamine dequenching. Run with and without Munc18-1, and with 50:50 wild-type:mutant donor liposomes to emulate the heterozygous state. This is the assay behind the entry's fusion claims, and behind their variant-specific limits.

Publication

PMID:30929742

Pathograph links

Impaired SNARE-Mediated Vesicle Fusion measures fidelity: moderate Isolates the SNARE fusion step from all other presynaptic biology, which is what makes it decisive for p.Ser75Pro and uninformative for variants whose defect lies in regulatory-protein interaction.

Limitations: Contains only the core SNAREs (plus Munc18-1 where added) — synaptotagmin-1, complexin, and Munc13 are absent, so a variant that acts through those regulators scores as normal. p.Glu78Ala is the worked example: pathogenic in patients, indistinguishable from wild-type here. p.Phe77Ser could not be purified and was never tested.

Readouts

Endpoint liposome fusion normalized to wild-type VAMP2

Direction: DECREASED

Interpretation: Fell to ~25% of wild-type for p.Ser75Pro; unchanged for p.Glu78Ala.

Show evidence (1 reference)

PMID:30929742 SUPPORT In Vitro

"the VAMP2 disease-associated variant p.Ser75Pro reduced the rate and extent of fusion compared to that seen with VAMP2 WT, whereas the p.Glu78Ala variant had little to no effect"

The primary readout, reported for both variants, including the negative result.

Show evidence (1 reference)

PMID:30929742 SUPPORT In Vitro

"To evaluate the functional consequence of VAMP2 variants, we employed the reconstituted, lipid-mixing assay based on NBD"

Establishes the assay as the functional test applied to the disease variants.

Show evidence (1 reference)

PMID:30929742 SUPPORT In Vitro

"We read out membrane fusion between the donor and acceptor liposome mixing by quantifying increased fluorescence resulting from the dequenching of NBD fluorescence"

Describes the reconstituted readout, establishing that this model system was applied to the disease variants.

Variant-expressing cultured neurons with synaptophysin-pHluorin imaging PRIMARY_CELL_CULTURE

Cultured neurons expressing VAMP2 disease variants, assayed by live-cell imaging of the synaptophysin-pHluorin optical reporter of synaptic vesicle recycling together with electrophysiology. Unlike the liposome assay this system contains the full presynaptic regulatory complement, and it is the system in which dominant-negative behaviour was separated from haploinsufficiency and in which aminopyridine rescue was tested.

Publication

PMID:32906212

Pathograph links

Dominant-Negative Interference with Wild-Type VAMP2 measures fidelity: moderate Distinguishes SNARE-motif missense variants, which suppress action-potential-triggered fusion in the presence of endogenous wild-type VAMP2, from the nonsense variant, which does not.

Limitations: Rat primary hippocampal neurons, not human cells — relevant because this system supplies the negative endocytosis result used to bound the recycling node and to anchor the HUMAN_MODEL_MISMATCH discussion. Variants are expressed on a wild-type background rather than knocked in at the endogenous locus, so expression level is not the patients'; only three variants were tested.

Readouts

Rate of exocytosis and size of the released recycling pool

Direction: DECREASED

Interpretation: Two of three tested variants reduced both measures relative to wild-type.

Show evidence (1 reference)

PMID:32906212 SUPPORT In Vitro

"In cellular models, two variants decrease both the rate of exocytosis and the number of synaptic vesicles released from the recycling pool, compared with wild-type."

The primary readout distinguishing variants with and without a cellular release defect.

Show evidence (1 reference)

PMID:32906212 SUPPORT In Vitro

"Synaptic vesicle recycling and neurotransmission were assayed in neurons expressing three VAMP2 variants by live-cell imaging and electrophysiology."

Establishes the model system and the assays applied.

Show evidence (1 reference)

PMID:32906212 SUPPORT In Vitro

"we used live cell imaging of an optical reporter of SV recycling, synaptophysin-pHluorin (syp-pH)."

Establishes the reporter and imaging approach that define this model system.

🐁

Animal Models

1

Synaptobrevin-2 (Vamp2) knockout mouse

Constitutive null mice are the source of the causal claim that VAMP2 is required for fast calcium-triggered synaptic vesicle fusion and for fast vesicle endocytosis. In their absence, spontaneous and sucrose-evoked fusion fall about 10-fold while fast calcium-triggered fusion falls more than 100-fold; endocytosis and recycling-pool replenishment are also delayed. The mice die immediately after birth.

Species

Mouse (Mus musculus)

Genotype

Vamp2 (synaptobrevin-2) homozygous knockout

Publication

PMID:11691998

Pathograph links

Impaired SNARE-Mediated Vesicle Fusion partially recapitulates fidelity: moderate Establishes the direction and the disproportionate sensitivity of calcium-triggered release to loss of VAMP2, which is the mechanism this node asserts.

Limitations: Homozygous null, not the heterozygous state of affected humans, and a complete absence of protein rather than a SNARE-motif missense allele acting dominant-negatively. The mice die perinatally and so model neither the surviving human neurodevelopmental course nor the graded genotype-phenotype correlation. The knockout is informative for the haploinsufficiency arm's direction of effect but cannot test dominant-negative interference, which requires mutant protein to be present.

Readouts

Fast calcium-triggered synaptic vesicle fusion

Direction: DECREASED

Interpretation: Electrophysiological measure of the fusion step this node models.

Show evidence (1 reference)

PMID:11691998 SUPPORT Model Organism

"In the absence of synaptobrevin 2, spontaneous synaptic vesicle fusion and fusion induced by hypertonic sucrose were decreased approximately 10-fold, but fast Ca2+-triggered fusion was decreased more than 100-fold."

Quantifies the fusion defect and shows calcium-triggered release is the most sensitive component.

Show evidence (1 reference)

PMID:11691998 SUPPORT Model Organism

"Thus, synaptobrevin 2 may function in catalyzing fusion reactions and stabilizing fusion intermediates but is not absolutely required for synaptic fusion."

The knockout supports a catalytic rather than strictly obligatory role, so it substantiates the node only partially — fusion is degraded, not abolished.

Impaired Synaptic Vesicle Endocytosis and Recycling partially recapitulates fidelity: low The knockout is the primary evidence that VAMP2 is required for fast endocytosis and readily-releasable-pool replenishment, not only exocytosis.

Limitations: Homozygous null rather than the human heterozygous missense/truncating state. More seriously, the direct test of endocytosis in human variant-expressing neurons was negative, so this is the one arm where the model and the human data disagree — hence LOW fidelity and PARTIALLY_RECAPITULATES rather than a claim that the model reproduces a human mechanism.

Readouts

Stimulus-dependent endocytosis of HRP and FM1-43

Direction: DECREASED

Interpretation: Tracer-uptake measure of the endocytic retrieval step.

Show evidence (1 reference)

PMID:15475946 SUPPORT Model Organism

"the stimulus-dependent endocytosis of horseradish peroxidase and fluorescent FM1-43 were delayed"

Direct measurement of delayed endocytosis in knockout synapses.

Show evidence (1 reference)

PMID:15475946 SUPPORT Model Organism

"replenishment of the pool is delayed by knockout of synaptobrevin."

Supports treating the knockout as informative for the recycling node.

Show evidence (1 reference)

PMID:30929742 SUPPORT Model Organism

"mice present severely decreased rates of both spontaneous and Ca2+-triggered synaptic-vesicle fusion, and these mice die immediately after birth."

The index clinical report's own framing of the knockout phenotype, including the perinatal lethality that bounds its use as a disease model.

{ }

Source YAML

click to show

name: VAMP2-Related Neurodevelopmental Disorder
creation_date: "2026-07-06T00:00:00Z"
description: >-
  A neurodevelopmental disorder caused by de novo variants in VAMP2, which encodes
  the vesicular SNARE protein VAMP2 (synaptobrevin-2). Together with its
  plasma-membrane partners syntaxin-1 and SNAP-25, VAMP2 forms the neuronal SNARE complex
  that mediates calcium-triggered fusion of synaptic vesicles and neurotransmitter
  release. Three allelic classes are reported (a scheme that is the literature's
  and not exhaustive — a de novo start-loss variant fits none of them):
  non-synonymous (missense) variants
  within the SNARE motif, of which the three index-cohort variants cluster in its
  C-terminal portion; in-frame single-amino-acid deletions at more N-terminal
  SNARE-motif residues; and truncating loss-of-function variants. Two mechanisms
  are correspondingly invoked — dominant-negative interference with wild-type
  VAMP2 by SNARE-motif missense variants, and haploinsufficiency from truncating
  variants — and the in vitro fusion defect is variant-specific rather than
  uniform across the allelic series. Affected individuals present from birth with
  axial hypotonia, intellectual disability, and autistic features with Rett-like
  motor stereotypies and a virtual absence of purposeful hand movements. Within the
  index cohort the three children with C-terminal missense variants were the more
  severely affected, additionally having central visual impairment and a
  hyperkinetic movement disorder. Neither association is curated as holding
  across all reported patients: hyperkinetic movement is directly documented
  outside that cluster, and for central visual impairment the poor visual
  fixation that precedes it is. Epilepsy does not track genotype as cleanly: within the index cohort
  one C-terminal missense carrier never had seizures while one
  single-amino-acid-deletion carrier did, and EEG abnormalities were recorded
  across the cohort. It completes the three core neuronal SNAREs among the synaptic
  vesicle cycle disorders — the vesicle-side (v-SNARE) counterpart of SNAP25
  (t-SNARE) and syntaxin-1B.
category: Mendelian
parents:
- Neurodevelopmental Disorder
disease_term:
  preferred_term: VAMP2-related neurodevelopmental disorder with hypotonia and autistic features
  term:
    id: MONDO:0032900
    label: neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare monogenic neurodevelopmental disorder; precise population prevalence
    not established. Only a handful of individuals have been reported since the
    disorder was delineated in 2019. The 2023 review counts 11 patients reported
    *previously* — the two five-patient cohorts plus the single Japanese case —
    and describes a twelfth of its own.
  evidence:
  - reference: PMID:37901860
    reference_title: "VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only three types of allelic variants (loss of function, in-frame
      deletions, and missense variants) in the VAMP2 gene have been previously
      reported in 11 patients with learning difficulties.
    explanation: >-
      A cumulative reported-case count in the low tens is the basis for the
      ULTRA_RARE class; no population-based rate has been estimated.
references:
- reference: PMID:30929742
  title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
- reference: PMID:32906212
  title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
- reference: PMID:32336483
  title: "Variant in the neuronal vesicular SNARE VAMP2 (synaptobrevin-2): First report in Japan."
- reference: PMID:37901860
  title: "VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders."
- reference: PMID:34653234
  title: "New genes involved in Angelman syndrome-like: Expanding the genetic spectrum."
- reference: PMID:11691998
  title: "SNARE function analyzed in synaptobrevin/VAMP knockout mice."
- reference: PMID:15475946
  title: "Synaptobrevin is essential for fast synaptic-vesicle endocytosis."
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 VAMP2 variants.
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report five heterozygous de novo mutations in VAMP2 in unrelated
      individuals presenting with a neurodevelopmental disorder characterized by
      axial hypotonia (which had been present since birth), intellectual
      disability, and autistic features.
    explanation: >-
      Establishes the de novo dominant genetic basis and core phenotype.
pathophysiology:
- name: VAMP2 v-SNARE Defect
  conforms_to: "synaptic_vesicle_cycle#Synaptic Vesicle Cycle Protein Deficiency"
  biological_scale: MOLECULAR
  description: >-
    De novo variants affect conserved residues of the VAMP2 SNARE motif (residues
    31-91) — the region whose zippering with syntaxin-1 and SNAP-25 provides the
    energy for membrane fusion. Three allelic classes are reported — a scheme that
    is the literature's and not exhaustive, since a de novo start-loss variant
    (c.1A>G, p.Met1?) fits none of them: non-synonymous variants within the
    motif, of which the three index-cohort variants
    (p.Ser75Pro, p.Phe77Ser, p.Glu78Ala) cluster in its C-terminal portion, with
    p.Gly73Trp reported adjacent to that cluster and p.Arg56Leu, p.Arg66Pro and
    p.Ala67Pro lying further N-terminally; in-frame single-amino-acid deletions at
    more N-terminal residues (p.Val43del, p.Ile45del); and truncating
    loss-of-function variants (p.Arg56*, p.Tyr113Glnfs*12). VAMP2 is the vesicle-associated (v-)SNARE essential for
    vesicular exocytosis and activity-dependent neurotransmitter release, so these
    variants act directly on the fusion machinery. The downstream route differs by
    allelic class: SNARE-motif missense variants act dominant-negatively, whereas
    truncating variants are proposed to act through haploinsufficiency.
  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:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      VAMP2 encodes the vesicular SNARE protein VAMP2 (also called
      synaptobrevin-2).
    explanation: >-
      Identifies VAMP2/synaptobrevin-2 as the vesicular SNARE whose defect defines
      this disorder. Definitional background rather than a study result, hence
      OTHER.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, we identified two single-amino-acid deletions and three
      non-synonymous variants affecting conserved residues within the C terminus of
      the VAMP2 SNARE motif.
    explanation: >-
      Defines the variant spectrum of the index cohort and localizes the lesion to
      the fusion machinery. Note this abstract sentence lumps all five variants as
      C-terminal; the discussion is more precise, and the genetic section records
      that the two deletions sit at residues 43 and 45.
  - reference: PMID:37901860
    reference_title: "VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only three types of allelic variants (loss of function, in-frame
      deletions, and missense variants) in the VAMP2 gene have been previously
      reported in 11 patients with learning difficulties.
    explanation: >-
      Establishes that the allelic series comprises three classes, including
      truncating loss-of-function variants beyond the original missense and
      in-frame-deletion spectrum.
  downstream:
  - target: Dominant-Negative Interference with Wild-Type VAMP2
    causal_link_type: DIRECT
    hypothesis_groups:
    - dominant_negative_snare_interference
    description: >-
      Route taken by SNARE-motif missense variants, which produce a stable protein
      that is incorporated into SNARE complexes.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This implies that p.Ser75Pro mutant dominantly interferes with WT
      explanation: >-
        Direct evidence that a SNARE-motif missense variant acts on wild-type
        VAMP2 rather than by simple loss of dose.
  - target: Impaired Synaptic Vesicle Endocytosis and Recycling
    causal_link_type: DIRECT
    description: >-
      A parallel arm, not a consequence of the fusion defect. VAMP2 is separately
      required for fast endocytic retrieval, so loss of the protein degrades both
      halves of the vesicle cycle independently. Drawn from the trigger rather
      than from the fusion node because the cited evidence establishes shared
      dependence on one protein, not that impaired fusion causes impaired
      retrieval — and because the module places endocytosis upstream of fusion,
      so a fusion-to-endocytosis edge would invert it.
    evidence:
    - reference: PMID:15475946
      reference_title: "Synaptobrevin is essential for fast synaptic-vesicle endocytosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thus, synaptobrevin is essential for two fast synapse-specific membrane
        trafficking reactions: fast exocytosis for neurotransmitter release and
        fast endocytosis that mediates rapid reuse of synaptic vesicles.
      explanation: >-
        States the two requirements as parallel functions of one protein, which is
        why this arm hangs off the shared molecular lesion rather than off the
        fusion node.
  - target: VAMP2 Haploinsufficiency
    causal_link_type: DIRECT
    hypothesis_groups:
    - truncating_haploinsufficiency
    description: >-
      Route proposed for truncating variants, where nonsense-mediated decay of the
      mutant transcript leaves a single functional allele.
    evidence:
    - reference: PMID:32906212
      reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        does not cause dominant-negative effects, suggesting that
        haploinsufficiency underlies the disease mechanism for the R56X variant
        patient
      explanation: >-
        The in vitro half of the claim: no dominant-negative effect was detected for the
        truncating allele. The authors note the effect was not directly tested and the
        construct lacked the transmembrane domain.
    - reference: PMID:32906212
      reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        who presented with a milder phenotype without epilepsy.
      explanation: >-
        The clinical half, split into its own item because the source sentence
        mixes an in vitro result with a patient phenotype. A milder phenotype is
        consistent with, but does not establish, the haploinsufficiency mechanism,
        hence INDIRECT.
- name: Dominant-Negative Interference with Wild-Type VAMP2
  biological_scale: MOLECULAR
  description: >-
    SNARE-motif missense variants produce a protein that is still incorporated
    into the SNARE complex but assembles or zippers defectively, so the mutant
    poisons complexes that also contain wild-type VAMP2. In the reconstituted
    fusion assay, liposomes carrying a 50:50 mixture of wild-type and p.Ser75Pro
    VAMP2 fused no better than liposomes carrying mutant protein alone — the
    signature of dominant-negative action, and a direct explanation for dominant
    inheritance of a heterozygous variant. Cellular assays extend this to
    p.Gly73Trp and p.Arg56Leu, which reduce action-potential-triggered vesicle
    fusion and are associated with the more severe, epilepsy-bearing phenotype.
  role: mediator
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      in the case of p.Ser75Pro, the fusion profile for the mixed v-liposomes
      (50:50 WT:mutant) was identical to the fusion profile for the homogenous
      samples containing only the mutant proteins
    explanation: >-
      The mixed-liposome experiment is the direct demonstration of dominant-negative
      interference, deliberately designed to emulate the heterozygous state.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      exert a dominant-negative effect on action potential-triggered SV fusion and
      neurotransmitter release in vitro
    explanation: >-
      Independent replication of dominant-negative action for further SNARE-motif
      missense variants, in neurons rather than liposomes.
  downstream:
  - target: Impaired SNARE-Mediated Vesicle Fusion
    causal_link_type: DIRECT
    hypothesis_groups:
    - dominant_negative_snare_interference
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the VAMP2 disease-associated variant p.Ser75Pro reduced the rate and extent
        of fusion compared to that seen with VAMP2 WT
      explanation: >-
        The dominant-negative allele's measured effect on the fusion step.
- name: VAMP2 Haploinsufficiency
  biological_scale: MOLECULAR
  description: >-
    Truncating variants (p.Arg56*, p.Tyr113Glnfs*12) are predicted to trigger
    nonsense-mediated decay, leaving a single functional VAMP2 allele. Unlike the
    missense variants, the truncated protein did not interfere with wild-type
    VAMP2 in cellular assays, so reduced gene dose rather than poisoning of the
    complex is the proposed mechanism. VAMP2 is strongly constrained in population
    databases, consistent with intolerance to loss of function. Two caveats keep
    this arm weaker than the dominant-negative one: nonsense-mediated decay is
    predicted rather than measured, and the authors attribute the absent
    dominant-negative effect possibly to their construct lacking the
    transmembrane domain, noting it was not directly tested.
  role: mediator
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the ExAC database (last accessed January 30, 2018), which contains
      exomes from 60,706 unrelated individuals, there are no listed
      loss-of-function variants in VAMP2
    explanation: >-
      Population-database constraint indicating VAMP2 loss of function is not
      tolerated in unaffected individuals — the background against which
      haploinsufficiency is plausible. The ExAC framing is quoted in full because
      the bare clause would otherwise read as a claim that no VAMP2 LoF variants
      exist, which this entry contradicts by curating two in affected children.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      predicting a premature truncation and haploinsufficiency from nonsense
      mediated decay.
    explanation: >-
      The proposed haploinsufficiency mechanism for the truncating allele. This is a
      prediction from the variant's position, not a measurement of transcript level,
      which is why the evidence source is OTHER.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sympathetic skin responses were very low amplitude, with relative
      preservation of response latencies, providing confirmation that VAMP2
      haploinsufficiency caused symptoms.
    explanation: >-
      The only in-human functional measurement bearing on this arm — reduced
      autonomic nerve responses in the truncating-variant carrier. The paper's
      "providing confirmation" is an n-of-1 overclaim: one patient, no controls,
      and an assay that cannot distinguish reduced gene dose from any other cause
      of impaired transmission, so the item carries the measurement and not the
      confirmation.
  downstream:
  - target: Impaired SNARE-Mediated Vesicle Fusion
    causal_link_type: DIRECT
    hypothesis_groups:
    - truncating_haploinsufficiency
    evidence:
    - reference: PMID:11691998
      reference_title: "SNARE function analyzed in synaptobrevin/VAMP knockout mice."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In the absence of synaptobrevin 2, spontaneous synaptic vesicle fusion and
        fusion induced by hypertonic sucrose were decreased approximately 10-fold,
        but fast Ca2+-triggered fusion was decreased more than 100-fold.
      explanation: >-
        Loss of VAMP2 dose degrades fusion — shown for complete loss in the mouse
        knockout, so it is graded INDIRECT for the human heterozygous reduced-dose
        state.
- name: Impaired SNARE-Mediated Vesicle Fusion
  conforms_to: "synaptic_vesicle_cycle#Impaired Calcium-Triggered SNARE-Mediated Vesicle Fusion"
  biological_scale: CELLULAR
  description: >-
    VAMP2 is one of the three core neuronal SNAREs whose zippering, triggered by the
    calcium sensor synaptotagmin-1, fuses the synaptic vesicle with the presynaptic
    membrane. The fusion defect is variant-specific rather than uniform across the
    allelic series: in the reconstituted lipid-mixing assay p.Ser75Pro reduced
    fusion to roughly 25% of wild-type and could not be activated by Munc18-1 (a
    >90% loss-of-function under Munc18-activated conditions), whereas p.Glu78Ala
    was indistinguishable from wild-type and p.Phe77Ser could not be purified for
    testing. In cultured neurons, two of three variants tested reduced both the
    rate of exocytosis and the size of the released recycling pool. The authors
    therefore frame impaired fusion as one of the possible mechanisms and
    explicitly invoke mutation-specific mechanisms; for variants without a
    reconstituted fusion defect, disrupted interaction with regulatory proteins
    absent from the assay is the proposed alternative. This is the module's key
    conformance target — the fusion-machinery 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:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Reconstituted fusion involving a lipid-mixing assay indicated impairment in
      vesicle fusion as one of the possible associated disease mechanisms.
    explanation: >-
      The authors' own hedged framing: reconstituted fusion impairment is one of
      the possible mechanisms, not the established sole mechanism.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The reduction in the fusion associated with p.Ser75Pro was estimated to be
      approximately 25% that in the WT
    explanation: >-
      Quantifies the fusion defect for the one variant with a clear reconstituted
      phenotype.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consequently, we observed a significant (>90%) loss-of-function phenotype
      with the p.Ser75Pro variant under these conditions.
    explanation: >-
      Under Munc18-activated (more physiological) conditions the p.Ser75Pro defect
      is far larger than the basal 25% reduction.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the fusion profile associated with the p.Glu78Ala was indistinguishable from
      that of the WT
    explanation: >-
      Bounds the claim: a pathogenic C-terminal variant had no reconstituted fusion
      defect, so impaired fusion cannot be asserted for the whole allelic series.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Variability in the effects of different VAMP2 mutants under in vitro
      conditions points toward mutation-specific mechanisms underlying the
      presynaptic defect of the affected children
    explanation: >-
      The authors' explicit statement that the mechanism is mutation-specific.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In cellular models, two variants decrease both the rate of exocytosis and the
      number of synaptic vesicles released from the recycling pool, compared with
      wild-type.
    explanation: >-
      Independent confirmation of the exocytosis defect in neurons. Note the
      "recycling pool released" figure is an exocytosis-extent measure, not a
      measure of endocytic retrieval.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Together with its partners syntaxin-1A and synaptosomal-associated protein 25
      (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release
      neurotransmitters.
    explanation: >-
      Establishes VAMP2 as a core SNARE partner of syntaxin-1 and SNAP-25 in the
      fusion reaction. Definitional background rather than a study result, hence
      OTHER.
  downstream:
  - target: Disrupted Neurotransmission and Impaired Neurodevelopment
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        Even a slight alteration of the fusion kinetics in vitro would translate to
        a dramatic effect on the release of neurotransmitters release at the
        neuronal synapses.
      explanation: >-
        The authors' inference bridging the in vitro fusion defect to in vivo release
        failure. It is reasoning in the Discussion, not a measurement — hence INDIRECT
        and OTHER rather than a clinical observation.
- name: Impaired Synaptic Vesicle Endocytosis and Recycling
  conforms_to: "synaptic_vesicle_cycle#Impaired Synaptic Vesicle Endocytosis and Recycling"
  biological_scale: CELLULAR
  description: >-
    Beyond its role in fusion, VAMP2 is required for fast, stimulus-dependent
    synaptic vesicle endocytosis and for replenishment of the readily releasable
    pool. Synaptobrevin-2 knockout synapses show delayed pool replenishment,
    altered vesicle shape and size, and delayed uptake of endocytic tracers.
    **This node rests on the mouse knockout only.** When the human disease
    variants were tested directly, post-stimulus syp-pHluorin decay — the
    endocytosis readout — was not significantly altered by any of them. The
    reduced "recycling pool released" measure reported for two variants is an
    exocytosis-extent measure, not a measure of endocytic retrieval, and it
    belongs to the fusion arm. Whether losing one VAMP2 allele or expressing a
    SNARE-motif variant impairs human endocytosis is therefore untested at best
    and negative on the one direct measurement available.
  role: mediator
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: synaptic vesicle endocytosis
    term:
      id: GO:0048488
      label: synaptic vesicle endocytosis
    modifier: DECREASED
  - preferred_term: synaptic vesicle recycling
    term:
      id: GO:0036465
      label: synaptic vesicle recycling
    modifier: DECREASED
  evidence:
  - reference: PMID:15475946
    reference_title: "Synaptobrevin is essential for fast synaptic-vesicle endocytosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here we show that synaptobrevin-2 is also essential for fast
      synaptic-vesicle endocytosis.
    explanation: >-
      Establishes the endocytic requirement for VAMP2 in knockout mouse synapses.
  - reference: PMID:15475946
    reference_title: "Synaptobrevin is essential for fast synaptic-vesicle endocytosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the stimulus-dependent endocytosis of horseradish peroxidase and fluorescent
      FM1-43 were delayed
    explanation: >-
      The direct measurement of delayed endocytosis behind this node.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      The post-stimulus fluorescence decay of syp-pH, representing endocytosis, is
      not significantly altered by any of the VAMP2 variants compared to WT
    explanation: >-
      The only direct test of endocytosis in the human disease variants was
      negative. Curated as REFUTE so the node cannot be read as an established
      human mechanism; it stands on the mouse knockout alone.
  downstream:
  - target: Disrupted Neurotransmission and Impaired Neurodevelopment
    causal_link_type: DIRECT
    description: >-
      A recycling pool that refills too slowly limits sustained release during
      repetitive activity, compounding the fusion deficit.
    evidence:
    - reference: PMID:15475946
      reference_title: "Synaptobrevin is essential for fast synaptic-vesicle endocytosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We demonstrate that after depletion of the readily releasable vesicle
        pool, replenishment of the pool is delayed by knockout of synaptobrevin.
      explanation: >-
        Delayed replenishment is the mechanism by which the recycling defect
        degrades ongoing synaptic transmission.
- name: Disrupted Neurotransmission and Impaired Neurodevelopment
  conforms_to: "synaptic_vesicle_cycle#Neurotransmitter Release Failure and Synaptic Transmission Deficit"
  biological_scale: ORGANISM
  description: >-
    Impaired SNARE-mediated fusion reduces activity-dependent neurotransmitter
    release, disturbing cortical synaptic transmission and activity-dependent brain
    development. This produces axial hypotonia from birth, intellectual disability,
    and autistic features with motor stereotypies. Within the index cohort the
    three C-terminal missense carriers were additionally the ones with central
    visual impairment and a hyperkinetic movement disorder, but neither is curated
    as holding across all reported patients: a p.Ala67Pro carrier developed a
    hyperkinetic movement disorder, and for central visual impairment it is the
    preceding poor visual fixation that is documented outside the cluster.
    Seizures occur across allelic classes and are likewise not curated as a
    genotype-specific consequence.
  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: DECREASED
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key
      roles of this gene in human brain development and function.
    explanation: >-
      Frames the disorder as a genetic synaptopathy in which impaired VAMP2 function
      disrupts brain development.
  downstream:
  - target: Axial Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The genetic synaptopathy caused by VAMP2 de novo mutations highlights the
        key roles of this gene in human brain development and function.
      explanation: >-
        A general framing sentence, not a demonstration of this specific edge. It
        establishes that VAMP2 disruption impairs brain development; the hypotonia
        association itself is evidenced on the phenotype. Graded INDIRECT accordingly.
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The genetic synaptopathy caused by VAMP2 de novo mutations highlights the
        key roles of this gene in human brain development and function.
      explanation: >-
        A general framing sentence rather than a demonstration that impaired
        release causes the cognitive phenotype specifically; no intermediate steps
        are established. Graded INDIRECT accordingly.
  - target: Autistic Behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These results further delineate an emerging spectrum of human core
        synaptopathies caused by variants in genes that encode SNAREs and essential
        regulatory components of the synaptic machinery.
      explanation: >-
        Places the behavioural phenotype within the shared synaptopathy mechanism rather
        than asserting a dedicated autism-specific pathway. No mechanistic route from
        impaired release to autistic behaviour is established.
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In all affected children, family histories, pregnancies, and birth
        histories were unremarkable, and neurodevelopmental impairment occurred
        within the first year of life.
      explanation: >-
        Establishes the developmental impairment as the presenting consequence, with no
        competing perinatal explanation; the mechanistic intermediates are not
        demonstrated.
  - target: Motor Stereotypies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      No mechanistic route from impaired presynaptic release to stereotyped motor
      output is established; the association is clinical.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All children showed autistic features, typically including flapping or
        flailing of the arms, as well as hand wringing or clapping.
      explanation: >-
        The clinical association behind this edge. No mechanistic intermediates are
        demonstrated, hence the indirect edge.
  - target: Absent Purposeful Hand Movements
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinically constant in the index cohort, but the intermediates between
      reduced neurotransmitter release and loss of purposeful hand use are unknown.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A virtual absence of purposeful hand movements was present in all cases
      explanation: >-
        The clinical association behind this edge; the intermediates are unknown, hence
        the indirect edge.
  - target: Absent Speech
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Severity tracks the allelic class, but no mechanistic route to the language
      phenotype specifically is established.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Severe language impairment was present in the three more severely affected
        children (individuals 1–3), none of whom had attained meaningful speech
        production
      explanation: >-
        The clinical association behind this edge, including its genotype gradient; no
        mechanistic route is established.
  - target: Inability to Walk
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Follows the severe end of the allelic series; intermediates between the
      release deficit and the motor outcome are not established.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Motor development in individuals 1–3 was severely impaired, and these
        children had not attained the ability to walk.
      explanation: >-
        The clinical association behind this edge; no mechanistic route is established.
  - target: Central Visual Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cortical rather than ocular. Optic nerve and chiasm hypoplasia was seen in
      the one individual with an abnormal MRI, offering a candidate structural
      correlate, but it was not looked for systematically.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        these individuals were later diagnosed with central visual impairment
      explanation: >-
        The clinical association behind this edge; the optic-pathway correlate is
        recorded separately under imaging findings and was seen in one individual.
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A presynaptic release deficit is a plausible route to network
      hyperexcitability, but the balance of excitatory versus inhibitory
      impairment in this disorder has not been measured. Note the aminopyridine
      work reports desynchronized GABA release, which would bear on this.
    evidence:
    - reference: PMID:32906212
      reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Aminopyridine treatment increases the rate and extent of exocytosis and
        total synaptic charge transfer and desynchronizes GABA release.
      explanation: >-
        The GABA-release observation that makes an excitation/inhibition imbalance route
        plausible. It is a drug-effect measurement, not a demonstration that the disease
        variants cause seizures, hence the indirect edge.
  - target: EEG Abnormality
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Recorded across the cohort including in individuals without clinical
      seizures, so it is curated as its own consequence rather than as a marker of
      the seizure node.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Individual 1 did not present with epileptic seizures, but ictal EEG
        recording at the age of 15 months showed high-voltage delta activity with
        interspersed sharp-and-slow-wave complexes over the right central and
        posterior brain regions.
      explanation: >-
        Shows the EEG abnormality arising independently of clinical seizures, which
        is why it is modelled as its own downstream consequence.
  - target: Attention Deficit Hyperactivity Disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the behavioural phenotype alongside autistic features; no
      mechanistic route from impaired presynaptic release is established.
    evidence:
    - reference: PMID:32906212
      reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Later he was diagnosed with ASD and attention deficit hyperactivity
        disorder (ADHD).
      explanation: >-
        The clinical association behind this edge; the intermediates are unknown, hence
        the indirect edge.
  - target: Chorea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A component movement type of the hyperkinetic movement disorder; the
      intermediates are the same unknown ones.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        moderate chorea (individuals 1 and 3) to a mixed-movement disorder with
        severe chorea and dystonic posturing (individual 2)
      explanation: >-
        The clinical association behind this edge; no mechanistic route is established,
        hence the indirect edge.
  - target: Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A component movement type of the hyperkinetic movement disorder.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Abnormal movements ranged from dystonic posturing (mainly involving the
        trunk, neck, and lower limbs)
      explanation: >-
        The clinical association behind this edge; no mechanistic route is established,
        hence the indirect edge.
  - target: Myoclonus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A component movement type of the hyperkinetic movement disorder, and a
      seizure semiology in an independently reported case.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        or myoclonic jerks (individual 3)
      explanation: >-
        The clinical association behind this edge; no mechanistic route is established,
        hence the indirect edge.
  - target: Infantile Spasms
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A seizure type reported in this disorder; modelled alongside Seizures rather
      than beneath it because the entry curates it as its own phenotype.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        At 12 months, individual 3 presented with infantile spasms that were
        associated with diffuse EEG paroxysms.
      explanation: >-
        The clinical association behind this edge; the route from presynaptic release
        failure to this seizure type is not established.
  - target: Hyperkinetic Movement Disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The intermediates are unknown. VAMP2 is most highly expressed in the putamen,
      which offers a candidate anatomical substrate for a hyperkinetic movement
      disorder, but no study connects the expression pattern to the phenotype.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        This analysis showed the highest VAMP2 expression in the putamen and the
        frontal lobes
      explanation: >-
        Regional expression is suggestive of a striatal substrate but does not
        establish the causal chain, hence INDIRECT and an indirect edge.
phenotypes:
- name: Axial Hypotonia
  category: Clinical
  description: >-
    Axial hypotonia present since birth, the earliest sign of neurological
    involvement.
  diagnostic: true
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  phenotype_contexts:
  - onset:
      onset_category: CONGENITAL
      notes: Present since birth; the earliest sign of neurological involvement.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The earliest sign of neurological involvement was axial hypotonia at
        birth.
      explanation: >-
        Establishes congenital onset for this phenotype.
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a neurodevelopmental disorder characterized by axial hypotonia (which had
      been present since birth), intellectual disability, and autistic features.
    explanation: >-
      Documents axial hypotonia from birth as a core feature.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we describe five unrelated individuals who had shown hypotonia since birth
    explanation: >-
      Frequency justification: hypotonia in 5/5 of the index cohort. Curated
      VERY_FREQUENT rather than OBLIGATE because five probands is a narrow
      denominator on which to assert universality.
- name: Intellectual Disability
  category: Clinical
  description: >-
    Intellectual disability, moderate in the two individuals with in-frame
    single-amino-acid deletions and severe in the three with C-terminal missense
    variants.
  diagnostic: true
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      axial hypotonia (which had been present since birth), intellectual
      disability, and autistic features.
    explanation: >-
      Documents intellectual disability as a core feature.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      who had intellectual disability (ID) with autistic features
    explanation: >-
      Frequency justification: intellectual disability in 5/5 of the index
      cohort. Curated VERY_FREQUENT rather than OBLIGATE because five probands is
      a narrow denominator, and the later cohort reports developmental delay and
      learning difficulty of varying degree rather than uniform severity.
- name: Autistic Behavior
  category: Clinical
  description: >-
    Autistic features in every individual of the index cohort, typically flapping
    or flailing of the arms and hand wringing or clapping. Not universal across
    all reported patients: one individual in the second cohort was formally
    evaluated and did not meet autism criteria.
  diagnostic: true
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      axial hypotonia (which had been present since birth), intellectual
      disability, and autistic features.
    explanation: >-
      Documents autistic features as a core feature.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All children showed autistic features, typically including flapping or
      flailing of the arms, as well as hand wringing or clapping.
    explanation: >-
      Frequency justification: explicit "all children" statement over the index
      cohort. Curated VERY_FREQUENT rather than OBLIGATE because the independent
      second cohort includes a patient formally evaluated for autism who did not
      meet criteria, so autistic features are not universal.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      reveal common features of global developmental delay, autistic tendencies,
      behavioral disturbances, and a higher propensity to develop epilepsy.
    explanation: >-
      Independent second cohort confirming autistic features as a common feature.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He received an autism evaluation at age 3, and did not meet criteria for
      autism, but displayed ADHD tendencies.
    explanation: >-
      A formally evaluated patient who did not meet autism criteria — the reason
      this phenotype is VERY_FREQUENT rather than OBLIGATE despite the index
      cohort's "all children" statement.
- name: Hyperkinetic Movement Disorder
  category: Clinical
  description: >-
    A hyperkinetic movement disorder in three of the five individuals of the index
    cohort — all C-terminal missense carriers — starting in the first year of life
    and ranging from dystonic posturing and moderate chorea to severe generalized
    chorea or myoclonic jerks. Neither the genotype restriction nor the infantile
    onset generalizes: an independently reported carrier of p.Ala67Pro, which lies
    N-terminal to that cluster, developed hyperkinetic movement at 8 years.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hyperkinetic movements
    term:
      id: HP:0002487
      label: Hyperkinetic movements
  phenotype_contexts:
  - onset:
      onset_category: INFANTILE
      notes: >-
        Infantile onset in the index-cohort C-terminal missense carriers. Not the
        only reported onset — see the JUVENILE context below.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        exhibited a hyperkinetic movement disorder starting in the first year of
        life
      explanation: >-
        Establishes infantile onset in the index cohort.
  - onset:
      onset_category: JUVENILE
      min_age_years: 8.0
      notes: >-
        Juvenile onset at 8 years in the independently reported p.Ala67Pro
        carrier, outside the C-terminal cluster. JUVENILE (HP:0003621) spans 5-15
        years and is the band that contains 8; CHILDHOOD (HP:0011463) is defined
        as 1-5 years and would contradict the cited age.
    evidence:
    - reference: PMID:32336483
      reference_title: "Variant in the neuronal vesicular SNARE VAMP2 (synaptobrevin-2): First report in Japan."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        At 8 years of age hyperkinetic movement occurred.
      explanation: >-
        Documents onset well beyond infancy, so the structured onset layer matches
        the phenotype description rather than contradicting it.
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abnormal movements ranged from dystonic posturing (mainly involving the
      trunk, neck, and lower limbs) and moderate chorea (individuals 1 and 3) to a
      mixed-movement disorder with severe chorea and dystonic posturing
      (individual 2) or myoclonic jerks (individual 3).
    explanation: >-
      Frequency justification: the movement disorder is documented in 3 of the 5
      individuals in the index cohort (60%), supporting the FREQUENT band, and
      details its component movement types. A sixth patient is captured by the
      juvenile-onset context above and by the next evidence item.
  - reference: PMID:32336483
    reference_title: "Variant in the neuronal vesicular SNARE VAMP2 (synaptobrevin-2): First report in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 8 years of age hyperkinetic movement occurred.
    explanation: >-
      A hyperkinetic movement disorder in a p.Ala67Pro carrier, outside the
      C-terminal cluster and with juvenile rather than infantile onset. This is
      why neither the genotype restriction nor the infantile-onset generalization
      is curated as holding across all reported patients.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a more severe phenotype with additional neurological features, including
      central visual impairment, hyperkinetic movement disorder, and epilepsy or
      electroencephalography abnormalities.
    explanation: >-
      Documents the hyperkinetic movement disorder in the more severe phenotype.
- name: Central Visual Impairment
  category: Clinical
  description: >-
    Central (cerebral) visual impairment in three of the five individuals of the
    index cohort — the C-terminal missense carriers — preceded by poor visual
    fixation evident in the first months of life. Poor visual fixation is also
    reported outside that cluster, in the p.Ala67Pro carrier.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cerebral visual impairment
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a more severe phenotype with additional neurological features, including
      central visual impairment, hyperkinetic movement disorder, and epilepsy or
      electroencephalography abnormalities.
    explanation: >-
      Documents central visual impairment in the more severe phenotype.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Poor visual fixation (with only brief and occasional visual contact, lasting
      up to a few seconds) had been evident since the first months of life in
      three affected individuals (1–3); these individuals were later diagnosed
      with central visual impairment
    explanation: >-
      Frequency justification: central visual impairment in 3 of the 5
      individuals in the index cohort (60%), supporting the FREQUENT band, and
      documents the preceding poor visual fixation. The denominator is the five
      index-cohort probands.
  - reference: PMID:32336483
    reference_title: "Variant in the neuronal vesicular SNARE VAMP2 (synaptobrevin-2): First report in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypotonia at early infancy, poor visual fixation, and absence of purposeful
      hand movements may be indicative of the diagnosis for VAMP2 variant.
    explanation: >-
      Independent case report proposing poor visual fixation as a diagnostically
      indicative feature.
- name: Seizures
  category: Clinical
  description: >-
    Epileptic seizures in a subset of individuals, with a wide semiology: focal
    seizures and generalized tonic-clonic seizures, infantile spasms with
    convulsive status epilepticus, and staring episodes with eyelid myoclonia.
    Infantile spasms with hypsarrhythmia are reported independently.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a more severe phenotype with additional neurological features, including
      central visual impairment, hyperkinetic movement disorder, and epilepsy or
      electroencephalography abnormalities.
    explanation: >-
      Documents epilepsy in the more severe phenotype.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual 2 suffered from multiple focal seizures per day; these started
      shortly after birth
    explanation: >-
      Documents focal seizure semiology and its neonatal onset in the index cohort.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a higher propensity to develop epilepsy.
    explanation: >-
      Independent second cohort confirming increased epilepsy propensity.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual 4 developed infrequent staring episodes with eyelid myoclonia at
      5 years of age and had a single episode of non-convulsive status epilepticus
      at the age of 11 years.
    explanation: >-
      A single-amino-acid-deletion carrier — from the milder group — who did have
      seizures. Together with the seizure-free p.Ser75Pro carrier this is why
      epilepsy is not curated as tracking the C-terminal missense genotype.
- name: Infantile Spasms
  category: Clinical
  description: >-
    Infantile spasms, reported with diffuse EEG paroxysms in the index cohort and
    with hypsarrhythmia responsive to adrenocorticotropic hormone in an
    independently reported case.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 12 months, individual 3 presented with infantile spasms that were
      associated with diffuse EEG paroxysms.
    explanation: >-
      Documents infantile spasms in the index cohort.
  - reference: PMID:32336483
    reference_title: "Variant in the neuronal vesicular SNARE VAMP2 (synaptobrevin-2): First report in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He presented with infantile spasms at 6 months, and electroencephalography
      (EEG) showed hypsarrhythmia.
    explanation: >-
      Independent confirmation of infantile spasms with hypsarrhythmia.
- name: EEG Abnormality
  category: Clinical
  description: >-
    Abnormal EEG, present in individuals with and without clinical seizures —
    high-voltage delta activity with sharp-and-slow-wave complexes, fast rhythmic
    activity, disorganized paroxysms, and generalized or multifocal abnormalities.
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures or abnormal EEG occurred in four affected individuals.
    explanation: >-
      Documents the combined seizure/EEG-abnormality burden in the index cohort.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual 1 did not present with epileptic seizures, but ictal EEG
      recording at the age of 15 months showed high-voltage delta activity with
      interspersed sharp-and-slow-wave complexes over the right central and
      posterior brain regions.
    explanation: >-
      Shows the EEG abnormality is dissociable from clinical seizures, which is why
      it is curated as a phenotype in its own right.
- name: Motor Stereotypies
  category: Clinical
  description: >-
    Rett-like motor stereotypies in every individual of the index cohort — arm
    flapping or flailing, hand wringing, washing or clapping, body rocking, and
    head banging, and documented again in an independently reported patient. The
    repertoire varies between individuals: one had body rocking and head banging
    without stereotyped hand movements.
  diagnostic: true
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Motor stereotypy
    term:
      id: HP:0000733
      label: Motor stereotypy
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All children showed autistic features, typically including flapping or
      flailing of the arms, as well as hand wringing or clapping.
    explanation: >-
      Frequency justification: stereotypies documented in all five index-cohort
      individuals, and in a sixth reported independently — 6/6 of the patients in
      whom they were assessed. VERY_FREQUENT rather than OBLIGATE because the
      denominator is narrow: the second cohort neither reports nor excludes
      stereotypies, and silence is not a documented absence.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional repetitive behavior patterns included body rocking and head
      banging.
    explanation: >-
      Documents the additional stereotypy repertoire.
  - reference: PMID:37901860
    reference_title: "VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 15-month-old girl presented with early onset hypotonia, global
      developmental delay, learning difficulties, microcephaly, nystagmus,
      strabismus, and stereotypies.
    explanation: >-
      An independently reported patient with stereotypies, outside the index
      cohort — the sixth assessed patient behind the frequency band.
- name: Absent Purposeful Hand Movements
  category: Clinical
  description: >-
    A virtual absence of purposeful hand movements, present in all five
    individuals of the index cohort and proposed as diagnostically indicative.
    Together with the hand stereotypies this is the feature that most strongly
    evokes Rett syndrome. It is not universal: several individuals in the
    independent second cohort retain purposeful hand use — colouring, scribbling
    with a coarse grasp, operating simple appliances.
  diagnostic: true
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Absent purposeful hand movements
    term:
      id: HP:0032588
      label: Hand apraxia
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A virtual absence of purposeful hand movements was present in all cases
    explanation: >-
      Frequency justification: explicit "in all cases" statement over the index
      cohort. Curated FREQUENT rather than VERY_FREQUENT because the index cohort
      is not the whole reported population — several individuals in the
      independent second cohort retain purposeful hand use, so the share across
      all reported patients falls below the 80% floor.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He can run, walk slowly upstairs, and scribble with a coarse grasp.
    explanation: >-
      A reported patient with retained purposeful hand use. It bounds
      the frequency of the feature rather than contradicting the
      disease-phenotype association, and it is what caps the band at FREQUENT.
  - reference: PMID:32336483
    reference_title: "Variant in the neuronal vesicular SNARE VAMP2 (synaptobrevin-2): First report in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypotonia at early infancy, poor visual fixation, and absence of purposeful
      hand movements may be indicative of the diagnosis for VAMP2 variant.
    explanation: >-
      Independent case report proposing this as diagnostically indicative.
- name: Absent Speech
  category: Clinical
  description: >-
    Absence of meaningful speech in the three more severely affected individuals
    of the index cohort. Named and bound to match that claim: the two carriers of
    in-frame single-amino-acid deletions were not speechless but severely limited,
    managing only five to ten words, and are excluded from the numerator behind
    the frequency band.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe language impairment was present in the three more severely affected
      children (individuals 1–3), none of whom had attained meaningful speech
      production, but individuals 4 and 5 were capable of saying 5–10 words
    explanation: >-
      Frequency justification: absent meaningful speech in 3 of 5 individuals
      (60%), supporting the FREQUENT band, and records the milder speech outcome
      in the deletion carriers. The denominator is five probands.
- name: Inability to Walk
  category: Clinical
  description: >-
    Severely impaired motor development with failure to attain independent
    walking in the three individuals with C-terminal missense variants; the two
    with in-frame single-amino-acid deletions acquired the ability to walk.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Inability to walk
    term:
      id: HP:0002540
      label: Inability to walk
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Motor development in individuals 1–3 was severely impaired, and these
      children had not attained the ability to walk.
    explanation: >-
      Frequency justification: inability to walk in 3 of 5 individuals (60%),
      supporting the FREQUENT band. The denominator is five probands.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals 4 and 5, carrying de novo single-amino-acid deletions involving
      residues at positions 43 and 45, presented a less severe neurological
      involvement, acquired the ability to walk, and were able to pronounce a few
      words.
    explanation: >-
      Records the genotype-dependent sparing of ambulation in the deletion
      carriers.
- name: Chorea
  category: Clinical
  description: >-
    Choreic movements, moderate in two individuals and severe and generalized in a
    third, as a component of the hyperkinetic movement disorder.
  phenotype_term:
    preferred_term: Chorea
    term:
      id: HP:0002072
      label: Chorea
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      moderate chorea (individuals 1 and 3) to a mixed-movement disorder with
      severe chorea and dystonic posturing (individual 2)
    explanation: >-
      Documents chorea and its severity range in the index cohort.
- name: Dystonia
  category: Clinical
  description: >-
    Dystonic posturing, mainly involving the trunk, neck, and lower limbs, as a
    component of the hyperkinetic movement disorder.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abnormal movements ranged from dystonic posturing (mainly involving the
      trunk, neck, and lower limbs)
    explanation: >-
      Documents dystonic posturing and its distribution.
- name: Myoclonus
  category: Clinical
  description: >-
    Myoclonic jerks as a component of the hyperkinetic movement disorder, and
    myoclonic seizures of the eyelid and tongue in an independently reported case.
  phenotype_term:
    preferred_term: Myoclonus
    term:
      id: HP:0001336
      label: Myoclonus
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      or myoclonic jerks (individual 3)
    explanation: >-
      Documents myoclonic jerks within the movement disorder.
  - reference: PMID:32336483
    reference_title: "Variant in the neuronal vesicular SNARE VAMP2 (synaptobrevin-2): First report in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      he suffered from myoclonic seizures of the eyelid and tongue, which
      propagated to unilateral fingers, and sometimes to the bilateral legs.
    explanation: >-
      Independent report of myoclonic seizure semiology.
- name: Self-Injurious Behavior
  category: Clinical
  description: >-
    Self-injurious behavior, reported in the index cohort and again as challenging
    behaviour with self-injury in a later case.
  phenotype_term:
    preferred_term: Self-injurious behavior
    term:
      id: HP:0100716
      label: Self-injurious behavior
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Self-injurious behaviors were evident in individual 2.
    explanation: >-
      Documents self-injurious behavior in the index cohort.
  - reference: PMID:37901860
    reference_title: "VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Later, she developed a sleep disorder, challenging behaviour with
      self-injury, and scoliosis.
    explanation: >-
      Independent confirmation of self-injurious behavior.
- name: Global Developmental Delay
  category: Clinical
  description: >-
    Global developmental delay, with neurodevelopmental impairment occurring
    within the first year of life.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all affected children, family histories, pregnancies, and birth histories
      were unremarkable, and neurodevelopmental impairment occurred within the
      first year of life.
    explanation: >-
      Frequency justification: explicit "in all affected children" statement over
      the index cohort, and dates onset to the first year. Curated VERY_FREQUENT
      rather than OBLIGATE because five probands is a narrow denominator.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      reveal common features of global developmental delay
    explanation: >-
      Independent second cohort confirming global developmental delay as a common
      feature.
- name: Microcephaly
  category: Clinical
  description: >-
    Microcephaly, reported in a later case. Head circumference was normal in all
    five individuals of the index cohort, so this is not a consistent feature.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:37901860
    reference_title: "VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 15-month-old girl presented with early onset hypotonia, global
      developmental delay, learning difficulties, microcephaly, nystagmus,
      strabismus, and stereotypies.
    explanation: >-
      Documents microcephaly in a later reported individual.
- name: Nystagmus
  category: Clinical
  description: >-
    Nystagmus, reported in a later case alongside strabismus and independently in
    the second cohort. Distinct from the central visual impairment of the index
    cohort, which is cortical rather than oculomotor.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:37901860
    reference_title: "VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 15-month-old girl presented with early onset hypotonia, global
      developmental delay, learning difficulties, microcephaly, nystagmus,
      strabismus, and stereotypies.
    explanation: >-
      Documents nystagmus in a later reported individual.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Parents noticed nystagmus during infancy.
    explanation: >-
      Independent report of nystagmus in the second cohort, with infantile onset.
- name: Strabismus
  category: Clinical
  description: >-
    Strabismus, reported in a later case alongside nystagmus.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:37901860
    reference_title: "VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 15-month-old girl presented with early onset hypotonia, global
      developmental delay, learning difficulties, microcephaly, nystagmus,
      strabismus, and stereotypies.
    explanation: >-
      Documents strabismus in a later reported individual.
- name: Scoliosis
  category: Clinical
  description: >-
    Scoliosis, developing later in the course in a reported case — the orthopedic
    complication that multidisciplinary supportive care has to anticipate in
    non-ambulant, hypotonic children.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:37901860
    reference_title: "VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Later, she developed a sleep disorder, challenging behaviour with
      self-injury, and scoliosis.
    explanation: >-
      Documents scoliosis as a later-developing feature.
- name: Attention Deficit Hyperactivity Disorder
  category: Clinical
  description: >-
    ADHD, diagnosed in one patient of the second cohort and reported as ADHD
    tendencies in another — including in the patient who was formally evaluated
    for autism and did not meet criteria. Curated because the behavioural
    phenotype is not exhausted by autistic features.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Later he was diagnosed with ASD and attention deficit hyperactivity
      disorder (ADHD).
    explanation: >-
      A formal ADHD diagnosis in a reported patient.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He received an autism evaluation at age 3, and did not meet criteria for
      autism, but displayed ADHD tendencies.
    explanation: >-
      ADHD tendencies rather than a formal diagnosis in a second patient. This is the
      same patient whose negative autism evaluation bounds the Autistic Behavior
      frequency.
- name: Sleep Disturbance
  category: Clinical
  description: >-
    Sleep disorder, reported in a later case; daytime somnolence was reported
    independently.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:37901860
    reference_title: "VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Later, she developed a sleep disorder, challenging behaviour with
      self-injury, and scoliosis.
    explanation: >-
      Documents a sleep disorder in a later reported individual.
  - reference: PMID:32336483
    reference_title: "Variant in the neuronal vesicular SNARE VAMP2 (synaptobrevin-2): First report in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had somnolence tendency in the daytime.
    explanation: >-
      Independent report of daytime somnolence.
genetic:
- name: VAMP2
  gene_term:
    preferred_term: VAMP2
    term:
      id: hgnc:12643
      label: VAMP2
  association: SNARE-Motif 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
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Chromatograms of individuals 1–5 and their parents confirm the de-novo
        occurrence of the VAMP2 variants in all cases.
      explanation: >-
        Sanger confirmation of de novo occurrence in every case establishes the
        de novo dominant mode for this gene-disease relationship.
  notes: >-
    Three allelic classes are reported. (1) De novo non-synonymous variants
    within the SNARE motif. The three index-cohort variants (p.Ser75Pro,
    p.Phe77Ser, p.Glu78Ala) cluster in the C-terminal portion of the motif and
    are the ones shown to act dominant-negatively. Of the later-reported missense
    variants, p.Gly73Trp is described as lying in close proximity to p.Ser75Pro
    and so sits adjacent to that cluster, while p.Arg56Leu, p.Arg66Pro and
    p.Ala67Pro lie further N-terminally within the motif; the "C-terminal cluster"
    claim should not be extended to those three. (2) De novo in-frame
    single-amino-acid deletions at more N-terminal SNARE-motif residues
    (p.Val43del, p.Ile45del), associated with milder involvement — these
    individuals walk and speak a few words. (3) Truncating loss-of-function
    variants (p.Arg56*, p.Tyr113Glnfs*12), proposed to act through
    haploinsufficiency. The SNARE motif spans residues 31-91; VAMP2 carried no
    loss-of-function variants in ExAC, consistent with constraint. The three-class
    scheme is the literature's and is not exhaustive: a de novo start-loss variant
    (c.1A>G, p.Met1?) has also been reported and fits none of them.
  variants:
  - name: NM_014232(VAMP2):c.223T>C (p.Ser75Pro)
    type: missense
    clinical_significance: PATHOGENIC
    description: >-
      C-terminal SNARE-motif missense variant. The only variant with a
      demonstrated reconstituted fusion defect: fusion reduced to ~25% of
      wild-type, no Munc18-1 activation (>90% loss of function under
      Munc18-activated conditions), and dominant interference with wild-type
      VAMP2 in 50:50 mixed liposomes. Predicted to lose two hydrogen bonds, one
      interchain with Tyr243 of STX1A and one intrachain with Gln71.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Replacement analysis shows that the p.Ser75Pro variant will result in the
        loss of two hydrogen bonds, one interchain between Ser75 of VAMP2 and
        Tyr243 of STX1A and one intrachain between Ser75 and Gln71
      explanation: >-
        Structural basis for the p.Ser75Pro fusion defect.
  - name: NM_014232(VAMP2):c.233A>C (p.Glu78Ala)
    type: missense
    clinical_significance: PATHOGENIC
    description: >-
      C-terminal SNARE-motif missense variant that disrupts the hydrogen bond
      between Glu78 of VAMP2 and Arg246 of STX1A, but whose reconstituted fusion
      profile was indistinguishable from wild-type and which remained
      Munc18-1-activatable. Its pathogenic mechanism is unresolved; the authors
      propose impaired interaction with regulatory proteins absent from the assay.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the p.Glu78Ala variant disrupts the hydrogen bond between Glu78 of VAMP2
        and Arg246 of STX1A
      explanation: >-
        Structural consequence, recorded alongside the absent functional effect in
        the fusion assay.
  - name: NM_014232(VAMP2):c.230T>C (p.Phe77Ser)
    type: missense
    clinical_significance: PATHOGENIC
    description: >-
      C-terminal SNARE-motif missense variant introducing a hydrophilic residue
      into an otherwise hydrophobic region. Could not be purified, so it was never
      tested in the reconstituted fusion assay.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        However, all attempts to isolate the p.Phe77Ser were unsuccessful.
      explanation: >-
        Records why no functional data exist for this variant.
  - name: NM_014232(VAMP2):c.128_130delTGG (p.Val43del)
    type: inframe_deletion
    clinical_significance: PATHOGENIC
    description: >-
      In-frame single-amino-acid deletion at a more N-terminal SNARE-motif
      residue, associated with the milder phenotype (walks, speaks 5-10 words, no
      movement disorder or visual impairment).
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        carrying a de novo single amino acid deletion at position 43
      explanation: >-
        Identifies the variant and its position within the SNARE motif.
  - name: NM_014232(VAMP2):c.135_137delCAT (p.Ile45del)
    type: inframe_deletion
    clinical_significance: PATHOGENIC
    description: >-
      In-frame single-amino-acid deletion at a more N-terminal SNARE-motif
      residue, associated with the milder phenotype.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        an additional child (individual 5) carrying a de novo single-amino-acid
        deletion at position 45
      explanation: >-
        Identifies the variant and its position within the SNARE motif.
  - name: VAMP2 c.166C>T (p.Arg56*) (nonsense)
    type: nonsense
    clinical_significance: PATHOGENIC
    description: >-
      Truncating variant predicted to cause nonsense-mediated decay and
      haploinsufficiency. In cellular assays the truncated protein did not exert
      dominant-negative effects, and the carrier had a milder phenotype without
      epilepsy. The authors caution that this null result may be an artifact of
      the reporter construct, which encodes only the first 55 residues and so
      lacks the transmembrane domain needed for membrane localization, and that a
      dominant-negative effect was not directly tested. This is the individual
      treated with off-label aminopyridine.
    evidence:
    - reference: PMID:32906212
      reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        predicting a premature truncation and haploinsufficiency from nonsense
        mediated decay.
      explanation: >-
        The predicted molecular consequence of the truncating allele — predicted from
        variant position, not measured, which is why the evidence source is OTHER.
  - name: VAMP2 c.167G>T (p.Arg56Leu)
    type: missense
    clinical_significance: PATHOGENIC
    description: >-
      SNARE-motif missense variant affecting the same residue as the p.Arg56*
      truncating allele. Predicted to act dominant-negatively, and among the
      variants tested in the cellular exocytosis assays.
    evidence:
    - reference: PMID:32906212
      reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        He carries a de novo VAMP2 variant (heterozygous de novo c.167 G>T,
        p.Arg56Leu)
      explanation: >-
        Identifies the variant and its de novo heterozygous status.
  - name: VAMP2 c.217G>T (p.Gly73Trp)
    type: missense
    clinical_significance: PATHOGENIC
    description: >-
      SNARE-motif missense variant predicted to act dominant-negatively, and among
      the variants shown to reduce action-potential-triggered vesicle fusion and
      neurotransmitter release in neurons.
    evidence:
    - reference: PMID:32906212
      reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Whole exome testing revealed a VAMP2 variant (heterozygous de novo
        c.217G>T, p.Gly73Trp).
      explanation: >-
        Identifies the variant and its de novo heterozygous status.
  - name: VAMP2 c.337_341delTACTT (p.Tyr113Glnfs*12)
    type: frameshift
    clinical_significance: PATHOGENIC
    description: >-
      Frameshift variant predicted to create a premature stop codon 12 residues
      downstream and to result in haploinsufficiency. The second truncating
      allele reported, alongside p.Arg56*.
    evidence:
    - reference: PMID:32906212
      reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Whole exome sequencing at 4 years of age revealed a variation in VAMP2
        (heterozygous de novo c.337_341 deletion TACTT p.Tyr113Gln frameshift,
      explanation: >-
        Identifies the frameshift variant and its de novo heterozygous status.
  - name: VAMP2 c.1A>G (p.Met1?) (start loss)
    type: start_lost
    clinical_significance: PATHOGENIC
    description: >-
      Start-loss variant eliminating the initiator methionine, thought to result
      in no protein or in a truncated protein initiating at a different residue.
      It does not fit any of the three allelic classes the literature describes
      (SNARE-motif missense, in-frame deletion, truncating) and is curated here so
      that the class scheme is not read as exhaustive.
    evidence:
    - reference: PMID:32906212
      reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Whole exome sequencing was performed and revealed a heterozygous de novo
        c.1 A>G, p. Met1? VAMP2 mutation.
      explanation: >-
        Identifies the start-loss variant and its de novo heterozygous status.
    - reference: PMID:32906212
      reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This change is thought to cause elimination of initiator methionine, which
        could result in no protein formation, or a truncated protein with a
        different initiator amino acid.
      explanation: >-
        The predicted consequence. Two alternative outcomes are proposed and neither was
        tested, which is why the evidence source is OTHER.
  - name: NM_014232.2(VAMP2):c.197G>C (p.Arg66Pro)
    type: missense
    clinical_significance: PATHOGENIC
    description: >-
      SNARE-motif missense variant reported in a girl with hypotonia, global
      developmental delay, microcephaly, nystagmus, strabismus, and stereotypies.
    evidence:
    - reference: PMID:37901860
      reference_title: "VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        identified a novel de novo heterozygous missense variant c.197G>C
        (p.Arg66Pro) in the VAMP2 gene SNARE motif region.
      explanation: >-
        Identifies this later-reported SNARE-motif missense variant.
  - name: NM_014232.2(VAMP2):c.199G>C (p.Ala67Pro)
    type: missense
    clinical_significance: PATHOGENIC
    description: >-
      SNARE-motif missense variant in exon 3, reported in a boy with infantile
      spasms and hypsarrhythmia, poor visual fixation, and absent purposeful hand
      movements.
    evidence:
    - reference: PMID:32336483
      reference_title: "Variant in the neuronal vesicular SNARE VAMP2 (synaptobrevin-2): First report in Japan."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        whole-exome sequence identified a heterozygous missense variant,
        NM_014232.2:c.199G>C,
      explanation: >-
        Identifies this later-reported SNARE-motif missense variant.
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, we identified two single-amino-acid deletions and three
      non-synonymous variants affecting conserved residues within the C terminus of
      the VAMP2 SNARE motif.
    explanation: >-
      Defines the de novo SNARE-motif variant spectrum of the index cohort.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The de novo non-synonymous variants identified in this study cluster in
      close proximity within the C-terminal portion of the SNARE motif
    explanation: >-
      Localizes specifically the missense variants to the C-terminal portion; the
      two in-frame deletions sit at residues 43 and 45, more N-terminally within
      the same motif.
  - reference: PMID:37901860
    reference_title: "VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only three types of allelic variants (loss of function, in-frame
      deletions, and missense variants) in the VAMP2 gene have been previously
      reported in 11 patients with learning difficulties.
    explanation: >-
      Establishes the three-class allelic series and the cumulative reported
      patient count.
diagnosis:
- name: VAMP2 Molecular Diagnosis
  description: >-
    Diagnosis is established by identifying a de novo heterozygous pathogenic VAMP2
    variant (SNARE-motif deletion or non-synonymous variant) in a child with
    congenital axial hypotonia, intellectual disability, and autistic features.
  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: VAMP2
        term:
          id: hgnc:12643
          label: VAMP2
  results: A de novo pathogenic VAMP2 SNARE-motif variant establishes the diagnosis.
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report five heterozygous de novo mutations in VAMP2 in unrelated
      individuals
    explanation: >-
      Molecular identification of de novo VAMP2 variants establishes the diagnosis.
differential_diagnoses:
- name: Rett syndrome and Rett-like disorders
  description: >-
    The autistic features with hand stereotypies, absent purposeful hand movements,
    and developmental impairment resemble Rett syndrome; VAMP2 disease is
    distinguished by molecular testing.
  distinguishing_features:
  - A de novo VAMP2 SNARE-motif variant favors this disorder.
  - MECP2 (or CDKL5/FOXG1) variants favor Rett syndrome or a Rett-like disorder.
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including variable motor stereotypies resembling Rett syndrome
    explanation: >-
      The index report itself frames the stereotypies as Rett-resembling, which is
      the source of the diagnostic confusion.
  - reference: PMID:37901860
    reference_title: "VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients presenting with features of either Rett syndrome or Angelman
      syndrome, in whom genetic testing is not suggestive, should be evaluated for
      variants in the VAMP2 gene, given the significant overlap in clinical
      presentation of these disorders.
    explanation: >-
      Explicit recommendation to test VAMP2 in genetically unexplained Rett- or
      Angelman-like presentations — the practical content of this differential.
- name: Angelman syndrome and Angelman-like disorders
  description: >-
    The developmental impairment, absent speech, movement disorder, and epilepsy
    overlap with Angelman syndrome. VAMP2 has been recovered by exome sequencing
    of a cohort assembled for an Angelman-syndrome-like phenotype with negative
    UBE3A/15q testing, so it belongs in that differential rather than only in the
    Rett one.
  distinguishing_features:
  - A de novo VAMP2 variant favors this disorder.
  - UBE3A variants or a 15q11-q13 imprinting/deletion defect favor Angelman syndrome.
  evidence:
  - reference: PMID:34653234
    reference_title: "New genes involved in Angelman syndrome-like: Expanding the genetic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The results of WES led to the identification of 10 new genes that cause an
      AS-like phenotype (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1,
      KCNQ3, SLC6A1 and LAS1L), all of them previously associated with other
      neurodevelopmental disorders.
    explanation: >-
      Places VAMP2 among the genes recovered from an Angelman-syndrome-like
      diagnostic cohort.
  - reference: PMID:37901860
    reference_title: "VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      highlights this condition as an important differential diagnosis of
      Rett/Angelman-type spectrum of disorders.
    explanation: >-
      States the Angelman-spectrum differential directly.
- name: Other SNAREopathies and synaptic vesicle cycle disorders
  description: >-
    Other SNARE-machinery and synaptic vesicle cycle disorders (SNAP25, STX1B,
    STXBP1, SYT1) overlap through developmental impairment, movement disorder, and
    epilepsy, and are distinguished by molecular testing.
  distinguishing_features:
  - A de novo VAMP2 variant favors this disorder.
  - A variant in another SNARE/vesicle-cycle gene favors the corresponding SNAREopathy.
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Together with its partners syntaxin-1A and synaptosomal-associated protein 25
      (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release
      neurotransmitters.
    explanation: >-
      Places VAMP2 within the SNARE complex shared with the other SNAREopathies.
      Definitional background rather than a study result, hence OTHER — matching
      how the same sentence is tagged on the fusion node.
progression:
- phase: Infancy to Childhood
  notes: >-
    Neurodevelopmental impairment occurs within the first year of life, beginning
    with axial hypotonia at birth. In the index cohort the C-terminal missense
    carriers additionally developed a hyperkinetic movement disorder in the first
    year, and were later diagnosed with central visual impairment after poor
    visual fixation from the first months of life. Hyperkinetic movement has also
    been reported with onset at 8 years in a carrier outside that cluster. Seizure
    onset ranges from shortly after birth to age 5 and is not confined to the
    severe group.
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      axial hypotonia (which had been present since birth)
    explanation: >-
      Documents the congenital onset with axial hypotonia.
treatments:
- name: Antiseizure Medication
  description: >-
    Epilepsy, when present, is managed with antiseizure medication. In the index
    cohort valproic acid, vigabatrin, and lamotrigine were trialed in the three
    individuals with seizures; benefit was noted only for valproic acid, in the
    individual with the mildest epilepsy phenotype, who became seizure-free with
    normal follow-up EEGs. No disease-specific antiseizure strategy has been
    established, and the evidence base is a handful of individual treatment
    courses rather than any trial. Adrenocorticotropic hormone for infantile
    spasms is curated as a separate treatment.
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
    - preferred_term: vigabatrin
      term:
        id: CHEBI:63638
        label: vigabatrin
    - preferred_term: lamotrigine
      term:
        id: CHEBI:6367
        label: lamotrigine
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Several anti-epileptic drugs, including valproic acid, vigabatrin, and
      lamotrigine, have been trialed in individuals 2–4
    explanation: >-
      Names the antiseizure agents actually used in the reported cohort.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      beneficial effects of valproic acid treatment were noted in individual 4,
      who has been seizure-free since the age of 12 years and has had normal
      follow-up EEGs
    explanation: >-
      The only reported antiseizure benefit, and it is a single uncontrolled
      observation, so it supports the observation having been made and not a general
      recommendation.
- name: Adrenocorticotropic Hormone for Infantile Spasms
  description: >-
    Infantile spasms with hypsarrhythmia were treated with adrenocorticotropic
    hormone in an independently reported case, with complete resolution of the
    spasms. Curated separately from maintenance antiseizure medication because
    the indication, the agent class, and the course of therapy are all distinct.
    The interictal EEG abnormality persisted after the spasms resolved, so the
    response was seizure-specific rather than a normalization of the underlying
    encephalopathy. This is a single case, not a disease-specific recommendation.
  therapeutic_modality: PEPTIDE
  target_phenotypes:
  - preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: adrenocorticotropic hormone
      term:
        id: CHEBI:3892
        label: corticotropin
  evidence:
  - reference: PMID:32336483
    reference_title: "Variant in the neuronal vesicular SNARE VAMP2 (synaptobrevin-2): First report in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His infantile spasms completely disappeared by adrenocorticotropic hormone
      therapy, but his EEG findings continued to show high voltage slow-waves with
      multi-focal spikes.
    explanation: >-
      Single uncontrolled case showing spasm resolution but persistent interictal EEG
      abnormality, which is why the EEG caveat is stated in the description.
- name: Aminopyridine Potassium-Channel Blockade (Investigational)
  description: >-
    An investigational, mechanism-directed strategy rather than established care.
    Blocking presynaptic potassium channels with 4-aminopyridine or
    3,4-diaminopyridine prolongs the action potential, increasing calcium entry
    and release probability, and so compensates for — rather than corrects — the
    VAMP2 fusion deficit. In neurons expressing VAMP2 variants, aminopyridine
    increased the rate and extent of exocytosis and total synaptic charge
    transfer. Clinical experience is a single patient with a nonsense variant
    treated off-label for two years, with improved emotional and behavioral
    regulation by parental report and improvement on standardized cognitive
    measures. This is an uncontrolled n-of-1 observation; the authors propose
    testing responsiveness in vitro before treating. Safety caveat that matters
    in this disorder specifically: 4-aminopyridine lowers the seizure threshold
    and the authors advise caution in patients with epilepsy — and epilepsy,
    infantile spasms, and EEG abnormality are all curated features here. The
    treated patient carried a truncating variant and had no epilepsy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: 4-aminopyridine
      term:
        id: CHEBI:34385
        label: 4-aminopyridine
    - preferred_term: 3,4-diaminopyridine
      term:
        id: CHEBI:135948
        label: amifampridine
  target_mechanisms:
  - target: Impaired SNARE-Mediated Vesicle Fusion
    treatment_effect: BYPASSES
    description: >-
      Aminopyridines do not repair the SNARE complex. They raise presynaptic
      calcium availability so that the residual fusion machinery achieves more
      release per action potential, compensating around the fusion deficit.
    evidence:
    - reference: PMID:32906212
      reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Aminopyridine treatment increases the rate and extent of exocytosis and
        total synaptic charge transfer and desynchronizes GABA release.
      explanation: >-
        Demonstrates the compensatory effect on the impaired exocytosis step in
        neurons expressing the disease variants.
  evidence:
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we tested a potential treatment strategy, enhancing neurotransmission by
      prolonging action potentials with the aminopyridine family of potassium
      channel blockers, 4-aminopyridine and 3,4-diaminopyridine, in vitro and in
      vivo.
    explanation: >-
      Defines the agents and the pharmacological rationale.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical response of the patient to 2 years of off-label aminopyridine
      treatment includes improved emotional and behavioral regulation by parental
      report, and objective improvement in standardized cognitive measures.
    explanation: >-
      The entire human evidence base is this single uncontrolled off-label treatment
      course, which is the limit of what the clinical claim can rest on.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      4-AP should be used cautiously in patients with epilepsy given risk of
      lowering seizure threshold, which can limit its broad-based utility.
    explanation: >-
      The authors' own safety limitation, material because epilepsy is a curated
      feature of this disorder and the single treated patient did not have it.
  notes: >-
    Curated deliberately as investigational. One treated patient, no control
    condition, and the responder carried a nonsense (haploinsufficiency) variant —
    whether dominant-negative missense variants respond equally is untested.
- name: Supportive and Developmental Care
  description: >-
    Multidisciplinary supportive care — developmental and behavioral therapies,
    management of the movement disorder, and vision support — is the mainstay.
    There is no disease-modifying therapy, and the care needs follow directly from
    the phenotype: absent speech and absent purposeful hand use, non-ambulation in
    the severe group, central visual impairment, and challenging or self-injurious
    behavior.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Motor development in individuals 1–3 was severely impaired, and these
      children had not attained the ability to walk.
    explanation: >-
      Documents the motor disability that defines the rehabilitative and supportive
      care need.
  - reference: PMID:37901860
    reference_title: "VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Later, she developed a sleep disorder, challenging behaviour with
      self-injury, and scoliosis.
    explanation: >-
      Documents the behavioural and orthopedic problems that multidisciplinary
      supportive care must address.
- name: Genetic Counseling
  description: >-
    Genetic counseling addresses the de novo dominant mechanism and generally low
    recurrence risk.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromatograms of individuals 1–5 and their parents confirm the de-novo
      occurrence of the VAMP2 variants in all cases.
    explanation: >-
      Confirmed de novo occurrence in unaffected parents is the basis for counseling
      a low sibling recurrence risk.
imaging_findings:
- name: Delayed Myelination
  modality: MRI
  description: >-
    Brain MRI was unrevealing in four of the five individuals of the index cohort.
    The exception showed a generalized delay in myelin maturation at age 2 years.
    Normal brain imaging does not argue against the diagnosis. The corpus callosum
    and cerebral white matter volume findings from the same individual, and the
    brain atrophy reported independently, are curated separately, since each is a
    distinct abnormality with its own HPO term.
  imaging_finding_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  located_in:
    preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging (MRI) was unrevealing in all children except
      in individual 1, for whom mild myelination delay and a posteriorly slender
      corpus callosum was observed at the age of 2 years
    explanation: >-
      Records the myelination delay and, importantly, that imaging is normal in
      most affected individuals. The corpus callosum half of this sentence is
      curated on its own finding.
- name: Brain Atrophy
  modality: MRI
  description: >-
    Slight brain atrophy on MRI in an independently reported individual. Curated
    as its own finding rather than on the myelination node, since atrophy and
    delayed maturation are different abnormalities; reported in a single patient.
  imaging_finding_term:
    preferred_term: Brain atrophy
    term:
      id: HP:0012444
      label: Brain atrophy
  located_in:
    preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:32336483
    reference_title: "Variant in the neuronal vesicular SNARE VAMP2 (synaptobrevin-2): First report in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Magnetic resonance imaging showed slight brain atrophy.
    explanation: >-
      The single reported observation of brain atrophy in this disorder.
- name: Reduced Cerebral White Matter Volume
  modality: MRI
  description: >-
    Reduced posterior cerebral white matter volume in the one index-cohort
    individual with an abnormal MRI, reported alongside the myelination delay in
    the same scan. Curated separately from the myelination finding because volume
    loss and delayed maturation are distinct abnormalities with distinct HPO
    terms.
  imaging_finding_term:
    preferred_term: Reduced cerebral white matter volume
    term:
      id: HP:0034295
      label: Reduced cerebral white matter volume
  located_in:
    preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is some generalized delay in the maturation of myelin and a reduced
      volume of the cerebral white matter posteriorly.
    explanation: >-
      Reports both findings from the one abnormal scan; the volume-loss half is
      curated here and the maturation delay on the myelination finding.
- name: Thin Corpus Callosum
  modality: MRI
  description: >-
    A posteriorly slender ("thin") corpus callosum in the one index-cohort
    individual with an abnormal MRI, and a mildly hypoplastic corpus callosum
    reported independently in the second cohort. Curated as its own finding rather
    than folded into the myelination node: it is a distinct abnormality with its
    own HPO term, and it is the one structural finding corroborated across two
    cohorts. Bound to HP:0033725 rather than HP:0002079 (Hypoplasia of the corpus
    callosum) because HP:0033725 is defined for thinning whose cause — hypoplasia
    versus atrophy after normal development — is not known, which is the case for
    the index cohort; only the second cohort calls it hypoplastic.
  imaging_finding_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  located_in:
    preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Yellow arrows show a posteriorly slender corpus callosum.
    explanation: >-
      The index-cohort finding, in the single individual with an abnormal MRI.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI of the brain demonstrated a mildly hypoplastic corpus callosum.
    explanation: >-
      Independent corroboration in a second cohort, which the index report had
      documented in only one individual.
- name: Optic Nerve and Chiasm Hypoplasia
  modality: MRI
  description: >-
    Hypoplastic optic nerves and chiasm in the individual with the abnormal MRI —
    a potential structural correlate of the central visual impairment, reported in
    a single individual.
  imaging_finding_term:
    preferred_term: Optic nerve hypoplasia
    term:
      id: HP:0000609
      label: Optic nerve hypoplasia
  located_in:
    preferred_term: optic nerve
    term:
      id: UBERON:0000941
      label: cranial nerve II
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The optic nerves and chiasm are hypoplastic
    explanation: >-
      Documents the optic pathway hypoplasia on MRI.
animal_models:
- name: Synaptobrevin-2 (Vamp2) knockout mouse
  species: Mouse (Mus musculus)
  genotype: Vamp2 (synaptobrevin-2) homozygous knockout
  description: >-
    Constitutive null mice are the source of the causal claim that VAMP2 is
    required for fast calcium-triggered synaptic vesicle fusion and for fast
    vesicle endocytosis. In their absence, spontaneous and sucrose-evoked fusion
    fall about 10-fold while fast calcium-triggered fusion falls more than
    100-fold; endocytosis and recycling-pool replenishment are also delayed. The
    mice die immediately after birth.
  publication: PMID:11691998
  modeled_mechanisms:
  - target: Impaired SNARE-Mediated Vesicle Fusion
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Establishes the direction and the disproportionate sensitivity of
      calcium-triggered release to loss of VAMP2, which is the mechanism this node
      asserts.
    limitations: >-
      Homozygous null, not the heterozygous state of affected humans, and a
      complete absence of protein rather than a SNARE-motif missense allele acting
      dominant-negatively. The mice die perinatally and so model neither the
      surviving human neurodevelopmental course nor the graded genotype-phenotype
      correlation. The knockout is informative for the haploinsufficiency arm's
      direction of effect but cannot test dominant-negative interference, which
      requires mutant protein to be present.
    readouts:
    - name: Fast calcium-triggered synaptic vesicle fusion
      target: Impaired SNARE-Mediated Vesicle Fusion
      direction: DECREASED
      interpretation: >-
        Electrophysiological measure of the fusion step this node models.
      evidence:
      - reference: PMID:11691998
        reference_title: "SNARE function analyzed in synaptobrevin/VAMP knockout mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In the absence of synaptobrevin 2, spontaneous synaptic vesicle fusion
          and fusion induced by hypertonic sucrose were decreased approximately
          10-fold, but fast Ca2+-triggered fusion was decreased more than 100-fold.
        explanation: >-
          Quantifies the fusion defect and shows calcium-triggered release is the
          most sensitive component.
    evidence:
    - reference: PMID:11691998
      reference_title: "SNARE function analyzed in synaptobrevin/VAMP knockout mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thus, synaptobrevin 2 may function in catalyzing fusion reactions and
        stabilizing fusion intermediates but is not absolutely required for
        synaptic fusion.
      explanation: >-
        The knockout supports a catalytic rather than strictly obligatory role, so
        it substantiates the node only partially — fusion is degraded, not
        abolished.
  - target: Impaired Synaptic Vesicle Endocytosis and Recycling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      The knockout is the primary evidence that VAMP2 is required for fast
      endocytosis and readily-releasable-pool replenishment, not only exocytosis.
    limitations: >-
      Homozygous null rather than the human heterozygous missense/truncating state.
      More seriously, the direct test of endocytosis in human variant-expressing
      neurons was negative, so this is the one arm where the model and the human
      data disagree — hence LOW fidelity and PARTIALLY_RECAPITULATES rather than a
      claim that the model reproduces a human mechanism.
    readouts:
    - name: Stimulus-dependent endocytosis of HRP and FM1-43
      target: Impaired Synaptic Vesicle Endocytosis and Recycling
      direction: DECREASED
      interpretation: >-
        Tracer-uptake measure of the endocytic retrieval step.
      evidence:
      - reference: PMID:15475946
        reference_title: "Synaptobrevin is essential for fast synaptic-vesicle endocytosis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          the stimulus-dependent endocytosis of horseradish peroxidase and
          fluorescent FM1-43 were delayed
        explanation: >-
          Direct measurement of delayed endocytosis in knockout synapses.
    evidence:
    - reference: PMID:15475946
      reference_title: "Synaptobrevin is essential for fast synaptic-vesicle endocytosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        replenishment of the pool is delayed by knockout of synaptobrevin.
      explanation: >-
        Supports treating the knockout as informative for the recycling node.
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      mice present severely decreased rates of both spontaneous and Ca2+-triggered
      synaptic-vesicle fusion, and these mice die immediately after birth.
    explanation: >-
      The index clinical report's own framing of the knockout phenotype, including
      the perinatal lethality that bounds its use as a disease model.
experimental_models:
- name: Reconstituted SNARE liposome lipid-mixing (fusion) assay
  description: >-
    Cell-free reconstitution in which purified wild-type or variant VAMP2 is
    incorporated into fluorescent donor liposomes and the syntaxin-1/SNAP-25
    t-SNARE complex into acceptor liposomes; fusion is read out as NBD-to-rhodamine
    dequenching. Run with and without Munc18-1, and with 50:50 wild-type:mutant
    donor liposomes to emulate the heterozygous state. This is the assay behind the
    entry's fusion claims, and behind their variant-specific limits.
  experimental_model_type: OTHER
  publication: PMID:30929742
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We read out membrane fusion between the donor and acceptor liposome mixing
      by quantifying increased fluorescence resulting from the dequenching of NBD
      fluorescence
    explanation: >-
      Describes the reconstituted readout, establishing that this model system was
      applied to the disease variants.
  modeled_mechanisms:
  - target: Impaired SNARE-Mediated Vesicle Fusion
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Isolates the SNARE fusion step from all other presynaptic biology, which is
      what makes it decisive for p.Ser75Pro and uninformative for variants whose
      defect lies in regulatory-protein interaction.
    limitations: >-
      Contains only the core SNAREs (plus Munc18-1 where added) — synaptotagmin-1,
      complexin, and Munc13 are absent, so a variant that acts through those
      regulators scores as normal. p.Glu78Ala is the worked example: pathogenic in
      patients, indistinguishable from wild-type here. p.Phe77Ser could not be
      purified and was never tested.
    readouts:
    - name: Endpoint liposome fusion normalized to wild-type VAMP2
      target: Impaired SNARE-Mediated Vesicle Fusion
      direction: DECREASED
      interpretation: >-
        Fell to ~25% of wild-type for p.Ser75Pro; unchanged for p.Glu78Ala.
      evidence:
      - reference: PMID:30929742
        reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          the VAMP2 disease-associated variant p.Ser75Pro reduced the rate and
          extent of fusion compared to that seen with VAMP2 WT, whereas the
          p.Glu78Ala variant had little to no effect
        explanation: >-
          The primary readout, reported for both variants, including the negative
          result.
    evidence:
    - reference: PMID:30929742
      reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        To evaluate the functional consequence of VAMP2 variants, we employed the
        reconstituted, lipid-mixing assay based on NBD
      explanation: >-
        Establishes the assay as the functional test applied to the disease
        variants.
- name: Variant-expressing cultured neurons with synaptophysin-pHluorin imaging
  description: >-
    Cultured neurons expressing VAMP2 disease variants, assayed by live-cell
    imaging of the synaptophysin-pHluorin optical reporter of synaptic vesicle
    recycling together with electrophysiology. Unlike the liposome assay this
    system contains the full presynaptic regulatory complement, and it is the
    system in which dominant-negative behaviour was separated from
    haploinsufficiency and in which aminopyridine rescue was tested.
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:32906212
  evidence:
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we used live cell imaging of an optical reporter of SV recycling,
      synaptophysin-pHluorin (syp-pH).
    explanation: >-
      Establishes the reporter and imaging approach that define this model system.
  modeled_mechanisms:
  - target: Dominant-Negative Interference with Wild-Type VAMP2
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Distinguishes SNARE-motif missense variants, which suppress
      action-potential-triggered fusion in the presence of endogenous wild-type
      VAMP2, from the nonsense variant, which does not.
    limitations: >-
      Rat primary hippocampal neurons, not human cells — relevant because this
      system supplies the negative endocytosis result used to bound the
      recycling node and to anchor the HUMAN_MODEL_MISMATCH discussion. Variants
      are expressed on a wild-type background rather than knocked in at the
      endogenous locus, so expression level is not the patients'; only three
      variants were tested.
    readouts:
    - name: Rate of exocytosis and size of the released recycling pool
      target: Dominant-Negative Interference with Wild-Type VAMP2
      direction: DECREASED
      interpretation: >-
        Two of three tested variants reduced both measures relative to wild-type.
      evidence:
      - reference: PMID:32906212
        reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          In cellular models, two variants decrease both the rate of exocytosis and
          the number of synaptic vesicles released from the recycling pool,
          compared with wild-type.
        explanation: >-
          The primary readout distinguishing variants with and without a cellular
          release defect.
    evidence:
    - reference: PMID:32906212
      reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Synaptic vesicle recycling and neurotransmission were assayed in neurons
        expressing three VAMP2 variants by live-cell imaging and
        electrophysiology.
      explanation: >-
        Establishes the model system and the assays applied.
mechanistic_hypotheses:
- hypothesis_group_id: dominant_negative_snare_interference
  hypothesis_label: Dominant-negative interference by SNARE-motif missense variants
  status: CANONICAL
  description: >-
    SNARE-motif missense variants encode a stable protein that is incorporated
    into SNARE complexes but assembles or zippers defectively, poisoning complexes
    that also contain wild-type VAMP2. The decisive experiment is the 50:50
    wild-type:mutant liposome, whose fusion profile matched pure mutant rather
    than falling halfway — reduced dose alone cannot produce that. This is the
    better-evidenced arm and accounts for dominant inheritance. PMID:32906212
    associates the two dominant-negatively acting missense variants it tested,
    p.Gly73Trp and p.Arg56Leu, with a more severe phenotype including epilepsy —
    but epilepsy does not track the C-terminal cluster itself: the p.Ser75Pro
    carrier had no seizures while a p.Val43del carrier did, so severity and
    epilepsy are curated separately from cluster membership.
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This implies that p.Ser75Pro mutant dominantly interferes with WT
    explanation: >-
      The authors' conclusion from the mixed-liposome experiment. Note this
      variant's carrier had no epileptic seizures, which is why this hypothesis is
      not curated as explaining an epilepsy phenotype.
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual 1 did not present with epileptic seizures
    explanation: >-
      Bounds this hypothesis: the carrier of the variant whose dominant-negative
      effect is the decisive experiment had no seizures.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      exert a dominant-negative effect on action potential-triggered SV fusion and
      neurotransmitter release in vitro
    explanation: >-
      Independent replication in neurons for additional missense variants
      (p.Gly73Trp, p.Arg56Leu), which are the variants the source ties to the more
      severe epilepsy-bearing phenotype — not the C-terminal cluster as such.
- hypothesis_group_id: truncating_haploinsufficiency
  hypothesis_label: Haploinsufficiency from truncating loss-of-function variants
  status: ALTERNATIVE
  description: >-
    Truncating variants act by reduced gene dose rather than by poisoning the
    complex: nonsense-mediated decay removes the mutant transcript and the
    truncated protein does not interfere with wild-type VAMP2 in cellular assays.
    Curated as ALTERNATIVE rather than a competing account of the same variants —
    the two arms are proposed for different allelic classes, and the phenotypic
    correlate is real (the truncating carrier was milder and had no epilepsy).
    It is the weaker arm on three counts: nonsense-mediated decay is predicted,
    not measured; the absent dominant-negative effect may be an artifact of a
    construct lacking the transmembrane domain and was not directly tested; and
    mouse Vamp2 heterozygous loss of function is reported to cause only a mild
    phenotype, which a pure gene-dose mechanism has to explain away.
  evidence:
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      does not cause dominant-negative effects, suggesting that haploinsufficiency
      underlies the disease mechanism for the R56X variant patient
    explanation: >-
      The in vitro basis of the haploinsufficiency proposal. Graded INDIRECT because the
      authors state the dominant-negative effect was not directly tested.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although not directly tested, this variant could also result in a dominant
      negative effect.
    explanation: >-
      The authors' explicit caveat that the haploinsufficiency attribution is not
      exclusive — kept on the hypothesis it qualifies.
discussions:
- discussion_id: gap_vamp2_glu78ala_no_fusion_defect
  prompt: >-
    Why is p.Glu78Ala pathogenic in patients when its reconstituted fusion profile
    is indistinguishable from wild-type and it remains fully Munc18-1-activatable —
    does it act through a regulatory protein absent from the assay (synaptotagmin-1,
    complexin, Munc13), and does the same apply to the untested p.Phe77Ser?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired SNARE-Mediated Vesicle Fusion
  rationale: >-
    The entry asserts impaired SNARE-mediated fusion as its central effector, but
    the assay supporting that node returned a clear defect for only one of the two
    variants it could test. A third could not be purified. Treating "disease
    variants impair fusion" as settled across the allelic series would overstate
    the evidence, and the alternative the authors themselves propose — disrupted
    binding to regulatory elements such as Munc18-1 or synaptotagmin — predicts
    different therapeutic leverage. Until this is resolved, the fusion node is
    curated as variant-specific.
  proposed_experiments:
  - experiment_id: exp_vamp2_glu78ala_full_regulatory_fusion
    name: Reconstituted fusion with the full regulatory complement
    description: >-
      Repeat the lipid-mixing assay for p.Glu78Ala with synaptotagmin-1,
      complexin, and Munc13 included, under calcium triggering, and compare with
      wild-type.
    supporting_outcome:
    - A calcium-triggered release defect appearing only when regulatory proteins are present would support the regulatory-interaction mechanism.
    refuting_outcome:
    - A normal profile even with the full regulatory complement would leave p.Glu78Ala pathogenicity unexplained by any fusion-step mechanism.
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The pathophysiological phenotype for the p.Glu78Ala variant might be due to
      impaired interactions with regulatory proteins that were not included in the
      in vitro assay.
    explanation: >-
      The authors' own statement of the gap and of the leading candidate
      explanation.
- discussion_id: mismatch_vamp2_null_mouse_vs_human_heterozygote
  prompt: >-
    How far does the homozygous Vamp2-null mouse, which dies immediately after
    birth, inform a human disorder caused by heterozygous missense and truncating
    variants in surviving children with a graded genotype-phenotype correlation?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired SNARE-Mediated Vesicle Fusion
  - pathophysiology#VAMP2 Haploinsufficiency
  - pathophysiology#Impaired Synaptic Vesicle Endocytosis and Recycling
  rationale: >-
    The knockout supplies the strongest causal evidence that VAMP2 is required for
    fast calcium-triggered fusion and for fast endocytosis, and the entry relies on
    it for both. But it models neither human allelic class: it removes the protein
    entirely, so it cannot exhibit dominant-negative interference, which requires
    mutant protein to be present, and it is homozygous and perinatally lethal,
    whereas affected humans are heterozygous and survive into adolescence with
    variable severity. The mismatch cuts against the haploinsufficiency arm
    specifically: mouse Vamp2 heterozygous loss of function is reported to cause
    only a mild phenotype, whereas the humans proposed to have a
    haploinsufficiency mechanism have a neurodevelopmental disorder. No knock-in
    of a human SNARE-motif variant has been reported, so the dominant-negative
    arm has never been tested in vivo at all. Separately, the one direct test of
    endocytosis in human variant-expressing neurons was negative, while the
    endocytic requirement is well established in the null mouse — so the
    recycling node's species evidence and its human evidence disagree.
  proposed_experiments:
  - experiment_id: exp_vamp2_snare_motif_knockin_mouse
    name: Knock-in mouse carrying a human SNARE-motif variant
    description: >-
      Generate and characterize knock-in mice carrying a human SNARE-motif
      missense variant (e.g. p.Ser75Pro) and a truncating variant, benchmarked
      against the already-reported heterozygous null, comparing survival, evoked
      release, endocytosis, and behaviour.
    supporting_outcome:
    - A missense knock-in more severely affected than the reported mild heterozygous null phenotype would confirm dominant-negative action in vivo and validate the two-arm model.
    refuting_outcome:
    - A missense knock-in no worse than the heterozygous null would argue that reduced dose accounts for both allelic classes and that the dominant-negative arm is an in vitro artifact.
  evidence:
  - reference: PMID:30929742
    reference_title: "Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      mice present severely decreased rates of both spontaneous and Ca2+-triggered
      synaptic-vesicle fusion, and these mice die immediately after birth.
    explanation: >-
      Establishes both the model's informativeness and the perinatal lethality that
      limits its translational reach.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      while VAMP2 heterozygosity loss of function in mice causes only a mild
      phenotype
    explanation: >-
      The heterozygous mouse — the genotype that actually matches the human
      truncating carriers — is only mildly affected, which is the substance of
      the mismatch for the haploinsufficiency arm.
  - reference: PMID:32906212
    reference_title: "Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The post-stimulus fluorescence decay of syp-pH, representing endocytosis, is
      not significantly altered by any of the VAMP2 variants compared to WT
    explanation: >-
      The human-versus-mouse disagreement on the endocytic arm, recorded here
      because it is the same translational-validity question.

📚

References & Deep Research

References

7

PMID:30929742

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment.

No top-level findings curated for this source.

PMID:32906212

Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment.

No top-level findings curated for this source.

PMID:32336483

Variant in the neuronal vesicular SNARE VAMP2 (synaptobrevin-2): First report in Japan.

No top-level findings curated for this source.

PMID:37901860

VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders.

No top-level findings curated for this source.

PMID:34653234

New genes involved in Angelman syndrome-like: Expanding the genetic spectrum.

No top-level findings curated for this source.

PMID:11691998

SNARE function analyzed in synaptobrevin/VAMP knockout mice.

No top-level findings curated for this source.

PMID:15475946

Synaptobrevin is essential for fast synaptic-vesicle endocytosis.

No top-level findings curated for this source.

VAMP2-Related Neurodevelopmental Disorder

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References