CYFIP2-Related Developmental and Epileptic Encephalopathy

Mendelian MONDO:0033374 Pathograph 30 Show in embeddings browser Epilepsy Neurological Disease

CYFIP2-related developmental and epileptic encephalopathy (DEE65) lies within an autosomal dominant neurodevelopmental spectrum associated mainly with heterozygous de novo CYFIP2 variants. CYFIP2 regulates the WAVE regulatory complex (WRC) and actin remodeling. Arg87 variants are associated with severe developmental impairment and early epilepsy, whereas other variants can cause milder intellectual or language impairment without seizures. Missense, splice-altering, in-frame deletion and frameshift variants have been reported; their functional consequences differ. Hypotonia, feeding and visual difficulties, microcephaly, sleep disturbance and movement abnormalities accompany the developmental phenotype. Seizures may be drug-resistant, but seizure control and temporary developmental or EEG improvement occur. Brain imaging ranges from normal findings to atrophy and cortical malformation.

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1
Inheritance
14
Pathophys.
20
Phenotypes
3
Hypotheses
3
Gaps
30
Pathograph
1
Genes
6
Variants
7
Medical Actions
3
Datasets
7
Models
14
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant disease associated predominantly with heterozygous de novo variants. Parental testing establishes de novo status when both parents are available; absence in one parent alone is insufficient. Counseling should account for possible germline mosaicism.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:30664714 SUPPORT Human Clinical
"we identified 12 independent patients carrying a total of eight distinct de novo variants in CYFIP2 with a shared phenotype of intellectual disability, seizures, and muscular hypotonia"
Establishes the de novo heterozygous architecture across twelve independent patients, together with the core phenotype triad.
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Mechanistic Hypotheses

3
wrc_activation_model
wrc_activation_model CANONICAL
Evidence balance 1 support
Tested activating missense variants release WAVE autoinhibition and dysregulate actin-dependent structures. This group describes demonstrated proximal cellular effects, not a universal consequence of all CYFIP2 variants.
Pathograph links
Weakened CYFIP2-WAVE1 Interface Binding -> Aberrant WAVE Regulatory Complex Activation DIRECT Reduced VCA sequestration relieves WAVE autoinhibition.
Aberrant WAVE Regulatory Complex Activation -> Dysregulated Actin Cytoskeleton Dynamics DIRECT WRC dysregulation alters actin-dependent protrusions in cellular assays.
Show evidence (1 reference)
PMID:32486060 SUPPORT In Vitro
"Almost all CYFIP2-derived mutations (7 out of 8) promoted WRC activation, but to variable extent and with at least two independent mechanisms."
Cellular reconstitution demonstrated variant-dependent activation; most substitutions were tested in homologous CYFIP1, with R87C also tested directly in CYFIP2.
abundance_actin_model
abundance_actin_model EMERGING
Evidence balance 1 support
Reduced CYFIP2 abundance may contribute to altered actin organization. This contribution can coexist with altered activity of mutant-containing complexes; simple haploinsufficiency does not explain all R87C mouse findings.
Pathograph links
Reduced CYFIP2 Protein Abundance -> Dysregulated Actin Cytoskeleton Dynamics INDIRECT UNKNOWN INTERMEDIATES Proposed contribution of reduced abundance to actin dysregulation in R87C neural models; residual mutant activity and transcript changes may also contribute.
Show evidence (1 reference)
PMID:41851324 SUPPORT In Vitro
"Thus, the decreased CYFIP2 levels with the R87C variant may cause an imbalance in actin polymerization between lamellipodia and filopodia."
The human neural-model paper proposes, rather than proves, an abundance-to-actin mechanism.
neural_remodeling_model
neural_remodeling_model EMERGING
Evidence balance 5 support
Dysregulated actin may alter synaptic architecture, which may promote network hyperexcitability. Seizure activity may in turn drive glial and metabolic responses, with possible astrocytic feedback on excitability. These disease-specific causal transitions remain proposed, chiefly from the R87C mouse study, and are not established human pathways.
Pathograph links
Dysregulated Actin Cytoskeleton Dynamics -> Disrupted Synaptic and Dendritic Spine Remodeling INDIRECT UNKNOWN INTERMEDIATES An inferred link from WRC-dependent actin remodeling to neuronal architecture. Disease-specific intermediates and direction relative to seizures remain unresolved.
Disrupted Synaptic and Dendritic Spine Remodeling -> Neuronal Network Hyperexcitability INDIRECT UNKNOWN INTERMEDIATES The R87C mouse study proposes that excitatory shaft contacts reduce spine compartmentalization and facilitate excitation; this remains an untested causal explanation.
Astrocytic Lysosomal Lipid Accumulation -> Neuronal Network Hyperexcitability INDIRECT UNKNOWN INTERMEDIATES Proposed metabolic feedback on excitability in the mouse model, requiring functional validation and human confirmation.
Neuronal Network Hyperexcitability -> Reactive Gliosis INDIRECT UNKNOWN INTERMEDIATES Neonatal seizure activity is proposed to initiate an early glial response in R87C mice. Temporal association alone does not establish causation.
Neuronal Network Hyperexcitability -> Astrocytic Lysosomal Lipid Accumulation INDIRECT UNKNOWN INTERMEDIATES The authors propose seizure-associated mitochondrial remodeling and disturbed astrocytic lipid metabolism as intervening steps; neither is a proven complete causal route.
Show evidence (5 references)
PMID:32486060 SUPPORT In Vitro
"All this suggests that a precisely tuned, narrow window of WRC activity in the human brain is required for its proper development and function, with both hyper-activation and downregulation leading to similarly drastic consequences."
The authors infer a neural-development mechanism from WRC perturbation assays; this is not a direct neuronal causal test.
PMID:41066510 SUPPORT Model Organism
"When excitatory synapses form directly on the dendritic shaft, bypassing this barrier, it likely becomes easier to activate neurons with each synaptic input, potentially contributing to the observed seizures."
The authors propose altered synaptic compartmentalization as a route to excitability; electrophysiological causal testing remains needed.
PMID:41066510 SUPPORT Model Organism
"one plausible explanation for the increased Olig2-positive cells observed at PWK 7 is that the spasm-like seizures experienced during the neonatal stage may have triggered this early glial response."
An early glial response to seizure activity is a proposed model mechanism, not a demonstrated direction of causation.
+ 2 more references
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Discussions and Knowledge Gaps

3
How do altered activity and reduced abundance jointly contribute to the effects of individual CYFIP2 variants?
KNOWLEDGE GAP OPEN gap_variant_activity_and_abundance
Attached to
pathophysiology#Aberrant WAVE Regulatory Complex Activation pathophysiology#Reduced CYFIP2 Protein Abundance
Cellular activating missense effects, reduced R87C protein abundance and loss of WRC incorporation by a late truncation are distinct observations. Severe adult phenotypes in R87C knock-in but not heterozygous-null mice argue against simple dosage loss as a complete account. Human heterozygous progenitors also have transcript changes. Variant-specific rescue experiments are needed before selecting a strategy to increase or suppress CYFIP2.
Show evidence (1 reference)
PMID:41066510 SUPPORT Model Organism
"The absence of this phenotype in Cyfip2+/− mice further supports the notion that the hotspot p.Arg87 variant likely confers a toxic gain-of-function, rather than simply destabilizing CYFIP2 proteins"
The knockout comparison limits a pure haploinsufficiency interpretation.
Which human seizure trajectories correspond to the quiescent interval and later seizures in the R87C mouse?
KNOWLEDGE GAP OPEN gap_human_longitudinal_course
Attached to
phenotypes#Seizures
The 2025 human Arg87Cys case had EEG and developmental normalization before later spasms, so a quiescent human interval cannot be excluded. Larger genotype-stratified longitudinal cohorts are needed to relate this trajectory to the mouse course; mouse lethality must not be used as a human prognosis.
Show evidence (1 reference)
PMID:42563853 SUPPORT Human Clinical
"Our patient demonstrated a transient period of seizure resolution and EEG normalization after seizure onset and before the onset of epileptic spasms"
Human longitudinal observations replace the assertion that such intervals never occur.
Which cellular changes cause seizures, and which are consequences of ongoing seizure activity?
KNOWLEDGE GAP OPEN gap_how_actin_dysregulation_becomes_hyperexcitability
Attached to
pathophysiology#Dysregulated Actin Cytoskeleton Dynamics pathophysiology#Neuronal Network Hyperexcitability pathophysiology#Reactive Gliosis pathophysiology#Astrocytic Lysosomal Lipid Accumulation
Mouse synaptic, glial and lipid changes accompany seizure evolution without establishing a complete causal sequence. Increased microglial engulfment of synapses did not reach statistical significance. Human homozygous monolayer neurons had no detected electrophysiological difference, despite progenitor and organoid abnormalities. Perturbation experiments and more complete human neural models are needed to test causality.
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Pathophysiology

14
Heterozygous CYFIP2 Variation
Disease-associated variants include recurrent Arg87 and Asp724 substitutions, other missense changes, and selected splice-altering or deletion variants. Molecular effects must be assigned to the tested variant rather than extrapolated to every CYFIP2 allele.
Downstream
Weakened CYFIP2-WAVE1 Interface Binding Demonstrated for tested Arg87 substitutions.
Enhanced CYFIP2 Ubiquitination Reported for p.Arg87Cys.
Impaired WRC Incorporation by a C-terminal Truncation Supported by a homologous CYFIP1 cellular proxy for the late CYFIP2 truncation.
Dysregulated Actin Cytoskeleton Dynamics Patient fibroblasts and neural progenitors show variant-dependent abnormalities; intervening molecular events differ.
Show evidence (2 references)
PMID:29534297 SUPPORT Human Clinical
"We identified three de novo CYFIP2 variants at the Arg87 residue in 4 unrelated individuals with early-onset epileptic encephalopathy."
The original clinical series establishes the Arg87-associated disease relationship.
PMID:33149277 SUPPORT BACKGROUND Human Clinical
"Recently, de novo missense variants affecting a small number of amino acids and one late-truncating variant in CYFIP2 have been associated with intellectual disability (ID), seizures, and muscular hypotonia"
The spectrum includes a disease-associated late truncation.
Weakened CYFIP2-WAVE1 Interface Binding
Arg87 substitutions weaken interaction with the WAVE VCA domain. This concerns regulatory sequestration of WAVE, not direct binding of CYFIP2 to actin. Activation can occur while the remaining WRC stays assembled.
None
CYFIP2 hgnc:13760 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CYFIP2 (hgnc:13760). hgnc:13760 is a gene from the HUGO Gene Nomenclature Committee.
WAVE VCA domain binding GO:0019904 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased WAVE VCA domain binding, annotated with protein domain specific binding (GO:0019904). GO:0019904 is a molecular function from the Gene Ontology.
SCAR complex GO:0031209 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves SCAR complex (GO:0031209). GO:0031209 is a cellular component from the Gene Ontology.
Downstream
Aberrant WAVE Regulatory Complex Activation Reduced VCA sequestration relieves WAVE autoinhibition. None
Show evidence (2 references)
PMID:29534297 SUPPORT In Vitro
"All mutant CYFIP2 showed comparatively weaker interactions to the VCA domain than wild-type CYFIP2."
The tested Arg87 substitutions weakened VCA binding in transfection experiments.
PMID:32486060 SUPPORT In Vitro
"we found the activating mutation R87C to normally interact with WRC components, including WAVE"
R87C retained WRC association in the homologous CYFIP1 assay; weakened VCA binding does not require whole-complex dissociation.
Enhanced CYFIP2 Ubiquitination
The p.Arg87Cys variant has increased ubiquitination in the reported mechanistic experiments. This event is distinct from the reduced steady-state protein abundance measured in mouse brain.
Downstream
Enhanced CYFIP2 Proteasomal Degradation The study links enhanced ubiquitination with proteasomal turnover.
Show evidence (1 reference)
PMID:36251395 SUPPORT In Vitro
"we demonstrated that the p.Arg87Cys variant enhances ubiquitination and proteasomal degradation of CYFIP2."
Ubiquitination and proteasome-inhibition experiments were performed in cultured cells; reduced mouse brain abundance is recorded separately.
Enhanced CYFIP2 Proteasomal Degradation
Accelerated proteasomal turnover is reported for p.Arg87Cys. Reduced abundance and altered activity of the residual mutant-containing complex need not be mutually exclusive.
proteasomal protein catabolic process GO:0010498 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased proteasomal protein catabolic process (GO:0010498). GO:0010498 is a biological process from the Gene Ontology.
Downstream
Reduced CYFIP2 Protein Abundance Enhanced turnover provides a mechanism for reduced protein abundance; patient-derived progenitors also show transcript changes.
Show evidence (1 reference)
PMID:36251395 SUPPORT In Vitro
"we demonstrated that the p.Arg87Cys variant enhances ubiquitination and proteasomal degradation of CYFIP2."
Ubiquitination and proteasome-inhibition experiments were performed in cultured cells; reduced mouse brain abundance is recorded separately.
Reduced CYFIP2 Protein Abundance
CYFIP2 protein is reduced in heterozygous knock-in mouse brain and human R87C neural models. Patient-derived heterozygous progenitors also have reduced CYFIP2 transcript abundance. These findings do not establish simple haploinsufficiency as the complete disease mechanism.
None
Experimental models
Patient-derived R87C neural progenitors and corrected control IPSC DERIVED MODEL Transcript and protein abundance are reduced.
CYFIP2 Arg87Cys ligand thermal-shift screen CELL LINE The assay measures soluble protein after heating as a candidate stabilization readout.
Animal models
Cyfip2 p.Arg87Cys knock-in mouse Mouse measures Brain protein abundance is reduced.
Downstream
Dysregulated Actin Cytoskeleton Dynamics Proposed contribution of reduced abundance to actin dysregulation in R87C neural models; residual mutant activity and transcript changes may also contribute. None
Show evidence (2 references)
PMID:36251395 SUPPORT Model Organism
"Beyond identifying a decrease in CYFIP2 protein levels in the Cyfip2+/R87C brains"
Reduced brain protein abundance was measured in heterozygous knock-in mice.
PMID:41851324 SUPPORT In Vitro
"Analysis of CYFIP2 and CYFIP1 expression revealed reduced mRNA and protein levels in R87C/WT NPCs"
Patient-derived heterozygous progenitors show both transcript and protein changes, so protein reduction alone does not establish accelerated degradation in this system.
Impaired WRC Incorporation by a C-terminal Truncation
A CYFIP1 E1150Dfs*3 construct modeling CYFIP2 Glu1174Aspfs*3 failed WRC incorporation and lamellipodia rescue in CYFIP1/2-null B16-F1 cells. This loss-of-function result contrasts with activating missense substitutions, but does not establish pathogenicity of every early truncating CYFIP2 allele.
Experimental models
CYFIP1/2-null B16-F1 reconstitution assays CELL LINE The truncating proxy fails WRC incorporation.
Downstream
Dysregulated Actin Cytoskeleton Dynamics Failure to assemble functional WRC prevents lamellipodia rescue in the surrogate assay.
Show evidence (1 reference)
PMID:32486060 SUPPORT In Vitro
"the E1150Dfs*3 mutant was unable to incorporate into endogenous WRC"
The homologous CYFIP1 construct modeling the CYFIP2 C-terminal truncation failed complex incorporation; this is a surrogate cellular assay.
Aberrant WAVE Regulatory Complex Activation
Many tested missense substitutions increase WRC activation. Most act at the WAVE-sequestering interface, whereas Tyr108His requires a functional Rac-binding A site. The experiments do not support a uniform, fully RAC1-independent mechanism across variants.
None
Arp2/3 complex-mediated actin nucleation GO:0034314 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Arp2/3 complex-mediated actin nucleation (GO:0034314). GO:0034314 is a biological process from the Gene Ontology.
SCAR complex GO:0031209 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves SCAR complex (GO:0031209). GO:0031209 is a cellular component from the Gene Ontology.
Experimental models
CYFIP1/2-null B16-F1 reconstitution assays CELL LINE Lamellipodia rescue under restricted Rac signaling measures activation.
Downstream
Dysregulated Actin Cytoskeleton Dynamics WRC dysregulation alters actin-dependent protrusions in cellular assays. None
Show evidence (1 reference)
PMID:32486060 SUPPORT In Vitro
"Almost all CYFIP2-derived mutations (7 out of 8) promoted WRC activation, but to variable extent and with at least two independent mechanisms."
Cellular reconstitution demonstrated variant-dependent activation; most substitutions were tested in homologous CYFIP1, with R87C also tested directly in CYFIP2.
Dysregulated Actin Cytoskeleton Dynamics
Readouts vary by cell type and allele. Arg87-transfected cells show ectopic actin accumulation; patient fibroblasts have reduced circular dorsal ruffles without apparent lamellipodia differences. Patient-derived R87C neural progenitors have altered lamellipodia. These are distinct readouts of dysregulation, not equivalent measurements of globally increased actin.
None
actin cytoskeleton organization GO:0030036 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated actin cytoskeleton organization (GO:0030036). GO:0030036 is a biological process from the Gene Ontology.
Experimental models
Patient-derived CYFIP2 fibroblasts PRIMARY CELL CULTURE Dorsal ruffle formation is reduced.
Patient-derived R87C neural progenitors and corrected control IPSC DERIVED MODEL Electron microscopy identifies altered morphology and lamellipodia.
Downstream
Disrupted Synaptic and Dendritic Spine Remodeling An inferred link from WRC-dependent actin remodeling to neuronal architecture. Disease-specific intermediates and direction relative to seizures remain unresolved. None
Show evidence (3 references)
PMID:29534297 SUPPORT In Vitro
"Immunofluorescence revealed that ectopic speckled accumulation of actin and CYFIP2 was significantly increased in cells transfected with mutant CYFIP2"
The original actin readout in a heterologous transfection system.
PMID:33149277 SUPPORT In Vitro
"a significantly reduced number of circular dorsal ruffles (CDRs) was observed in all patient fibroblast lines compared with fibroblasts of three controls"
Six patient lines showed impaired growth-factor-induced actin remodeling, not a uniform increase in actin accumulation.
PMID:41851324 SUPPORT In Vitro
"hiPSC-derived R87C/WT NPCs also exhibited altered cell morphology and lamellipodia formation as analyzed by electron microscopy"
Patient-derived heterozygous neural progenitors differed from the corrected isogenic control.
Reduced Neural Progenitor Motility
Engineered homozygous R87C/R87C human neural progenitors show reduced speed and displacement. This motility result should not be generalized to every patient fibroblast line or treated as demonstrated cortical migration failure in patients. This remains an unconnected experimental observation because a causal link to patient seizures or brain growth has not been established.
Experimental models
Engineered homozygous R87C neural cells and cortical organoids ORGANOID Cell tracking measures reduced speed and displacement.
Show evidence (1 reference)
PMID:41851324 SUPPORT In Vitro
"NPC motility, including speed and displacement, was decreased in the R87C variant cells"
Cell tracking measured motility in the homozygous engineered progenitor model.
Loss of SOX2-positive Progenitor Staining in R87C Organoids
Homozygous R87C/R87C cortical organoids lack SOX2-positive progenitor staining at day 30 and are enlarged at days 30 and 60. Premature progenitor depletion is proposed; these findings neither demonstrate cell death nor recapitulate patient microcephaly. This remains an unconnected experimental observation because a causal link to patient seizures or brain growth has not been established.
Experimental models
Engineered homozygous R87C neural cells and cortical organoids ORGANOID Day30 organoids lose SOX2-positive progenitor staining.
Show evidence (1 reference)
PMID:41851324 SUPPORT In Vitro
"Immunostaining revealed SOX2 + neural progenitors within rosettes in WT organoids, whereas R87C/R87C organoids lacked SOX2 + cells"
Loss of progenitor-marker staining was observed in homozygous engineered organoids; depletion is an interpretation rather than directly established cell death.
Disrupted Synaptic and Dendritic Spine Remodeling
Adult heterozygous R87C knock-in hippocampal CA1 has fewer excitatory synapses, reduced dendritic spines and excitatory contacts shifted onto dendritic shafts. Synaptic remodeling accompanies seizures; direction of causation remains unresolved.
None
glutamatergic neuron CL:0000679 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glutamatergic neuron (CL:0000679). CL:0000679 is a cell type from the Cell Ontology.
dendritic spine GO:0043197 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves dendritic spine (GO:0043197). GO:0043197 is a cellular component from the Gene Ontology.
Animal models
Cyfip2 p.Arg87Cys knock-in mouse Mouse measures Electron microscopy measures altered excitatory contacts.
Downstream
Neuronal Network Hyperexcitability The R87C mouse study proposes that excitatory shaft contacts reduce spine compartmentalization and facilitate excitation; this remains an untested causal explanation. None
Show evidence (2 references)
PMID:41066510 SUPPORT Model Organism
"the number of excitatory (asymmetric) synapses decreased, while the number of inhibitory (symmetric) synapses remained normal in Cyfip2+/R87C mice at PWK 28"
Ultrastructure shows selective reduction of excitatory synapses in adult knock-in hippocampal CA1.
PMID:41066510 SUPPORT Model Organism
"excitatory synapses were predominantly located on dendritic shafts, with multiple presynaptic terminals clustering nearby"
Adult knock-in neurons have fewer spines and altered excitatory-contact geometry; its effect on excitability remains proposed.
Reactive Gliosis
Knock-in mouse brain shows age-dependent oligodendroglial, microglial and astrocytic marker changes, with altered microglial and astrocytic morphology. Their contributions to seizure progression and exact temporal ordering require further testing.
astrocyte CL:0000127 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves astrocyte (CL:0000127). CL:0000127 is a cell type from the Cell Ontology.
Animal models
Cyfip2 p.Arg87Cys knock-in mouse Mouse measures Age-dependent glial marker changes accompany the model phenotype.
Show evidence (1 reference)
PMID:41066510 SUPPORT Model Organism
"glial markers in the hippocampal CA1 region of Cyfip2+/R87C mice exhibited an age-related increase compared to WT mice, with oligodendrocyte, microglia, and astrocytes in that order"
Marker changes suggest an ordered glial response, but broad sampling intervals do not resolve exact timing or causality.
Astrocytic Lysosomal Lipid Accumulation
Adult R87C knock-in hippocampal astrocytes accumulate lipid droplets in lysosomes. Associated crystals have not been chemically identified. Lipid accumulation is a late accompaniment of disease in this model, with no demonstrated corresponding human lesion.
None
astrocyte CL:0000127 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves astrocyte (CL:0000127). CL:0000127 is a cell type from the Cell Ontology.
Animal models
Cyfip2 p.Arg87Cys knock-in mouse Mouse measures Adult astrocytes accumulate lysosomal lipid droplets.
Downstream
Neuronal Network Hyperexcitability Proposed metabolic feedback on excitability in the mouse model, requiring functional validation and human confirmation. None
Show evidence (1 reference)
PMID:41066510 SUPPORT Model Organism
"both the number and volume of LDs within astrocytic lysosomes were significantly increased in the hippocampus of Cyfip2+/R87C mice compared to WT mice at PWK 28, but not at PWK 14"
Lipid accumulation is a late model finding; it is not established as the initiating seizure mechanism or a human biomarker.
Neuronal Network Hyperexcitability
Heterozygous R87C knock-in mice develop adult electroclinical seizures after neonatal spasms and a quiescent interval. The steps connecting CYFIP2-dependent cellular abnormalities to seizures remain incompletely established.
None
Experimental models
Engineered homozygous R87C neural cells and cortical organoids ORGANOID Parallel two-dimensional cortical neuron cultures did not show altered electrical activity.
Animal models
Cyfip2 p.Arg87Cys knock-in mouse Mouse partially recapitulates The model has adult electroclinical seizures.
Xenopus laevis cyfip2 gain-of-function tadpole Xenopus laevis recapitulates Expression of either pathogenic variant produced spontaneous epileptic activity in the brain.
Downstream
Seizures Seizures are the clinical manifestation of abnormal network activity; drug resistance is a separate treatment-response property.
Reactive Gliosis Neonatal seizure activity is proposed to initiate an early glial response in R87C mice. Temporal association alone does not establish causation. None
Astrocytic Lysosomal Lipid Accumulation The authors propose seizure-associated mitochondrial remodeling and disturbed astrocytic lipid metabolism as intervening steps; neither is a proven complete causal route. None
Epileptic Spasms Epileptic spasms are one electroclinical manifestation of abnormal network activity in affected individuals; they do not occur in every case.
Show evidence (1 reference)
PMID:41066510 SUPPORT Model Organism
"we observed tonic-clonic seizures and myoclonic jerks that correlated with behavioral seizures, events that were never observed in WT mice"
Video-EEG in three surviving knock-in mice at postnatal week 20 established electroclinical seizures; age progression was assessed behaviorally.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for CYFIP2-Related Developmental and Epileptic Encephalopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

20
Blood 1
Neutropenia OCCASIONAL Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42563853 SUPPORT Human Clinical
"5/42 (12%) had neutropenia of unclear etiology and significance."
The review reports a hematologic association with unresolved causation.
Digestive 2
Feeding Difficulties FREQUENT HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:30664714 SUPPORT Human Clinical
"Dysphagia with dependency on gastric tube feeding was present in five of 12 patients."
The primary cohort documents severe feeding impairment.
PMID:36968925 SUPPORT Human Clinical
"was fed exclusively by nasogastric tube"
The index infant required exclusive tube feeding.
PMID:33149277 SUPPORT Human Clinical
"| Feeding difficulties | 9/11 | 0/2 | 3/5 | 3/12 | 15/30 (50%) |"
Table 2 reports feeding difficulties in 15/30 individuals with available information.
Dysphagia FREQUENT HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33149277 SUPPORT Human Clinical
"Dysphagia was reported in seven individuals; three of them were dependent on gastric tube feeding."
Counts refer to the 16 new likely disease-associated missense cases.
Eye 2
Visual Impairment FREQUENT HP:0000505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visual impairment (HP:0000505). HP:0000505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33149277 SUPPORT Human Clinical
"Variable visual problems were present in six individuals"
The primary cohort reports visual problems without a uniform mechanism or subtype.
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30664714 SUPPORT Human Clinical
"Nine of 12 patients had visual impairment and/or strabismus."
The cohort reports this combined ocular category.
Head and Neck 2
Microcephaly FREQUENT HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33149277 SUPPORT Human Clinical
"Microcephaly with a HC below 2 standard deviations was diagnosed in 5/16 individuals of the current cohort."
Primary human data support microcephaly.
Facial Dysmorphism Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33149277 SUPPORT Human Clinical
"Morphological features revealed a shared but not clearly recognizable facial gestalt including high, narrow forehead; apparent hypertelorism; depressed nasal bridge; bulbous nasal tip; full cheeks; everted lip vermilion"
Primary clinical examination supports variable facial dysmorphism.
Metabolism 1
Drug-Resistant Epilepsy Refractory drug response HP:0020174 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Refractory drug response (HP:0020174). HP:0020174 is a phenotype from the Human Phenotype Ontology.
Drug resistance is a treatment-response property. No specific causal mechanism distinguishing resistant from responsive CYFIP2-associated seizures is established, so it is not drawn as a necessary downstream consequence of seizures.
Show evidence (2 references)
PMID:36968925 SUPPORT Human Clinical
"The seizures were of different types, frequent and refractory to treatment, including different anticonvulsant drugs"
Documents refractoriness across multiple anticonvulsant classes in a genotype-confirmed patient.
PMID:36968925 SUPPORT Human Clinical
"He maintained refractory epilepsy despite being medicated with vigabatrin, phenobarbital, valproic acid, and a ketogenic diet"
Names the specific agents that failed, which is stronger than a general statement of drug resistance.
Musculoskeletal 2
Muscular Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33149277 SUPPORT Human Clinical
"Ten of 16 individuals showed generalized or truncal muscular hypotonia, combined with limb hypertonicity in two cases."
Primary cohort supports hypotonia and the frequency denominator.
Limb Spasticity FREQUENT HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30664714 SUPPORT Human Clinical
"All patients showed generalized or truncal hypotonia, in four cases combined with limb spasticity."
Four of twelve patients had coexisting limb spasticity.
Nervous System 10
Seizures FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42563853 SUPPORT Human Clinical
"32/42 (76%) developed epilepsy, and 25/42 (60%) experienced seizure onset in the first year of life."
Published-case review denominators; these are not population penetrance estimates.
Epileptic Spasms FREQUENT HP:0011097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epileptic spasm (HP:0011097). HP:0011097 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42563853 SUPPORT Human Clinical
"Of those with seizures, 16/32 (50%) had epileptic spasms"
The denominator is individuals with seizures; 16/42 overall also falls within the FREQUENT band.
Global Developmental Delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33149277 SUPPORT Human Clinical
"14/16 with global DD and 2/16 with normal motor but delayed language development"
The primary cohort distinguishes global from language-only delay.
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33149277 SUPPORT Human Clinical
"Intellectual disability was classified as severe or profound in 9 of 14 evaluated individuals, as moderate in 4/14, and as mild in 1/14 cases"
Formal assessment demonstrates variable severity, not uniformly severe or profound impairment.
Sleep Disturbance FREQUENT HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33149277 SUPPORT Human Clinical
"sleep difficulties were reported in seven individuals"
The primary cohort denominator is 16 new missense cases.
PMID:42563853 SUPPORT Human Clinical
"15/42 (36%) had sleep disturbances"
The later review also identifies sleep disturbance.
Atypical Behavior FREQUENT HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33149277 SUPPORT Human Clinical
"| Behavioral problems | 3/8 | 1/2 | 2/5 | 9/12 | 15/27 (56%) |"
Table 2 pools likely disease-associated variants; the final column gives the combined count. The three putative loss-of-function VUS were excluded.
Choreoathetosis HP:0001266 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Choreoathetosis (HP:0001266). HP:0001266 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42563853 SUPPORT Human Clinical
"A hyperkinetic choreoathetoid movement disorder emerged at age 7 months"
The index case had a non-epileptic hyperkinetic movement disorder.
PMID:40425513 SUPPORT Human Clinical
"movement disorders, including dystonia, choreoathetosis, and dyskinetic crises."
The Gln95ProfsTer15 case expands the movement phenotype.
Bilateral Perisylvian Polymicrogyria HP:0032407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral perisylvian polymicrogyria (HP:0032407). HP:0032407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37975178 SUPPORT Human Clinical
"Brain magnetic resonance imaging (MRI) showed (Figure 1) extensive polymicrogyria with thickening involving bilateral perisylvian cortex of frontal and temporal lobes extending to parietal lobes."
MRI documents the cortical malformation in the reported child.
Developmental Regression HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42563853 SUPPORT Human Clinical
"Following the onset of epileptic spasms, he experienced significant developmental regression."
Regression occurred after a period of developmental improvement in the Arg87Cys index case.
Cerebral Atrophy HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral atrophy (HP:0002059). HP:0002059 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30664714 SUPPORT Human Clinical
"including cerebellar, white matter or diffuse atrophy in four patients"
The primary cohort reports variable brain volume loss.
🧬

Genetic Associations

1
CYFIP2 (Heterozygous CYFIP2 variants cause a neurodevelopmental spectrum, often through de novo missense changes. Arg87 substitutions tend toward severe DEE, while Asp724 and other substitutions are more variable. Specific late splice-altering, in-frame deletion and frameshift alleles are also reported.)
Gene: CYFIP2 hgnc:13760 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CYFIP2 (hgnc:13760). hgnc:13760 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:33149277 SUPPORT Human Clinical
"Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions"
States the hotspot-dependent severity difference that makes the genotype prognostically informative: Arg87 consistently severe, Asp724 variable.
PMID:40425513 SUPPORT Human Clinical
"We report a novel CYFIP2 frameshift variant (c.281_282insA/p.(Gln95ProfsTer15)) causing dyskinetic crises"
A specific frameshift case has severe DEE and movement abnormalities; the abstract does not establish a universal haploinsufficiency mechanism.
Variants (6)
CYFIP2 p.Arg87 substitutions
Gene: CYFIP2 hgnc:13760 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CYFIP2 (hgnc:13760). hgnc:13760 is a gene from the HUGO Gene Nomenclature Committee.
Recurrent de novo missense hotspot, including Arg87Cys, Arg87Leu and Arg87Pro in the founding cohort. Arg87Cys has the most extensively studied cellular and animal models.
Show evidence (1 reference)
PMID:29534297 SUPPORT Human Clinical
"We identified three de novo CYFIP2 variants at the Arg87 residue in 4 unrelated individuals with early-onset epileptic encephalopathy."
The original clinical series establishes the Arg87-associated disease relationship.
CYFIP2 p.Asp724 substitutions
Gene: CYFIP2 hgnc:13760 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CYFIP2 (hgnc:13760). hgnc:13760 is a gene from the HUGO Gene Nomenclature Committee.
A second recurrent site with variable severity, including individuals without epilepsy.
Show evidence (1 reference)
PMID:33149277 SUPPORT Human Clinical
"the total of five Asp724 individuals (including patient 11 in Zweier et al.5) present with a more variable phenotype ranging from profound ID with intractable epilepsy to moderate ID without epilepsy."
Clinical severity varies at the Asp724 hotspot.
CYFIP2 p.Trp86_Ser88del
Gene: CYFIP2 hgnc:13760 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CYFIP2 (hgnc:13760). hgnc:13760 is a gene from the HUGO Gene Nomenclature Committee.
De novo in-frame deletion removing codon87, reclassified as likely pathogenic in the reported infant. Phenotypic similarity does not demonstrate the same molecular consequence as an Arg87 substitution.
Show evidence (2 references)
PMID:36968925 SUPPORT Human Clinical
"Analysis of a whole exome sequencing-based multigene panel for epilepsy disclosed a heterozygous in-frame deletion of three amino acids in CYFIP2: NM_001291722.1 c.258_266del; p.(Trp86_Ser88del)"
The molecular result identifies the in-frame deletion.
PMID:36968925 SUPPORT Human Clinical
"activation of the PM6 criteria allowed its reclassification as likely pathogenic."
The authors reclassified the variant after parental segregation testing.
CYFIP2 c.3669+1G>T / p.Glu1174Aspfs*3
Gene: CYFIP2 hgnc:13760 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CYFIP2 (hgnc:13760). hgnc:13760 is a gene from the HUGO Gene Nomenclature Committee.
Late splice-altering variant with exon skipping and predicted C-terminal truncation escaping nonsense-mediated decay; associated with profound ID and epilepsy. Functional work used a homologous CYFIP1 truncation.
Show evidence (2 references)
PMID:30664714 SUPPORT Human Clinical
"RT-PCR performed using RNA from peripheral blood leukocytes of P2 confirmed skipping of exon 31"
RNA analysis directly demonstrated the splice defect.
PMID:30664714 SUPPORT Human Clinical
"Lack of exon 31, which is the second to last exon, is predicted to result in a frameshift followed by a premature stop codon (p.(Glu1174Aspfs*3)). Accordingly, this aberrant transcript is not expected to be subject to nonsense-mediated mRNA decay"
Protein truncation and NMD escape are predictions accompanying the demonstrated exon skip.
CYFIP2 p.Val551Leu
Gene: CYFIP2 hgnc:13760 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CYFIP2 (hgnc:13760). hgnc:13760 is a gene from the HUGO Gene Nomenclature Committee.
c.1651G>C, reported as likely pathogenic in a child with bilateral perisylvian polymicrogyria; absent from the maternal sample, with paternal sample unavailable.
Show evidence (2 references)
PMID:37975178 SUPPORT Human Clinical
"A paternal sample was not obtained."
Complete segregation was unavailable; de novo status is not established.
PMID:37975178 SUPPORT Human Clinical
"a heterozygous variant NM_001291722.2: c.1651G>C: p.(Val551Leu)"
The sequencing result identifies the reported variant.
CYFIP2 p.Gln95ProfsTer15
Gene: CYFIP2 hgnc:13760 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CYFIP2 (hgnc:13760). hgnc:13760 is a gene from the HUGO Gene Nomenclature Committee.
c.281_282insA, associated with DEE, refractory seizures and dyskinetic crises. Patient-derived fibroblasts showed actin and motility abnormalities; inheritance and protein fate are not established by the available abstract.
Show evidence (1 reference)
PMID:40425513 SUPPORT Human Clinical
"We report a novel CYFIP2 frameshift variant (c.281_282insA/p.(Gln95ProfsTer15)) causing dyskinetic crises"
Reports a specific frameshift-associated severe phenotype.
💊

Medical Actions

7
Antiseizure Medication
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Individualized antiseizure treatment is guided by seizure type and an epilepsy specialist. Published patients show both drug resistance and seizure freedom. Observed responses do not establish a preferred CYFIP2-specific agent.
Show evidence (1 reference)
PMID:33149277 SUPPORT Human Clinical
"Two individuals were seizure-free on antiepileptic polytherapy, while six remained refractory to treatment."
Response varied among the eight new patients with epilepsy.
Lacosamide
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: lacosamide CHEBI:135939 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses lacosamide (CHEBI:135939). CHEBI:135939 is a therapeutic agent from Chemical Entities of Biological Interest.
In the 2025 Arg87Cys case, seizures were well controlled on lacosamide monotherapy before later onset of spasms; subsequent seizure freedom occurred on combination therapy. This is a case observation, not controlled evidence or a genotype-specific recommendation.
Show evidence (1 reference)
PMID:42563853 SUPPORT Human Clinical
"Seizures were initially managed with phenobarbital, levetiracetam, and lacosamide and remained well‐controlled on lacosamide monotherapy, with only one seizure over a 3‐month span."
The index case had temporary control before spasms developed.
ACTH and Vigabatrin for Epileptic Spasms
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: corticotropin CHEBI:3892 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticotropin (CHEBI:3892). CHEBI:3892 is a therapeutic agent from Chemical Entities of Biological Interest. vigabatrin CHEBI:63638 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses vigabatrin (CHEBI:63638). CHEBI:63638 is a therapeutic agent from Chemical Entities of Biological Interest.
The 2025 index case had spasm resolution following ACTH, with vigabatrin added during taper. Other published patients remained refractory despite hormonal treatment. In the Trp86_Ser88del case, levetiracetam and zonisamide lacked benefit, phenobarbital had mild benefit, and vigabatrin gave transient improvement.
Show evidence (2 references)
PMID:42563853 SUPPORT Human Clinical
"His spasms resolved following adrenocorticotropic hormone (ACTH) therapy. Vigabatrin was initiated during the ACTH taper"
Reports the treatment sequence and observed spasm resolution.
PMID:36968925 SUPPORT Human Clinical
"Phenobarbital was later associated with mild benefits. When he started having infantile spasms, and there was evidence of small fragments of disorganized activity on EEG, vigabatrin was also started with transitory clinical improvement."
A separate patient had limited medication responses.
Ketogenic Diet
Action: Ketogenic DietNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Ketogenic Diet (NCIT:C173168). NCIT:C173168 is a clinical intervention from the NCI Thesaurus. NCIT:C173168
The Trp86_Ser88del infant had partial clinical seizure control for several months after diet initiation, followed by recurrent refractory epilepsy despite continued diet and medications.
Show evidence (1 reference)
PMID:36968925 SUPPORT Human Clinical
"a ketogenic diet was implemented, and there was partial clinical control of seizures for several months"
Diet produced a time-limited partial response in one case.
Clonazepam for Movement and Sleep Symptoms
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: clonazepam CHEBI:3756 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses clonazepam (CHEBI:3756). CHEBI:3756 is a therapeutic agent from Chemical Entities of Biological Interest.
Nightly clonazepam improved hyperkinetic movements and sleep disturbance in the 2025 Arg87Cys index case. General efficacy has not been established.
Show evidence (1 reference)
PMID:42563853 SUPPORT Human Clinical
"Both the movement disorder and sleep disturbance improved with clonazepam."
A case-level symptomatic response.
Developmental and Feeding Support
Developmental assessment guides physical, occupational, speech and feeding therapy and educational support. Swallowing impairment may require enteral feeding.
Show evidence (2 references)
url:https://humandiseasegenes.nl/cyfip2/parents/management SUPPORT Other
"For developmental delay, early intervention by referral to occupational, physical, speech, and feeding therapy as well as special educators is important."
Disease-specific expert guidance recommends developmental and feeding support.
PMID:33149277 SUPPORT Human Clinical
"Dysphagia was reported in seven individuals; three of them were dependent on gastric tube feeding."
Counts refer to the 16 new likely disease-associated missense cases.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling addresses autosomal dominant transmission, parental testing and residual recurrence risk from germline mosaicism after an apparently de novo finding. Reproductive testing can be discussed for the identified variant.
Show evidence (1 reference)
url:https://humandiseasegenes.nl/cyfip2/parents/management SUPPORT Other
"the recurrence risk in subsequent pregnancies of the proband’s parents is low (approx. 1% due to the possibility of germline mosaicism). Prenatal diagnosis is possible."
Expert counseling guidance gives an approximate residual risk, not a measured CYFIP2-specific mosaicism rate.
🔬

Diagnosis

3
Trio Exome or Genome Sequencing
Exome or genome sequencing, or an epilepsy gene panel, can establish a molecular diagnosis in the appropriate phenotype. Parental testing helps interpret de novo status. Reanalysis may be useful when initial testing is unrevealing; a normal MRI does not exclude the disorder.
Whole Exome Sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29534297 SUPPORT Human Clinical
"We performed trio-based whole-exome sequencing (WES) in 210 families and case-only WES in 489 individuals with epileptic encephalopathies"
Describes the sequencing strategy through which the gene-disease relationship was established.
Electroencephalography
EEG characterizes seizure types and evolving epileptic encephalopathy. Hypsarrhythmia can develop after earlier seizure types and even a period of EEG normalization.
Electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:42563853 SUPPORT Human Clinical
"A repeat EEG at age 3 months demonstrated a normal background with no epileptiform or ictal activity"
The index child had a temporary normal EEG before later spasms.
PMID:42563853 SUPPORT Human Clinical
"EEG was consistent with hypsarrhythmia"
The same child developed hypsarrhythmia when epileptic spasms emerged at six months.
Brain Magnetic Resonance Imaging
MRI findings are variable. Normal imaging was documented in the Trp86_Ser88del infant, whereas other cases show atrophy, callosal abnormalities or cortical malformation. Imaging is descriptive and cannot alone exclude CYFIP2-related disease.
Show evidence (2 references)
PMID:36968925 SUPPORT Human Clinical
"Brain MRI showed no pathological changes"
Normal imaging in one genotype-confirmed case.
PMID:37975178 SUPPORT Human Clinical
"Brain magnetic resonance imaging (MRI) showed (Figure 1) extensive polymicrogyria with thickening involving bilateral perisylvian cortex of frontal and temporal lobes extending to parietal lobes."
MRI documents the cortical malformation in the reported child.
📊

Prevalence

1
Published cases reviewed through March 2025
Cases In Literature
The Squire review combined its index case with 41 literature cases. This is a historical literature count, not a current worldwide total or population prevalence; the review includes several variants previously classified as uncertain.
Show evidence (1 reference)
PMID:42563853 SUPPORT Human Clinical
"We identified 41 additional patients with pathogenic or likely pathogenic CYFIP2 variants."
The authors describe their literature sample; variant classifications should be reconciled with the original reports.
📊

Related Datasets

3
Brain transcriptome analysis in the cortex and hippocampus of Cyfip2 Arg87Cys knock-in mice at four different postnatal stages geo:GSE292221
Bulk cortex and hippocampus transcriptomes from heterozygous Arg87Cys knock-in and control mice at postnatal weeks 1, 7, 14 and 28.
mouse
PMID:41066510
Show evidence (1 reference)
GEO:GSE292221 SUPPORT Model Organism
"To investigate age-dependent molecular changes in the cortex and hippocampus of Cyfip2 Arg87Cys knock-in mice, we conducted transcriptome analysis at postnatal weeks 1, 7, 14, 28."
The GEO record confirms the model, tissue and sampling ages.
Brain transcriptome analysis in the cortex and hippocampus of Cyfip2 heterozygous mice at three different postnatal stages geo:GSE292102
Bulk cortex and hippocampus transcriptomes from heterozygous Cyfip2-null and control mice at postnatal weeks 1, 7 and 14, providing the dosage-loss comparator.
mouse
PMID:41066510
Show evidence (1 reference)
GEO:GSE292102 SUPPORT Model Organism
"To investigate age-dependent molecular changes in the cortex and hippocampus of Cyfip2 heterozygous mice, we conducted transcriptome analysis at postnatal weeks 1, 7, and 14."
The GEO record confirms the model, tissue and sampling ages.
Seizure evolution in a mouse model of West syndrome involves complex and time-dependent 4 synapse remodeling, gliosis and alterations in lipid metabolism geo:GSE293769
Single-nucleus transcriptomes from hippocampus of Arg87Cys knock-in and control mice at postnatal week 28; used to investigate cell-type-specific changes.
mouse
PMID:41066510
Show evidence (1 reference)
GEO:GSE293769 SUPPORT Model Organism
"To investigate molecular changes in the hippocampus of Cyfip2 Arg87Cys knock-in mice at the cell-type-specific manner, we conducted single-nucleus transcriptomic analysis at postnatal weeks 28."
The GEO record confirms the model, tissue and sampling ages.
🧫

Experimental Models

5
Patient-derived CYFIP2 fibroblasts PRIMARY_CELL_CULTURE
PDGF-stimulated fibroblast assays test dorsal ruffle formation and wound closure.
Cell source
Primary fibroblasts from six individuals with heterozygous CYFIP2 missense variants and three controls
Publication
PMID:33149277
Pathograph links
Dysregulated Actin Cytoskeleton Dynamics measures fidelity: unknown Dorsal ruffle formation is reduced.
Limitations: Fibroblasts do not directly measure neuronal network function. Lamellipodia were not apparently different; slower migration was restricted to Tyr108His.
Show evidence (1 reference)
PMID:33149277 SUPPORT In Vitro
"a significantly reduced number of circular dorsal ruffles (CDRs) was observed in all patient fibroblast lines compared with fibroblasts of three controls"
Six patient lines showed impaired growth-factor-induced actin remodeling, not a uniform increase in actin accumulation.
Patient-derived R87C neural progenitors and corrected control IPSC_DERIVED_MODEL
Human progenitors model expression and lamellipodial changes in the patient heterozygous genotype.
Cell source
Patient heterozygous R87C/WT iPSCs and CRISPR-corrected isogenic line
Publication
PMID:41851324
Pathograph links
Reduced CYFIP2 Protein Abundance measures fidelity: unknown Transcript and protein abundance are reduced.
Limitations: These measurements do not distinguish transcriptional from turnover contributions.
Show evidence (1 reference)
PMID:41851324 SUPPORT In Vitro
"Analysis of CYFIP2 and CYFIP1 expression revealed reduced mRNA and protein levels in R87C/WT NPCs"
Patient-derived heterozygous progenitors show both transcript and protein changes, so protein reduction alone does not establish accelerated degradation in this system.
Dysregulated Actin Cytoskeleton Dynamics measures fidelity: unknown Electron microscopy identifies altered morphology and lamellipodia.
Limitations: This experiment does not demonstrate seizure activity or the homozygous organoid phenotype.
Show evidence (1 reference)
PMID:41851324 SUPPORT In Vitro
"hiPSC-derived R87C/WT NPCs also exhibited altered cell morphology and lamellipodia formation as analyzed by electron microscopy"
Patient-derived heterozygous neural progenitors differed from the corrected isogenic control.
Engineered homozygous R87C neural cells and cortical organoids ORGANOID
Parallel two-dimensional cultures and three-dimensional cortical organoids test early neural development. Organoids are enlarged and lose SOX2-positive staining; monolayer neurons show no detected electrophysiological difference.
Cell source
H9 human embryonic stem cells edited to R87C/R87C, with wild-type controls
Publication
PMID:41851324
Pathograph links
Reduced Neural Progenitor Motility measures fidelity: unknown Cell tracking measures reduced speed and displacement.
Limitations: Homozygous engineered cells differ from the usual heterozygous patient genotype.
Show evidence (1 reference)
PMID:41851324 SUPPORT In Vitro
"NPC motility, including speed and displacement, was decreased in the R87C variant cells"
Cell tracking measured motility in the homozygous engineered progenitor model.
Loss of SOX2-positive Progenitor Staining in R87C Organoids measures fidelity: unknown Day30 organoids lose SOX2-positive progenitor staining.
Limitations: SOX2 staining loss does not prove cell death; increased organoid size does not model microcephaly.
Show evidence (1 reference)
PMID:41851324 SUPPORT In Vitro
"Immunostaining revealed SOX2 + neural progenitors within rosettes in WT organoids, whereas R87C/R87C organoids lacked SOX2 + cells"
Loss of progenitor-marker staining was observed in homozygous engineered organoids; depletion is an interpretation rather than directly established cell death.
Neuronal Network Hyperexcitability fails to recapitulate fidelity: low Parallel two-dimensional cortical neuron cultures did not show altered electrical activity.
Limitations: This negative result applies to homozygous engineered monolayer cultures and the measured parameters, not to patients or to unmeasured organoid activity.
Show evidence (1 reference)
PMID:41851324 SUPPORT In Vitro
"electrophysiological parameters were similar between WT and R87C/R87C cultures, even after 90 days of differentiation"
A negative model result limits claims that these cultures reproduce epilepsy.
Findings
Monolayer cortical neurons did not show altered electrophysiological parameters under the tested culture conditions.
Show evidence (1 reference)
PMID:41851324 SUPPORT In Vitro
"electrophysiological parameters were similar between WT and R87C/R87C cultures, even after 90 days of differentiation"
A negative model result limits claims that these cultures reproduce epilepsy.
CYFIP1/2-null B16-F1 reconstitution assays CELL_LINE
Most disease-associated substitutions were transferred to homologous CYFIP1 positions; Arg87Cys was additionally tested directly in CYFIP2. Assays distinguish activating missense effects from a C-terminal truncation unable to assemble WRC.
Cell source
Mouse melanoma cells lacking CYFIP1 and CYFIP2, reconstituted with engineered constructs
Publication
PMID:32486060
Pathograph links
Aberrant WAVE Regulatory Complex Activation measures fidelity: unknown Lamellipodia rescue under restricted Rac signaling measures activation.
Limitations: Most constructs are CYFIP1 proxies in non-neural cells; effects cannot be treated as direct patient-neuron measurements.
Show evidence (1 reference)
PMID:32486060 SUPPORT In Vitro
"Almost all CYFIP2-derived mutations (7 out of 8) promoted WRC activation, but to variable extent and with at least two independent mechanisms."
Cellular reconstitution demonstrated variant-dependent activation; most substitutions were tested in homologous CYFIP1, with R87C also tested directly in CYFIP2.
Impaired WRC Incorporation by a C-terminal Truncation measures fidelity: unknown The truncating proxy fails WRC incorporation.
Limitations: CYFIP1 E1150Dfs*3 models CYFIP2 Glu1174Aspfs*3; general CYFIP2 haploinsufficiency is not established.
Show evidence (1 reference)
PMID:32486060 SUPPORT In Vitro
"the E1150Dfs*3 mutant was unable to incorporate into endogenous WRC"
The homologous CYFIP1 construct modeling the CYFIP2 C-terminal truncation failed complex incorporation; this is a surrogate cellular assay.
CYFIP2 Arg87Cys ligand thermal-shift screen CELL_LINE
Docking nominated compounds for a modified cellular thermal-shift assay. Minocycline, tipifarnib, torcetrapib and pomalidomide produced candidate stabilization signals under selected conditions. The small screen used a nominal p<0.1 threshold and did not test functional rescue or seizure efficacy.
Cell source
SH-SY5Y cells expressing tagged wild-type or Arg87Cys CYFIP2
Publication
PMID:38540093
Pathograph links
Reduced CYFIP2 Protein Abundance measures fidelity: unknown The assay measures soluble protein after heating as a candidate stabilization readout.
Limitations: Thermal solubility is not a measurement of brain abundance or clinical benefit.
Show evidence (1 reference)
PMID:38540093 SUPPORT In Vitro
"in the CYFIP2 Arg87Cys group, protein abundance increased in the presence of all ligands at both temperatures"
Soluble protein increased in the screen; this does not establish correction of WRC signaling.
🐁

Animal Models

2
Cyfip2 p.Arg87Cys knock-in mouse
Heterozygous Arg87Cys knock-in mice reproduce neonatal spasmlike movements and later develop spontaneous recurrent seizures after a quiescent interval. Adult hippocampal abnormalities include synaptic remodeling, glial changes and astrocytic lipid accumulation. Heterozygous null mice do not share the severe adult phenotype.
Species
Mouse
Genotype
Cyfip2+/R87C
Publication
PMID:36251395
Pathograph links
Reduced CYFIP2 Protein Abundance measures fidelity: unknown Brain protein abundance is reduced.
Limitations: Protein abundance is distinct from direct measurement of degradation in brain.
Show evidence (1 reference)
PMID:36251395 SUPPORT Model Organism
"Beyond identifying a decrease in CYFIP2 protein levels in the Cyfip2+/R87C brains"
Reduced brain protein abundance was measured in heterozygous knock-in mice.
Neuronal Network Hyperexcitability partially recapitulates fidelity: unknown The model has adult electroclinical seizures.
Limitations: Adult video-EEG was obtained in three mice at week20; worsening at weeks14/28 was assessed behaviorally. Mouse lethality does not establish human mortality risk.
Show evidence (1 reference)
PMID:41066510 SUPPORT Model Organism
"we observed tonic-clonic seizures and myoclonic jerks that correlated with behavioral seizures, events that were never observed in WT mice"
Video-EEG in three surviving knock-in mice at postnatal week 20 established electroclinical seizures; age progression was assessed behaviorally.
Disrupted Synaptic and Dendritic Spine Remodeling measures fidelity: unknown Electron microscopy measures altered excitatory contacts.
Limitations: Causation of seizures and corresponding human synaptic pathology remain unestablished.
Show evidence (2 references)
PMID:41066510 SUPPORT Model Organism
"the number of excitatory (asymmetric) synapses decreased, while the number of inhibitory (symmetric) synapses remained normal in Cyfip2+/R87C mice at PWK 28"
Ultrastructure shows selective reduction of excitatory synapses in adult knock-in hippocampal CA1.
+ 1 more reference
Reactive Gliosis measures fidelity: unknown Age-dependent glial marker changes accompany the model phenotype.
Limitations: Sampling intervals do not establish the precise activation order or causal contributions.
Show evidence (1 reference)
PMID:41066510 SUPPORT Model Organism
"glial markers in the hippocampal CA1 region of Cyfip2+/R87C mice exhibited an age-related increase compared to WT mice, with oligodendrocyte, microglia, and astrocytes in that order"
Marker changes suggest an ordered glial response, but broad sampling intervals do not resolve exact timing or causality.
Astrocytic Lysosomal Lipid Accumulation measures fidelity: unknown Adult astrocytes accumulate lysosomal lipid droplets.
Limitations: No equivalent lesion or diagnostic lipid biomarker is established in human CYFIP2 disease.
Show evidence (1 reference)
PMID:41066510 SUPPORT Model Organism
"both the number and volume of LDs within astrocytic lysosomes were significantly increased in the hippocampus of Cyfip2+/R87C mice compared to WT mice at PWK 28, but not at PWK 14"
Lipid accumulation is a late model finding; it is not established as the initiating seizure mechanism or a human biomarker.
Xenopus laevis cyfip2 gain-of-function tadpole
The cited preprint reports transient ectopic expression of cyfip2 Arg87Cys or Tyr108Cys mRNA in Xenopus tadpoles, with epileptic brain activity and variant-dependent swimming behavior. This is an overexpression model rather than an endogenous heterozygous knock-in.
Species
Xenopus laevis
Genotype
transient ectopic expression of Arg87Cys or Tyr108Cys cyfip2 mRNA
Publication
DOI:10.1101/2022.12.07.519540
Pathograph links
Neuronal Network Hyperexcitability recapitulates fidelity: moderate Expression of either pathogenic variant produced spontaneous epileptic activity in the brain.
Limitations: Transient ectopic expression and species context limit translation to patients. The cited source is a preprint. Suppression of activity by valproate does not establish clinical efficacy.
Readouts
Spontaneous epileptic brain activity
Direction: INCREASED
Interpretation: Both variants produced spontaneous epileptic activity, and it was reduced by valproate - a pharmacological control that argues the activity is genuinely seizure-like rather than an artefact of overexpression.
Show evidence (2 references)
DOI:10.1101/2022.12.07.519540 Preprint · not peer-reviewed SUPPORT Model Organism
"Expression of either pathogenic variant resulted in spontaneous epileptic activity in the brain"
The electrophysiological measurement behind this readout.
+ 1 more reference
Show evidence (1 reference)
DOI:10.1101/2022.12.07.519540 Preprint · not peer-reviewed SUPPORT Model Organism
"transient ectopic expression of the Arg87Cys pathogenic variant of"
Establishes that the model expresses the human hotspot variant, which is what makes it informative for this disorder rather than for CYFIP2 biology generally.
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Source YAML

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name: CYFIP2-Related Developmental and Epileptic Encephalopathy
creation_date: '2026-08-20T00:20:00Z'
category: Mendelian
synonyms:
- Developmental and epileptic encephalopathy 65
- DEE65
- EIEE65
- CYFIP2-related neurodevelopmental disorder
description: >-
  CYFIP2-related developmental and epileptic encephalopathy (DEE65) lies within an autosomal dominant
  neurodevelopmental spectrum associated mainly with heterozygous de novo CYFIP2 variants. CYFIP2 regulates
  the WAVE regulatory complex (WRC) and actin remodeling. Arg87 variants are associated with severe developmental
  impairment and early epilepsy, whereas other variants can cause milder intellectual or language impairment
  without seizures. Missense, splice-altering, in-frame deletion and frameshift variants have been reported;
  their functional consequences differ. Hypotonia, feeding and visual difficulties, microcephaly, sleep
  disturbance and movement abnormalities accompany the developmental phenotype. Seizures may be drug-resistant,
  but seizure control and temporary developmental or EEG improvement occur. Brain imaging ranges from
  normal findings to atrophy and cortical malformation.
disease_term:
  preferred_term: developmental and epileptic encephalopathy, 65
  term:
    id: MONDO:0033374
    label: developmental and epileptic encephalopathy, 65
parents:
- Epilepsy
- Neurological Disease
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant disease associated predominantly with heterozygous de novo variants. Parental testing
    establishes de novo status when both parents are available; absence in one parent alone is insufficient.
    Counseling should account for possible germline mosaicism.
  evidence:
  - reference: PMID:30664714
    reference_title: >-
      Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein
      2, cause intellectual disability and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified 12 independent patients carrying a total of eight distinct de novo variants in CYFIP2
      with a shared phenotype of intellectual disability, seizures, and muscular hypotonia
    explanation: >-
      Establishes the de novo heterozygous architecture across twelve independent patients, together with
      the core phenotype triad.
pathophysiology:
- name: Heterozygous CYFIP2 Variation
  biological_scale: MOLECULAR
  description: >-
    Disease-associated variants include recurrent Arg87 and Asp724 substitutions, other missense changes,
    and selected splice-altering or deletion variants. Molecular effects must be assigned to the tested
    variant rather than extrapolated to every CYFIP2 allele.
  evidence:
  - reference: PMID:29534297
    reference_title: De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified three de novo CYFIP2 variants at the Arg87 residue in 4 unrelated individuals with
      early-onset epileptic encephalopathy.
    explanation: The original clinical series establishes the Arg87-associated disease relationship.
  - reference: PMID:33149277
    reference_title: >-
      New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
      disorder and impairment of the WRC-mediated actin dynamics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recently, de novo missense variants affecting a small number of amino acids and one late-truncating
      variant in CYFIP2 have been associated with intellectual disability (ID), seizures, and muscular
      hypotonia
    explanation: The spectrum includes a disease-associated late truncation.
    quote_role: BACKGROUND
  downstream:
  - target: Weakened CYFIP2-WAVE1 Interface Binding
    causal_link_type: DIRECT
    description: Demonstrated for tested Arg87 substitutions.
  - target: Enhanced CYFIP2 Ubiquitination
    causal_link_type: DIRECT
    description: Reported for p.Arg87Cys.
  - target: Impaired WRC Incorporation by a C-terminal Truncation
    causal_link_type: DIRECT
    description: Supported by a homologous CYFIP1 cellular proxy for the late CYFIP2 truncation.
  - target: Dysregulated Actin Cytoskeleton Dynamics
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Patient fibroblasts and neural progenitors show variant-dependent abnormalities; intervening molecular
      events differ.
- name: Weakened CYFIP2-WAVE1 Interface Binding
  biological_scale: MOLECULAR
  description: >-
    Arg87 substitutions weaken interaction with the WAVE VCA domain. This concerns regulatory sequestration
    of WAVE, not direct binding of CYFIP2 to actin. Activation can occur while the remaining WRC stays
    assembled.
  evidence:
  - reference: PMID:29534297
    reference_title: De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All mutant CYFIP2 showed comparatively weaker interactions to the VCA domain than wild-type CYFIP2.
    explanation: The tested Arg87 substitutions weakened VCA binding in transfection experiments.
  - reference: PMID:32486060
    reference_title: Molecular Dissection of Neurodevelopmental Disorder-Causing Mutations in CYFIP2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we found the activating mutation R87C to normally interact with WRC components, including WAVE
    explanation: >-
      R87C retained WRC association in the homologous CYFIP1 assay; weakened VCA binding does not require
      whole-complex dissociation.
  cellular_components:
  - preferred_term: SCAR complex
    term:
      id: GO:0031209
      label: SCAR complex
  downstream:
  - target: Aberrant WAVE Regulatory Complex Activation
    causal_link_type: DIRECT
    description: Reduced VCA sequestration relieves WAVE autoinhibition.
    hypothesis_groups:
    - wrc_activation_model
  genes:
  - preferred_term: CYFIP2
    term:
      id: hgnc:13760
      label: CYFIP2
  molecular_functions:
  - preferred_term: WAVE VCA domain binding
    term:
      id: GO:0019904
      label: protein domain specific binding
    modifier: DECREASED
- name: Enhanced CYFIP2 Ubiquitination
  biological_scale: MOLECULAR
  description: >-
    The p.Arg87Cys variant has increased ubiquitination in the reported mechanistic experiments. This
    event is distinct from the reduced steady-state protein abundance measured in mouse brain.
  evidence:
  - reference: PMID:36251395
    reference_title: CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we demonstrated that the p.Arg87Cys variant enhances ubiquitination and proteasomal degradation
      of CYFIP2.
    explanation: >-
      Ubiquitination and proteasome-inhibition experiments were performed in cultured cells; reduced mouse
      brain abundance is recorded separately.
  downstream:
  - target: Enhanced CYFIP2 Proteasomal Degradation
    causal_link_type: DIRECT
    description: The study links enhanced ubiquitination with proteasomal turnover.
- name: Enhanced CYFIP2 Proteasomal Degradation
  biological_scale: MOLECULAR
  description: >-
    Accelerated proteasomal turnover is reported for p.Arg87Cys. Reduced abundance and altered activity
    of the residual mutant-containing complex need not be mutually exclusive.
  evidence:
  - reference: PMID:36251395
    reference_title: CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we demonstrated that the p.Arg87Cys variant enhances ubiquitination and proteasomal degradation
      of CYFIP2.
    explanation: >-
      Ubiquitination and proteasome-inhibition experiments were performed in cultured cells; reduced mouse
      brain abundance is recorded separately.
  biological_processes:
  - preferred_term: proteasomal protein catabolic process
    term:
      id: GO:0010498
      label: proteasomal protein catabolic process
    modifier: INCREASED
  downstream:
  - target: Reduced CYFIP2 Protein Abundance
    causal_link_type: DIRECT
    description: >-
      Enhanced turnover provides a mechanism for reduced protein abundance; patient-derived progenitors
      also show transcript changes.
- name: Reduced CYFIP2 Protein Abundance
  biological_scale: MOLECULAR
  description: >-
    CYFIP2 protein is reduced in heterozygous knock-in mouse brain and human R87C neural models. Patient-derived
    heterozygous progenitors also have reduced CYFIP2 transcript abundance. These findings do not establish
    simple haploinsufficiency as the complete disease mechanism.
  evidence:
  - reference: PMID:36251395
    reference_title: CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Beyond identifying a decrease in CYFIP2 protein levels in the Cyfip2+/R87C brains
    explanation: Reduced brain protein abundance was measured in heterozygous knock-in mice.
  - reference: PMID:41851324
    reference_title: Impact of the CYFIP2 R87C variant in a human neuronal model in vitro.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Analysis of CYFIP2 and CYFIP1 expression revealed reduced mRNA and protein levels in R87C/WT NPCs
    explanation: >-
      Patient-derived heterozygous progenitors show both transcript and protein changes, so protein reduction
      alone does not establish accelerated degradation in this system.
  downstream:
  - target: Dysregulated Actin Cytoskeleton Dynamics
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed contribution of reduced abundance to actin dysregulation in R87C neural models; residual
      mutant activity and transcript changes may also contribute.
    hypothesis_groups:
    - abundance_actin_model
    evidence:
    - reference: PMID:41851324
      reference_title: Impact of the CYFIP2 R87C variant in a human neuronal model in vitro.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Thus, the decreased CYFIP2 levels with the R87C variant may cause an imbalance in actin polymerization
        between lamellipodia and filopodia.
      explanation: >-
        The human neural-model paper proposes, rather than proves, an abundance-to-actin mechanism.
- name: Impaired WRC Incorporation by a C-terminal Truncation
  biological_scale: MOLECULAR
  description: >-
    A CYFIP1 E1150Dfs*3 construct modeling CYFIP2 Glu1174Aspfs*3 failed WRC incorporation and lamellipodia
    rescue in CYFIP1/2-null B16-F1 cells. This loss-of-function result contrasts with activating missense
    substitutions, but does not establish pathogenicity of every early truncating CYFIP2 allele.
  evidence:
  - reference: PMID:32486060
    reference_title: Molecular Dissection of Neurodevelopmental Disorder-Causing Mutations in CYFIP2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the E1150Dfs*3 mutant was unable to incorporate into endogenous WRC
    explanation: >-
      The homologous CYFIP1 construct modeling the CYFIP2 C-terminal truncation failed complex incorporation;
      this is a surrogate cellular assay.
  downstream:
  - target: Dysregulated Actin Cytoskeleton Dynamics
    causal_link_type: DIRECT
    description: Failure to assemble functional WRC prevents lamellipodia rescue in the surrogate assay.
- name: Aberrant WAVE Regulatory Complex Activation
  biological_scale: MOLECULAR
  description: >-
    Many tested missense substitutions increase WRC activation. Most act at the WAVE-sequestering interface,
    whereas Tyr108His requires a functional Rac-binding A site. The experiments do not support a uniform,
    fully RAC1-independent mechanism across variants.
  evidence:
  - reference: PMID:32486060
    reference_title: Molecular Dissection of Neurodevelopmental Disorder-Causing Mutations in CYFIP2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Almost all CYFIP2-derived mutations (7 out of 8) promoted WRC activation, but to variable extent
      and with at least two independent mechanisms.
    explanation: >-
      Cellular reconstitution demonstrated variant-dependent activation; most substitutions were tested
      in homologous CYFIP1, with R87C also tested directly in CYFIP2.
  cellular_components:
  - preferred_term: SCAR complex
    term:
      id: GO:0031209
      label: SCAR complex
  biological_processes:
  - preferred_term: Arp2/3 complex-mediated actin nucleation
    term:
      id: GO:0034314
      label: Arp2/3 complex-mediated actin nucleation
    modifier: INCREASED
  downstream:
  - target: Dysregulated Actin Cytoskeleton Dynamics
    causal_link_type: DIRECT
    description: WRC dysregulation alters actin-dependent protrusions in cellular assays.
    hypothesis_groups:
    - wrc_activation_model
- name: Dysregulated Actin Cytoskeleton Dynamics
  biological_scale: CELLULAR
  description: >-
    Readouts vary by cell type and allele. Arg87-transfected cells show ectopic actin accumulation; patient
    fibroblasts have reduced circular dorsal ruffles without apparent lamellipodia differences. Patient-derived
    R87C neural progenitors have altered lamellipodia. These are distinct readouts of dysregulation, not
    equivalent measurements of globally increased actin.
  evidence:
  - reference: PMID:29534297
    reference_title: De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunofluorescence revealed that ectopic speckled accumulation of actin and CYFIP2 was significantly
      increased in cells transfected with mutant CYFIP2
    explanation: The original actin readout in a heterologous transfection system.
  - reference: PMID:33149277
    reference_title: >-
      New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
      disorder and impairment of the WRC-mediated actin dynamics.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      a significantly reduced number of circular dorsal ruffles (CDRs) was observed in all patient fibroblast
      lines compared with fibroblasts of three controls
    explanation: >-
      Six patient lines showed impaired growth-factor-induced actin remodeling, not a uniform increase
      in actin accumulation.
  - reference: PMID:41851324
    reference_title: Impact of the CYFIP2 R87C variant in a human neuronal model in vitro.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      hiPSC-derived R87C/WT NPCs also exhibited altered cell morphology and lamellipodia formation as
      analyzed by electron microscopy
    explanation: >-
      Patient-derived heterozygous neural progenitors differed from the corrected isogenic control.
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
    modifier: DYSREGULATED
  downstream:
  - target: Disrupted Synaptic and Dendritic Spine Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      An inferred link from WRC-dependent actin remodeling to neuronal architecture. Disease-specific
      intermediates and direction relative to seizures remain unresolved.
    hypothesis_groups:
    - neural_remodeling_model
    evidence:
    - reference: PMID:32486060
      reference_title: Molecular Dissection of Neurodevelopmental Disorder-Causing Mutations in CYFIP2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        All this suggests that a precisely tuned, narrow window of WRC activity in the human brain is
        required for its proper development and function, with both hyper-activation and downregulation
        leading to similarly drastic consequences.
      explanation: >-
        The authors infer a neural-development mechanism from WRC perturbation assays; this is not a direct
        neuronal causal test.
- name: Reduced Neural Progenitor Motility
  biological_scale: CELLULAR
  description: >-
    Engineered homozygous R87C/R87C human neural progenitors show reduced speed and displacement. This
    motility result should not be generalized to every patient fibroblast line or treated as demonstrated
    cortical migration failure in patients. This remains an unconnected experimental observation because
    a causal link to patient seizures or brain growth has not been established.
  evidence:
  - reference: PMID:41851324
    reference_title: Impact of the CYFIP2 R87C variant in a human neuronal model in vitro.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: NPC motility, including speed and displacement, was decreased in the R87C variant cells
    explanation: Cell tracking measured motility in the homozygous engineered progenitor model.
- name: Loss of SOX2-positive Progenitor Staining in R87C Organoids
  biological_scale: CELLULAR
  description: >-
    Homozygous R87C/R87C cortical organoids lack SOX2-positive progenitor staining at day 30 and are enlarged
    at days 30 and 60. Premature progenitor depletion is proposed; these findings neither demonstrate
    cell death nor recapitulate patient microcephaly. This remains an unconnected experimental observation
    because a causal link to patient seizures or brain growth has not been established.
  evidence:
  - reference: PMID:41851324
    reference_title: Impact of the CYFIP2 R87C variant in a human neuronal model in vitro.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunostaining revealed SOX2 + neural progenitors within rosettes in WT organoids, whereas R87C/R87C
      organoids lacked SOX2 + cells
    explanation: >-
      Loss of progenitor-marker staining was observed in homozygous engineered organoids; depletion is
      an interpretation rather than directly established cell death.
- name: Disrupted Synaptic and Dendritic Spine Remodeling
  biological_scale: CELLULAR
  description: >-
    Adult heterozygous R87C knock-in hippocampal CA1 has fewer excitatory synapses, reduced dendritic
    spines and excitatory contacts shifted onto dendritic shafts. Synaptic remodeling accompanies seizures;
    direction of causation remains unresolved.
  evidence:
  - reference: PMID:41066510
    reference_title: >-
      Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
      remodeling, gliosis and alterations in lipid metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the number of excitatory (asymmetric) synapses decreased, while the number of inhibitory (symmetric)
      synapses remained normal in Cyfip2+/R87C mice at PWK 28
    explanation: >-
      Ultrastructure shows selective reduction of excitatory synapses in adult knock-in hippocampal CA1.
  - reference: PMID:41066510
    reference_title: >-
      Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
      remodeling, gliosis and alterations in lipid metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      excitatory synapses were predominantly located on dendritic shafts, with multiple presynaptic terminals
      clustering nearby
    explanation: >-
      Adult knock-in neurons have fewer spines and altered excitatory-contact geometry; its effect on
      excitability remains proposed.
  cellular_components:
  - preferred_term: dendritic spine
    term:
      id: GO:0043197
      label: dendritic spine
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  downstream:
  - target: Neuronal Network Hyperexcitability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The R87C mouse study proposes that excitatory shaft contacts reduce spine compartmentalization and
      facilitate excitation; this remains an untested causal explanation.
    hypothesis_groups:
    - neural_remodeling_model
    evidence:
    - reference: PMID:41066510
      reference_title: >-
        Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
        remodeling, gliosis and alterations in lipid metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        When excitatory synapses form directly on the dendritic shaft, bypassing this barrier, it likely
        becomes easier to activate neurons with each synaptic input, potentially contributing to the observed
        seizures.
      explanation: >-
        The authors propose altered synaptic compartmentalization as a route to excitability; electrophysiological
        causal testing remains needed.
- name: Reactive Gliosis
  biological_scale: TISSUE
  description: >-
    Knock-in mouse brain shows age-dependent oligodendroglial, microglial and astrocytic marker changes,
    with altered microglial and astrocytic morphology. Their contributions to seizure progression and
    exact temporal ordering require further testing.
  evidence:
  - reference: PMID:41066510
    reference_title: >-
      Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
      remodeling, gliosis and alterations in lipid metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      glial markers in the hippocampal CA1 region of Cyfip2+/R87C mice exhibited an age-related increase
      compared to WT mice, with oligodendrocyte, microglia, and astrocytes in that order
    explanation: >-
      Marker changes suggest an ordered glial response, but broad sampling intervals do not resolve exact
      timing or causality.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
- name: Astrocytic Lysosomal Lipid Accumulation
  biological_scale: CELLULAR
  description: >-
    Adult R87C knock-in hippocampal astrocytes accumulate lipid droplets in lysosomes. Associated crystals
    have not been chemically identified. Lipid accumulation is a late accompaniment of disease in this
    model, with no demonstrated corresponding human lesion.
  evidence:
  - reference: PMID:41066510
    reference_title: >-
      Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
      remodeling, gliosis and alterations in lipid metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      both the number and volume of LDs within astrocytic lysosomes were significantly increased in the
      hippocampus of Cyfip2+/R87C mice compared to WT mice at PWK 28, but not at PWK 14
    explanation: >-
      Lipid accumulation is a late model finding; it is not established as the initiating seizure mechanism
      or a human biomarker.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  downstream:
  - target: Neuronal Network Hyperexcitability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed metabolic feedback on excitability in the mouse model, requiring functional validation
      and human confirmation.
    hypothesis_groups:
    - neural_remodeling_model
    evidence:
    - reference: PMID:41066510
      reference_title: >-
        Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
        remodeling, gliosis and alterations in lipid metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Bidirectionally, mitochondrial metabolic dysfunction and lipid accumulation in astrocytes may
        exacerbate seizures through various mechanisms, including disruption of the GABA-glutamate-glutamine
        cycle
      explanation: >-
        The paper proposes feedback from astrocytic metabolic changes to seizures; the mechanism remains
        hypothetical in CYFIP2 disease.
- name: Neuronal Network Hyperexcitability
  biological_scale: CELLULAR
  description: >-
    Heterozygous R87C knock-in mice develop adult electroclinical seizures after neonatal spasms and a
    quiescent interval. The steps connecting CYFIP2-dependent cellular abnormalities to seizures remain
    incompletely established.
  evidence:
  - reference: PMID:41066510
    reference_title: >-
      Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
      remodeling, gliosis and alterations in lipid metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we observed tonic-clonic seizures and myoclonic jerks that correlated with behavioral seizures,
      events that were never observed in WT mice
    explanation: >-
      Video-EEG in three surviving knock-in mice at postnatal week 20 established electroclinical seizures;
      age progression was assessed behaviorally.
  conforms_to: epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony
  downstream:
  - target: Seizures
    causal_link_type: DIRECT
    description: >-
      Seizures are the clinical manifestation of abnormal network activity; drug resistance is a separate
      treatment-response property.
  - target: Reactive Gliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Neonatal seizure activity is proposed to initiate an early glial response in R87C mice. Temporal
      association alone does not establish causation.
    hypothesis_groups:
    - neural_remodeling_model
    evidence:
    - reference: PMID:41066510
      reference_title: >-
        Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
        remodeling, gliosis and alterations in lipid metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        one plausible explanation for the increased Olig2-positive cells observed at PWK 7 is that the
        spasm-like seizures experienced during the neonatal stage may have triggered this early glial
        response.
      explanation: >-
        An early glial response to seizure activity is a proposed model mechanism, not a demonstrated
        direction of causation.
  - target: Astrocytic Lysosomal Lipid Accumulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The authors propose seizure-associated mitochondrial remodeling and disturbed astrocytic lipid metabolism
      as intervening steps; neither is a proven complete causal route.
    hypothesis_groups:
    - neural_remodeling_model
    evidence:
    - reference: PMID:41066510
      reference_title: >-
        Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
        remodeling, gliosis and alterations in lipid metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This remodeling likely disrupted lipid metabolism in astrocytes, including the β-oxidation of
        fatty acids, ultimately leading to lipid accumulation
      explanation: >-
        The proposed intermediate is seizure-associated mitochondrial remodeling; this causal route was
        not directly tested.
  - target: Epileptic Spasms
    causal_link_type: DIRECT
    description: >-
      Epileptic spasms are one electroclinical manifestation of abnormal network activity in affected
      individuals; they do not occur in every case.
    evidence:
    - reference: PMID:42563853
      reference_title: >-
        Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report
        and Literature Review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: At age 6 months, he developed epileptic spasms. EEG was consistent with hypsarrhythmia
      explanation: The index child had electroclinical spasms.
phenotypes:
- category: Neurological
  name: Seizures
  description: >-
    Seizures vary in onset and type and are not universal across the broader CYFIP2 neurodevelopmental
    spectrum. The 2025 published-case review reported epilepsy in 32/42 individuals and first-year onset
    in 25/42; its case set includes variants whose significance was uncertain in their original reports.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:42563853
    reference_title: >-
      Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and
      Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      32/42 (76%) developed epilepsy, and 25/42 (60%) experienced seizure onset in the first year of life.
    explanation: Published-case review denominators; these are not population penetrance estimates.
- category: Neurological
  name: Epileptic Spasms
  description: >-
    Epileptic spasms are reported particularly with Arg87 variants and may follow other seizure types.
    The 2025 review reported spasms in 16/32 individuals with epilepsy (16/42 overall).
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Epileptic spasm
    term:
      id: HP:0011097
      label: Epileptic spasm
  evidence:
  - reference: PMID:42563853
    reference_title: >-
      Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and
      Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Of those with seizures, 16/32 (50%) had epileptic spasms
    explanation: >-
      The denominator is individuals with seizures; 16/42 overall also falls within the FREQUENT band.
- category: Neurological
  name: Drug-Resistant Epilepsy
  description: >-
    Drug-resistant epilepsy occurs, including the Trp86_Ser88del case, but other patients achieve seizure
    control. Refractoriness is neither universal nor necessarily present from the first seizure.
  phenotype_term:
    preferred_term: Refractory drug response
    term:
      id: HP:0020174
      label: Refractory drug response
  evidence:
  - reference: PMID:36968925
    reference_title: >-
      Clinical Role of Codon 87 of the CYFIP2 Gene in Early Infantile Epileptic Encephalopathy: A Clinical
      Case Description.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The seizures were of different types, frequent and refractory to treatment, including different
      anticonvulsant drugs
    explanation: >-
      Documents refractoriness across multiple anticonvulsant classes in a genotype-confirmed patient.
  - reference: PMID:36968925
    reference_title: >-
      Clinical Role of Codon 87 of the CYFIP2 Gene in Early Infantile Epileptic Encephalopathy: A Clinical
      Case Description.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He maintained refractory epilepsy despite being medicated with vigabatrin, phenobarbital, valproic
      acid, and a ketogenic diet
    explanation: >-
      Names the specific agents that failed, which is stronger than a general statement of drug resistance.
  notes: >-
    Drug resistance is a treatment-response property. No specific causal mechanism distinguishing resistant
    from responsive CYFIP2-associated seizures is established, so it is not drawn as a necessary downstream
    consequence of seizures.
- category: Neurological
  name: Global Developmental Delay
  description: >-
    Global delay was reported in 14/16 new likely disease-associated missense cases in the 2021 cohort;
    two had language delay with normal motor development. Global delay should not be equated with formally
    assessed intellectual disability.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:33149277
    reference_title: >-
      New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
      disorder and impairment of the WRC-mediated actin dynamics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 14/16 with global DD and 2/16 with normal motor but delayed language development
    explanation: The primary cohort distinguishes global from language-only delay.
  frequency: VERY_FREQUENT
- category: Neurological
  name: Intellectual Disability
  description: >-
    Intellectual disability ranges from mild to profound. Arg87 substitutions tend to be severe; other
    variants have broader severity. Children too young for formal evaluation are not counted as having
    assessed intellectual disability.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:33149277
    reference_title: >-
      New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
      disorder and impairment of the WRC-mediated actin dynamics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intellectual disability was classified as severe or profound in 9 of 14 evaluated individuals, as
      moderate in 4/14, and as mild in 1/14 cases
    explanation: >-
      Formal assessment demonstrates variable severity, not uniformly severe or profound impairment.
- category: Neurological
  name: Muscular Hypotonia
  description: >-
    Generalized or truncal hypotonia was reported in 10/16 new missense cases, with additional limb hypertonia
    in two.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:33149277
    reference_title: >-
      New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
      disorder and impairment of the WRC-mediated actin dynamics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ten of 16 individuals showed generalized or truncal muscular hypotonia, combined with limb hypertonicity
      in two cases.
    explanation: Primary cohort supports hypotonia and the frequency denominator.
  frequency: FREQUENT
- category: Neurological
  name: Microcephaly
  description: >-
    Absolute microcephaly was diagnosed in 5/16 new missense cases. The larger pooled count also included
    relative microcephaly and is not used as an absolute-microcephaly frequency.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:33149277
    reference_title: >-
      New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
      disorder and impairment of the WRC-mediated actin dynamics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly with a HC below 2 standard deviations was diagnosed in 5/16 individuals of the current
      cohort.
    explanation: Primary human data support microcephaly.
  frequency: FREQUENT
- category: Gastrointestinal
  name: Feeding Difficulties
  description: >-
    Feeding difficulty can require enteral support, including nasogastric or gastrostomy feeding in severely
    affected individuals.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:30664714
    reference_title: >-
      Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein
      2, cause intellectual disability and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Dysphagia with dependency on gastric tube feeding was present in five of 12 patients.
    explanation: The primary cohort documents severe feeding impairment.
  - reference: PMID:36968925
    reference_title: >-
      Clinical Role of Codon 87 of the CYFIP2 Gene in Early Infantile Epileptic Encephalopathy: A Clinical
      Case Description.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: was fed exclusively by nasogastric tube
    explanation: The index infant required exclusive tube feeding.
  - reference: PMID:33149277
    reference_title: >-
      New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
      disorder and impairment of the WRC-mediated actin dynamics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Feeding difficulties | 9/11 | 0/2 | 3/5 | 3/12 | 15/30 (50%) |'
    explanation: Table 2 reports feeding difficulties in 15/30 individuals with available information.
  frequency: FREQUENT
- category: Gastrointestinal
  name: Dysphagia
  description: >-
    Swallowing difficulty affected seven of the 16 new missense cases in the 2021 cohort; three required
    gastric tube feeding.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:33149277
    reference_title: >-
      New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
      disorder and impairment of the WRC-mediated actin dynamics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysphagia was reported in seven individuals; three of them were dependent on gastric tube feeding.
    explanation: Counts refer to the 16 new likely disease-associated missense cases.
  frequency: FREQUENT
- category: Ophthalmological
  name: Visual Impairment
  description: >-
    Variable visual problems were reported in six of the 16 new missense cases. Findings include poor
    visual fixation and pursuit in severe disease; the cohort does not assign a uniform ophthalmic diagnosis.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:33149277
    reference_title: >-
      New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
      disorder and impairment of the WRC-mediated actin dynamics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Variable visual problems were present in six individuals
    explanation: The primary cohort reports visual problems without a uniform mechanism or subtype.
  frequency: FREQUENT
- category: Neurological
  name: Sleep Disturbance
  description: >-
    Sleep difficulty was reported in seven of the 16 new missense cases and in 15/42 individuals in the
    later literature review.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:33149277
    reference_title: >-
      New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
      disorder and impairment of the WRC-mediated actin dynamics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: sleep difficulties were reported in seven individuals
    explanation: The primary cohort denominator is 16 new missense cases.
  - reference: PMID:42563853
    reference_title: >-
      Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and
      Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 15/42 (36%) had sleep disturbances
    explanation: The later review also identifies sleep disturbance.
  frequency: FREQUENT
- category: Neurological
  name: Atypical Behavior
  description: >-
    Behavioral problems were reported in 15/27 individuals with available information in the pooled 2021
    cohort of likely disease-associated variants. The broad category includes variable manifestations
    and does not establish autism in every affected individual.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:33149277
    reference_title: >-
      New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
      disorder and impairment of the WRC-mediated actin dynamics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Behavioral problems | 3/8 | 1/2 | 2/5 | 9/12 | 15/27 (56%) |'
    explanation: >-
      Table 2 pools likely disease-associated variants; the final column gives the combined count. The
      three putative loss-of-function VUS were excluded.
  frequency: FREQUENT
- category: Neurological
  name: Choreoathetosis
  description: >-
    Choreoathetoid movements may occur separately from seizures. The 2025 index case had episodic movements
    without an EEG correlate; a separate frameshift case had dystonia, choreoathetosis and dyskinetic
    crises.
  phenotype_term:
    preferred_term: Choreoathetosis
    term:
      id: HP:0001266
      label: Choreoathetosis
  evidence:
  - reference: PMID:42563853
    reference_title: >-
      Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and
      Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A hyperkinetic choreoathetoid movement disorder emerged at age 7 months
    explanation: The index case had a non-epileptic hyperkinetic movement disorder.
  - reference: PMID:40425513
    reference_title: >-
      Novel CYFIP2 Frameshift Variant Linked to Dyskinetic Crises: Functional Studies Show Impaired Cell
      Motility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: movement disorders, including dystonia, choreoathetosis, and dyskinetic crises.
    explanation: The Gln95ProfsTer15 case expands the movement phenotype.
- category: Neuroimaging
  name: Bilateral Perisylvian Polymicrogyria
  description: >-
    Reported in one child with a likely pathogenic Val551Leu variant. This is part of the reported imaging
    spectrum, not an obligate feature; paternal segregation was unavailable.
  phenotype_term:
    preferred_term: Bilateral perisylvian polymicrogyria
    term:
      id: HP:0032407
      label: Bilateral perisylvian polymicrogyria
  evidence:
  - reference: PMID:37975178
    reference_title: >-
      A novel variant in CYFIP2 in a girl with severe disabilities and bilateral perisylvian polymicrogyria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging (MRI) showed (Figure 1) extensive polymicrogyria with thickening
      involving bilateral perisylvian cortex of frontal and temporal lobes extending to parietal lobes.
    explanation: MRI documents the cortical malformation in the reported child.
- category: Hematological
  name: Neutropenia
  description: >-
    The 2025 review reported neutropenia in 5/42 individuals, but its cause and relationship to CYFIP2
    remain unresolved. This is an observed association rather than an established downstream mechanism.
  phenotype_term:
    preferred_term: Decreased total neutrophil count
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:42563853
    reference_title: >-
      Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and
      Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 5/42 (12%) had neutropenia of unclear etiology and significance.
    explanation: The review reports a hematologic association with unresolved causation.
  frequency: OCCASIONAL
- name: Strabismus
  category: Ophthalmological
  description: >-
    Visual abnormalities can include strabismus. The combined count of visual impairment and/or strabismus
    does not establish a separate strabismus frequency.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:30664714
    reference_title: >-
      Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein
      2, cause intellectual disability and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Nine of 12 patients had visual impairment and/or strabismus.
    explanation: The cohort reports this combined ocular category.
- name: Limb Spasticity
  category: Neurological
  description: >-
    Limb spasticity can accompany generalized or truncal hypotonia, as in four individuals in the twelve-patient
    series.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  frequency: FREQUENT
  evidence:
  - reference: PMID:30664714
    reference_title: >-
      Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein
      2, cause intellectual disability and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients showed generalized or truncal hypotonia, in four cases combined with limb spasticity.
    explanation: Four of twelve patients had coexisting limb spasticity.
- name: Developmental Regression
  category: Neurological
  description: >-
    Developmental regression can follow seizure or spasm onset, but is not established as a universal
    course.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:42563853
    reference_title: >-
      Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and
      Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Following the onset of epileptic spasms, he experienced significant developmental regression.
    explanation: >-
      Regression occurred after a period of developmental improvement in the Arg87Cys index case.
- name: Cerebral Atrophy
  category: Neuroimaging
  description: >-
    Some patients have cerebral or cerebellar volume loss, while others have normal MRI. The twelve-patient
    series reported cerebellar, white-matter or diffuse atrophy in four individuals; that combined imaging
    count is not a frequency estimate for cerebral atrophy alone.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:30664714
    reference_title: >-
      Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein
      2, cause intellectual disability and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: including cerebellar, white matter or diffuse atrophy in four patients
    explanation: The primary cohort reports variable brain volume loss.
- name: Facial Dysmorphism
  category: Craniofacial
  description: >-
    Affected individuals may share facial features such as a high narrow forehead, apparent hypertelorism,
    depressed nasal bridge, bulbous nasal tip, full cheeks and everted lip vermilion. The primary cohort
    did not identify a consistently recognizable facial gestalt.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:33149277
    reference_title: >-
      New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
      disorder and impairment of the WRC-mediated actin dynamics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Morphological features revealed a shared but not clearly recognizable facial gestalt including high,
      narrow forehead; apparent hypertelorism; depressed nasal bridge; bulbous nasal tip; full cheeks;
      everted lip vermilion
    explanation: Primary clinical examination supports variable facial dysmorphism.
prevalence:
- population: Published cases reviewed through March 2025
  measure_type: CASES_IN_LITERATURE
  notes: >-
    The Squire review combined its index case with 41 literature cases. This is a historical literature
    count, not a current worldwide total or population prevalence; the review includes several variants
    previously classified as uncertain.
  evidence:
  - reference: PMID:42563853
    reference_title: >-
      Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and
      Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified 41 additional patients with pathogenic or likely pathogenic CYFIP2 variants.
    explanation: >-
      The authors describe their literature sample; variant classifications should be reconciled with
      the original reports.
genetic:
- name: CYFIP2
  gene_term:
    preferred_term: CYFIP2
    term:
      id: hgnc:13760
      label: CYFIP2
  relationship_type: CAUSATIVE
  association: >-
    Heterozygous CYFIP2 variants cause a neurodevelopmental spectrum, often through de novo missense changes.
    Arg87 substitutions tend toward severe DEE, while Asp724 and other substitutions are more variable.
    Specific late splice-altering, in-frame deletion and frameshift alleles are also reported.
  evidence:
  - reference: PMID:33149277
    reference_title: >-
      New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
      disorder and impairment of the WRC-mediated actin dynamics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but
      a more variable phenotype in p.Asp724 and other substitutions
    explanation: >-
      States the hotspot-dependent severity difference that makes the genotype prognostically informative:
      Arg87 consistently severe, Asp724 variable.
  - reference: PMID:40425513
    reference_title: >-
      Novel CYFIP2 Frameshift Variant Linked to Dyskinetic Crises: Functional Studies Show Impaired Cell
      Motility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a novel CYFIP2 frameshift variant (c.281_282insA/p.(Gln95ProfsTer15)) causing dyskinetic
      crises
    explanation: >-
      A specific frameshift case has severe DEE and movement abnormalities; the abstract does not establish
      a universal haploinsufficiency mechanism.
  notes: >-
    Early truncating variants in the 2021 cohort remained of uncertain significance and had milder phenotypes
    with confounding family histories. They should not be conflated with the late splice variant escaping
    nonsense-mediated decay or the later Gln95ProfsTer15 case. CYFIP1 is a separate paralog; its 15q11.2
    deletion phenotype is outside this entry.
  variants:
  - name: CYFIP2 p.Arg87 substitutions
    gene:
      preferred_term: CYFIP2
      term:
        id: hgnc:13760
        label: CYFIP2
    description: >-
      Recurrent de novo missense hotspot, including Arg87Cys, Arg87Leu and Arg87Pro in the founding cohort.
      Arg87Cys has the most extensively studied cellular and animal models.
    evidence:
    - reference: PMID:29534297
      reference_title: De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified three de novo CYFIP2 variants at the Arg87 residue in 4 unrelated individuals with
        early-onset epileptic encephalopathy.
      explanation: The original clinical series establishes the Arg87-associated disease relationship.
  - name: CYFIP2 p.Asp724 substitutions
    gene:
      preferred_term: CYFIP2
      term:
        id: hgnc:13760
        label: CYFIP2
    description: A second recurrent site with variable severity, including individuals without epilepsy.
    evidence:
    - reference: PMID:33149277
      reference_title: >-
        New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
        disorder and impairment of the WRC-mediated actin dynamics.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the total of five Asp724 individuals (including patient 11 in Zweier et al.5) present with a more
        variable phenotype ranging from profound ID with intractable epilepsy to moderate ID without epilepsy.
      explanation: Clinical severity varies at the Asp724 hotspot.
  - name: CYFIP2 p.Trp86_Ser88del
    gene:
      preferred_term: CYFIP2
      term:
        id: hgnc:13760
        label: CYFIP2
    description: >-
      De novo in-frame deletion removing codon87, reclassified as likely pathogenic in the reported infant.
      Phenotypic similarity does not demonstrate the same molecular consequence as an Arg87 substitution.
    evidence:
    - reference: PMID:36968925
      reference_title: >-
        Clinical Role of Codon 87 of the CYFIP2 Gene in Early Infantile Epileptic Encephalopathy: A Clinical
        Case Description.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Analysis of a whole exome sequencing-based multigene panel for epilepsy disclosed a heterozygous
        in-frame deletion of three amino acids in CYFIP2: NM_001291722.1 c.258_266del; p.(Trp86_Ser88del)
      explanation: The molecular result identifies the in-frame deletion.
    - reference: PMID:36968925
      reference_title: >-
        Clinical Role of Codon 87 of the CYFIP2 Gene in Early Infantile Epileptic Encephalopathy: A Clinical
        Case Description.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: activation of the PM6 criteria allowed its reclassification as likely pathogenic.
      explanation: The authors reclassified the variant after parental segregation testing.
  - name: CYFIP2 c.3669+1G>T / p.Glu1174Aspfs*3
    gene:
      preferred_term: CYFIP2
      term:
        id: hgnc:13760
        label: CYFIP2
    description: >-
      Late splice-altering variant with exon skipping and predicted C-terminal truncation escaping nonsense-mediated
      decay; associated with profound ID and epilepsy. Functional work used a homologous CYFIP1 truncation.
    evidence:
    - reference: PMID:30664714
      reference_title: >-
        Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein
        2, cause intellectual disability and seizures.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        RT-PCR performed using RNA from peripheral blood leukocytes of P2 confirmed skipping of exon 31
      explanation: RNA analysis directly demonstrated the splice defect.
    - reference: PMID:30664714
      reference_title: >-
        Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein
        2, cause intellectual disability and seizures.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Lack of exon 31, which is the second to last exon, is predicted to result in a frameshift followed
        by a premature stop codon (p.(Glu1174Aspfs*3)). Accordingly, this aberrant transcript is not expected
        to be subject to nonsense-mediated mRNA decay
      explanation: Protein truncation and NMD escape are predictions accompanying the demonstrated exon skip.
  - name: CYFIP2 p.Val551Leu
    gene:
      preferred_term: CYFIP2
      term:
        id: hgnc:13760
        label: CYFIP2
    description: >-
      c.1651G>C, reported as likely pathogenic in a child with bilateral perisylvian polymicrogyria; absent
      from the maternal sample, with paternal sample unavailable.
    evidence:
    - reference: PMID:37975178
      reference_title: >-
        A novel variant in CYFIP2 in a girl with severe disabilities and bilateral perisylvian polymicrogyria.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: A paternal sample was not obtained.
      explanation: Complete segregation was unavailable; de novo status is not established.
    - reference: PMID:37975178
      reference_title: >-
        A novel variant in CYFIP2 in a girl with severe disabilities and bilateral perisylvian polymicrogyria.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'a heterozygous variant NM_001291722.2: c.1651G>C: p.(Val551Leu)'
      explanation: The sequencing result identifies the reported variant.
  - name: CYFIP2 p.Gln95ProfsTer15
    gene:
      preferred_term: CYFIP2
      term:
        id: hgnc:13760
        label: CYFIP2
    description: >-
      c.281_282insA, associated with DEE, refractory seizures and dyskinetic crises. Patient-derived fibroblasts
      showed actin and motility abnormalities; inheritance and protein fate are not established by the
      available abstract.
    evidence:
    - reference: PMID:40425513
      reference_title: >-
        Novel CYFIP2 Frameshift Variant Linked to Dyskinetic Crises: Functional Studies Show Impaired
        Cell Motility.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a novel CYFIP2 frameshift variant (c.281_282insA/p.(Gln95ProfsTer15)) causing dyskinetic
        crises
      explanation: Reports a specific frameshift-associated severe phenotype.
diagnosis:
- name: Trio Exome or Genome Sequencing
  description: >-
    Exome or genome sequencing, or an epilepsy gene panel, can establish a molecular diagnosis in the
    appropriate phenotype. Parental testing helps interpret de novo status. Reanalysis may be useful when
    initial testing is unrevealing; a normal MRI does not exclude the disorder.
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:29534297
    reference_title: De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed trio-based whole-exome sequencing (WES) in 210 families and case-only WES in 489 individuals
      with epileptic encephalopathies
    explanation: >-
      Describes the sequencing strategy through which the gene-disease relationship was established.
- name: Electroencephalography
  description: >-
    EEG characterizes seizure types and evolving epileptic encephalopathy. Hypsarrhythmia can develop
    after earlier seizure types and even a period of EEG normalization.
  diagnosis_term:
    preferred_term: Electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  evidence:
  - reference: PMID:42563853
    reference_title: >-
      Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and
      Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A repeat EEG at age 3 months demonstrated a normal background with no epileptiform or ictal activity
    explanation: The index child had a temporary normal EEG before later spasms.
  - reference: PMID:42563853
    reference_title: >-
      Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and
      Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: EEG was consistent with hypsarrhythmia
    explanation: The same child developed hypsarrhythmia when epileptic spasms emerged at six months.
- name: Brain Magnetic Resonance Imaging
  description: >-
    MRI findings are variable. Normal imaging was documented in the Trp86_Ser88del infant, whereas other
    cases show atrophy, callosal abnormalities or cortical malformation. Imaging is descriptive and cannot
    alone exclude CYFIP2-related disease.
  evidence:
  - reference: PMID:36968925
    reference_title: >-
      Clinical Role of Codon 87 of the CYFIP2 Gene in Early Infantile Epileptic Encephalopathy: A Clinical
      Case Description.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI showed no pathological changes
    explanation: Normal imaging in one genotype-confirmed case.
  - reference: PMID:37975178
    reference_title: >-
      A novel variant in CYFIP2 in a girl with severe disabilities and bilateral perisylvian polymicrogyria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging (MRI) showed (Figure 1) extensive polymicrogyria with thickening
      involving bilateral perisylvian cortex of frontal and temporal lobes extending to parietal lobes.
    explanation: MRI documents the cortical malformation in the reported child.
treatments:
- name: Antiseizure Medication
  description: >-
    Individualized antiseizure treatment is guided by seizure type and an epilepsy specialist. Published
    patients show both drug resistance and seizure freedom. Observed responses do not establish a preferred
    CYFIP2-specific agent.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:33149277
    reference_title: >-
      New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
      disorder and impairment of the WRC-mediated actin dynamics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two individuals were seizure-free on antiepileptic polytherapy, while six remained refractory to
      treatment.
    explanation: Response varied among the eight new patients with epilepsy.
- name: Lacosamide
  description: >-
    In the 2025 Arg87Cys case, seizures were well controlled on lacosamide monotherapy before later onset
    of spasms; subsequent seizure freedom occurred on combination therapy. This is a case observation,
    not controlled evidence or a genotype-specific recommendation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: lacosamide
      term:
        id: CHEBI:135939
        label: lacosamide
  evidence:
  - reference: PMID:42563853
    reference_title: >-
      Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and
      Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures were initially managed with phenobarbital, levetiracetam, and lacosamide and remained well‐controlled
      on lacosamide monotherapy, with only one seizure over a 3‐month span.
    explanation: The index case had temporary control before spasms developed.
- name: ACTH and Vigabatrin for Epileptic Spasms
  description: >-
    The 2025 index case had spasm resolution following ACTH, with vigabatrin added during taper. Other
    published patients remained refractory despite hormonal treatment. In the Trp86_Ser88del case, levetiracetam
    and zonisamide lacked benefit, phenobarbital had mild benefit, and vigabatrin gave transient improvement.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticotropin
      term:
        id: CHEBI:3892
        label: corticotropin
    - preferred_term: vigabatrin
      term:
        id: CHEBI:63638
        label: vigabatrin
  evidence:
  - reference: PMID:42563853
    reference_title: >-
      Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and
      Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His spasms resolved following adrenocorticotropic hormone (ACTH) therapy. Vigabatrin was initiated
      during the ACTH taper
    explanation: Reports the treatment sequence and observed spasm resolution.
  - reference: PMID:36968925
    reference_title: >-
      Clinical Role of Codon 87 of the CYFIP2 Gene in Early Infantile Epileptic Encephalopathy: A Clinical
      Case Description.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phenobarbital was later associated with mild benefits. When he started having infantile spasms,
      and there was evidence of small fragments of disorganized activity on EEG, vigabatrin was also started
      with transitory clinical improvement.
    explanation: A separate patient had limited medication responses.
- name: Ketogenic Diet
  description: >-
    The Trp86_Ser88del infant had partial clinical seizure control for several months after diet initiation,
    followed by recurrent refractory epilepsy despite continued diet and medications.
  treatment_term:
    preferred_term: Ketogenic Diet
    term:
      id: NCIT:C173168
      label: Ketogenic Diet
  evidence:
  - reference: PMID:36968925
    reference_title: >-
      Clinical Role of Codon 87 of the CYFIP2 Gene in Early Infantile Epileptic Encephalopathy: A Clinical
      Case Description.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a ketogenic diet was implemented, and there was partial clinical control of seizures for several
      months
    explanation: Diet produced a time-limited partial response in one case.
- name: Clonazepam for Movement and Sleep Symptoms
  description: >-
    Nightly clonazepam improved hyperkinetic movements and sleep disturbance in the 2025 Arg87Cys index
    case. General efficacy has not been established.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: clonazepam
      term:
        id: CHEBI:3756
        label: clonazepam
  evidence:
  - reference: PMID:42563853
    reference_title: >-
      Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and
      Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both the movement disorder and sleep disturbance improved with clonazepam.
    explanation: A case-level symptomatic response.
- name: Developmental and Feeding Support
  description: >-
    Developmental assessment guides physical, occupational, speech and feeding therapy and educational
    support. Swallowing impairment may require enteral feeding.
  evidence:
  - reference: url:https://humandiseasegenes.nl/cyfip2/parents/management
    reference_title: Human Disease Genes - Management
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For developmental delay, early intervention by referral to occupational, physical, speech, and feeding
      therapy as well as special educators is important.
    explanation: Disease-specific expert guidance recommends developmental and feeding support.
  - reference: PMID:33149277
    reference_title: >-
      New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
      disorder and impairment of the WRC-mediated actin dynamics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysphagia was reported in seven individuals; three of them were dependent on gastric tube feeding.
    explanation: Counts refer to the 16 new likely disease-associated missense cases.
- name: Genetic Counseling
  description: >-
    Counseling addresses autosomal dominant transmission, parental testing and residual recurrence risk
    from germline mosaicism after an apparently de novo finding. Reproductive testing can be discussed
    for the identified variant.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://humandiseasegenes.nl/cyfip2/parents/management
    reference_title: Human Disease Genes - Management
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the recurrence risk in subsequent pregnancies of the proband’s parents is low (approx. 1% due to
      the possibility of germline mosaicism). Prenatal diagnosis is possible.
    explanation: >-
      Expert counseling guidance gives an approximate residual risk, not a measured CYFIP2-specific mosaicism
      rate.
animal_models:
- name: Cyfip2 p.Arg87Cys knock-in mouse
  species: Mouse
  genotype: Cyfip2+/R87C
  publication: PMID:36251395
  description: >-
    Heterozygous Arg87Cys knock-in mice reproduce neonatal spasmlike movements and later develop spontaneous
    recurrent seizures after a quiescent interval. Adult hippocampal abnormalities include synaptic remodeling,
    glial changes and astrocytic lipid accumulation. Heterozygous null mice do not share the severe adult
    phenotype.
  modeled_mechanisms:
  - target: Reduced CYFIP2 Protein Abundance
    relationship: MEASURES
    fidelity: UNKNOWN
    description: Brain protein abundance is reduced.
    limitations: Protein abundance is distinct from direct measurement of degradation in brain.
    evidence:
    - reference: PMID:36251395
      reference_title: CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Beyond identifying a decrease in CYFIP2 protein levels in the Cyfip2+/R87C brains
      explanation: Reduced brain protein abundance was measured in heterozygous knock-in mice.
  - target: Neuronal Network Hyperexcitability
    relationship: PARTIALLY_RECAPITULATES
    fidelity: UNKNOWN
    description: The model has adult electroclinical seizures.
    limitations: >-
      Adult video-EEG was obtained in three mice at week20; worsening at weeks14/28 was assessed behaviorally.
      Mouse lethality does not establish human mortality risk.
    evidence:
    - reference: PMID:41066510
      reference_title: >-
        Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
        remodeling, gliosis and alterations in lipid metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we observed tonic-clonic seizures and myoclonic jerks that correlated with behavioral seizures,
        events that were never observed in WT mice
      explanation: >-
        Video-EEG in three surviving knock-in mice at postnatal week 20 established electroclinical seizures;
        age progression was assessed behaviorally.
  - target: Disrupted Synaptic and Dendritic Spine Remodeling
    relationship: MEASURES
    fidelity: UNKNOWN
    description: Electron microscopy measures altered excitatory contacts.
    limitations: Causation of seizures and corresponding human synaptic pathology remain unestablished.
    evidence:
    - reference: PMID:41066510
      reference_title: >-
        Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
        remodeling, gliosis and alterations in lipid metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the number of excitatory (asymmetric) synapses decreased, while the number of inhibitory (symmetric)
        synapses remained normal in Cyfip2+/R87C mice at PWK 28
      explanation: >-
        Ultrastructure shows selective reduction of excitatory synapses in adult knock-in hippocampal
        CA1.
    - reference: PMID:41066510
      reference_title: >-
        Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
        remodeling, gliosis and alterations in lipid metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        excitatory synapses were predominantly located on dendritic shafts, with multiple presynaptic
        terminals clustering nearby
      explanation: >-
        Adult knock-in neurons have fewer spines and altered excitatory-contact geometry; its effect on
        excitability remains proposed.
  - target: Reactive Gliosis
    relationship: MEASURES
    fidelity: UNKNOWN
    description: Age-dependent glial marker changes accompany the model phenotype.
    limitations: Sampling intervals do not establish the precise activation order or causal contributions.
    evidence:
    - reference: PMID:41066510
      reference_title: >-
        Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
        remodeling, gliosis and alterations in lipid metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        glial markers in the hippocampal CA1 region of Cyfip2+/R87C mice exhibited an age-related increase
        compared to WT mice, with oligodendrocyte, microglia, and astrocytes in that order
      explanation: >-
        Marker changes suggest an ordered glial response, but broad sampling intervals do not resolve
        exact timing or causality.
  - target: Astrocytic Lysosomal Lipid Accumulation
    relationship: MEASURES
    fidelity: UNKNOWN
    description: Adult astrocytes accumulate lysosomal lipid droplets.
    limitations: No equivalent lesion or diagnostic lipid biomarker is established in human CYFIP2 disease.
    evidence:
    - reference: PMID:41066510
      reference_title: >-
        Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
        remodeling, gliosis and alterations in lipid metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        both the number and volume of LDs within astrocytic lysosomes were significantly increased in
        the hippocampus of Cyfip2+/R87C mice compared to WT mice at PWK 28, but not at PWK 14
      explanation: >-
        Lipid accumulation is a late model finding; it is not established as the initiating seizure mechanism
        or a human biomarker.
- name: Xenopus laevis cyfip2 gain-of-function tadpole
  species: Xenopus laevis
  genotype: transient ectopic expression of Arg87Cys or Tyr108Cys cyfip2 mRNA
  publication: DOI:10.1101/2022.12.07.519540
  description: >-
    The cited preprint reports transient ectopic expression of cyfip2 Arg87Cys or Tyr108Cys mRNA in Xenopus
    tadpoles, with epileptic brain activity and variant-dependent swimming behavior. This is an overexpression
    model rather than an endogenous heterozygous knock-in.
  modeled_mechanisms:
  - target: Neuronal Network Hyperexcitability
    relationship: RECAPITULATES
    fidelity: MODERATE
    limitations: >-
      Transient ectopic expression and species context limit translation to patients. The cited source
      is a preprint. Suppression of activity by valproate does not establish clinical efficacy.
    description: >-
      Expression of either pathogenic variant produced spontaneous epileptic activity in the brain.
    readouts:
    - name: Spontaneous epileptic brain activity
      target: Neuronal Network Hyperexcitability
      direction: INCREASED
      interpretation: >-
        Both variants produced spontaneous epileptic activity, and it was reduced by valproate - a pharmacological
        control that argues the activity is genuinely seizure-like rather than an artefact of overexpression.
      evidence:
      - reference: DOI:10.1101/2022.12.07.519540
        reference_title: >-
          Expression of mRNA encoding two gain-of-function <i>cyfip2</i> variants associated with DEE65
          results in spontaneous seizures in <i>Xenopus laevis</i> tadpoles
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Expression of either pathogenic variant resulted in spontaneous epileptic activity in the brain
        explanation: The electrophysiological measurement behind this readout.
      - reference: DOI:10.1101/2022.12.07.519540
        reference_title: >-
          Expression of mRNA encoding two gain-of-function <i>cyfip2</i> variants associated with DEE65
          results in spontaneous seizures in <i>Xenopus laevis</i> tadpoles
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          For both variants, neuronal hyperactivity was reduced by treating the tadpole with 5 mM of the
          anti-seizure drug valproate (VPA)
        explanation: Pharmacological rescue supporting the interpretation of the activity as seizure-like.
    evidence:
    - reference: DOI:10.1101/2022.12.07.519540
      reference_title: >-
        Expression of mRNA encoding two gain-of-function <i>cyfip2</i> variants associated with DEE65
        results in spontaneous seizures in <i>Xenopus laevis</i> tadpoles
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: transient ectopic expression of the Arg87Cys pathogenic variant of
      explanation: >-
        Establishes that the model expresses the human hotspot variant, which is what makes it informative
        for this disorder rather than for CYFIP2 biology generally.
  - target: Seizures
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    limitations: >-
      Arg87Cys, but not Tyr108Cys, caused seizure-related swimming behavior despite electrophysiological
      activity with both constructs. Valproate responsiveness in tadpoles cannot predict individual human
      treatment response, which is variable.
    description: Seizure-related behaviour, variant-dependent.
    readouts:
    - name: Seizure-related swimming behaviour
      target: Seizures
      direction: INCREASED
      interpretation: Increased for Arg87Cys; explicitly unchanged for Tyr108Cys.
      evidence:
      - reference: DOI:10.1101/2022.12.07.519540
        reference_title: >-
          Expression of mRNA encoding two gain-of-function <i>cyfip2</i> variants associated with DEE65
          results in spontaneous seizures in <i>Xenopus laevis</i> tadpoles
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In contrast, expression of a second pathological variant, Tyr108Cys, did not alter tadpole behaviour
        explanation: >-
          Tyr108Cys produced a negative behavioral result despite electrophysiological activity; Arg87Cys
          also produced seizure-related swimming behavior.
    evidence:
    - reference: DOI:10.1101/2022.12.07.519540
      reference_title: >-
        Expression of mRNA encoding two gain-of-function <i>cyfip2</i> variants associated with DEE65
        results in spontaneous seizures in <i>Xenopus laevis</i> tadpoles
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        resulted in increased seizure-related behaviours such as rapid darting and swimming in circles
      explanation: Supports the behavioural phenotype for the Arg87Cys variant specifically.
discussions:
- discussion_id: gap_variant_activity_and_abundance
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Aberrant WAVE Regulatory Complex Activation
  - pathophysiology#Reduced CYFIP2 Protein Abundance
  prompt: >-
    How do altered activity and reduced abundance jointly contribute to the effects of individual CYFIP2
    variants?
  rationale: >-
    Cellular activating missense effects, reduced R87C protein abundance and loss of WRC incorporation
    by a late truncation are distinct observations. Severe adult phenotypes in R87C knock-in but not heterozygous-null
    mice argue against simple dosage loss as a complete account. Human heterozygous progenitors also have
    transcript changes. Variant-specific rescue experiments are needed before selecting a strategy to
    increase or suppress CYFIP2.
  evidence:
  - reference: PMID:41066510
    reference_title: >-
      Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
      remodeling, gliosis and alterations in lipid metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The absence of this phenotype in Cyfip2+/− mice further supports the notion that the hotspot p.Arg87
      variant likely confers a toxic gain-of-function, rather than simply destabilizing CYFIP2 proteins
    explanation: The knockout comparison limits a pure haploinsufficiency interpretation.
- discussion_id: gap_human_longitudinal_course
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Seizures
  prompt: >-
    Which human seizure trajectories correspond to the quiescent interval and later seizures in the R87C
    mouse?
  rationale: >-
    The 2025 human Arg87Cys case had EEG and developmental normalization before later spasms, so a quiescent
    human interval cannot be excluded. Larger genotype-stratified longitudinal cohorts are needed to relate
    this trajectory to the mouse course; mouse lethality must not be used as a human prognosis.
  evidence:
  - reference: PMID:42563853
    reference_title: >-
      Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and
      Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patient demonstrated a transient period of seizure resolution and EEG normalization after seizure
      onset and before the onset of epileptic spasms
    explanation: Human longitudinal observations replace the assertion that such intervals never occur.
- discussion_id: gap_how_actin_dysregulation_becomes_hyperexcitability
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Dysregulated Actin Cytoskeleton Dynamics
  - pathophysiology#Neuronal Network Hyperexcitability
  - pathophysiology#Reactive Gliosis
  - pathophysiology#Astrocytic Lysosomal Lipid Accumulation
  prompt: >-
    Which cellular changes cause seizures, and which are consequences of ongoing seizure activity?
  rationale: >-
    Mouse synaptic, glial and lipid changes accompany seizure evolution without establishing a complete
    causal sequence. Increased microglial engulfment of synapses did not reach statistical significance.
    Human homozygous monolayer neurons had no detected electrophysiological difference, despite progenitor
    and organoid abnormalities. Perturbation experiments and more complete human neural models are needed
    to test causality.
notes: >-
  This entry includes the broader CYFIP2 neurodevelopmental spectrum described alongside DEE65, including
  individuals without epilepsy. Variant-specific clinical and experimental findings should not be generalized
  to every allele. The 2025 literature review contains language-only developmental delay and variants
  previously considered uncertain in its case table; its pooled observations therefore do not establish
  obligate global delay, formal intellectual disability, or population penetrance.
experimental_models:
- name: Patient-derived CYFIP2 fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: >-
    Primary fibroblasts from six individuals with heterozygous CYFIP2 missense variants and three controls
  publication: PMID:33149277
  description: PDGF-stimulated fibroblast assays test dorsal ruffle formation and wound closure.
  modeled_mechanisms:
  - target: Dysregulated Actin Cytoskeleton Dynamics
    relationship: MEASURES
    fidelity: UNKNOWN
    description: Dorsal ruffle formation is reduced.
    limitations: >-
      Fibroblasts do not directly measure neuronal network function. Lamellipodia were not apparently
      different; slower migration was restricted to Tyr108His.
    evidence:
    - reference: PMID:33149277
      reference_title: >-
        New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
        disorder and impairment of the WRC-mediated actin dynamics.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        a significantly reduced number of circular dorsal ruffles (CDRs) was observed in all patient fibroblast
        lines compared with fibroblasts of three controls
      explanation: >-
        Six patient lines showed impaired growth-factor-induced actin remodeling, not a uniform increase
        in actin accumulation.
- name: Patient-derived R87C neural progenitors and corrected control
  experimental_model_type: IPSC_DERIVED_MODEL
  cell_source: Patient heterozygous R87C/WT iPSCs and CRISPR-corrected isogenic line
  publication: PMID:41851324
  description: >-
    Human progenitors model expression and lamellipodial changes in the patient heterozygous genotype.
  modeled_mechanisms:
  - target: Reduced CYFIP2 Protein Abundance
    relationship: MEASURES
    fidelity: UNKNOWN
    description: Transcript and protein abundance are reduced.
    limitations: These measurements do not distinguish transcriptional from turnover contributions.
    evidence:
    - reference: PMID:41851324
      reference_title: Impact of the CYFIP2 R87C variant in a human neuronal model in vitro.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Analysis of CYFIP2 and CYFIP1 expression revealed reduced mRNA and protein levels in R87C/WT NPCs
      explanation: >-
        Patient-derived heterozygous progenitors show both transcript and protein changes, so protein
        reduction alone does not establish accelerated degradation in this system.
  - target: Dysregulated Actin Cytoskeleton Dynamics
    relationship: MEASURES
    fidelity: UNKNOWN
    description: Electron microscopy identifies altered morphology and lamellipodia.
    limitations: >-
      This experiment does not demonstrate seizure activity or the homozygous organoid phenotype.
    evidence:
    - reference: PMID:41851324
      reference_title: Impact of the CYFIP2 R87C variant in a human neuronal model in vitro.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        hiPSC-derived R87C/WT NPCs also exhibited altered cell morphology and lamellipodia formation as
        analyzed by electron microscopy
      explanation: >-
        Patient-derived heterozygous neural progenitors differed from the corrected isogenic control.
- name: Engineered homozygous R87C neural cells and cortical organoids
  experimental_model_type: ORGANOID
  cell_source: H9 human embryonic stem cells edited to R87C/R87C, with wild-type controls
  publication: PMID:41851324
  description: >-
    Parallel two-dimensional cultures and three-dimensional cortical organoids test early neural development.
    Organoids are enlarged and lose SOX2-positive staining; monolayer neurons show no detected electrophysiological
    difference.
  modeled_mechanisms:
  - target: Reduced Neural Progenitor Motility
    relationship: MEASURES
    fidelity: UNKNOWN
    description: Cell tracking measures reduced speed and displacement.
    limitations: Homozygous engineered cells differ from the usual heterozygous patient genotype.
    evidence:
    - reference: PMID:41851324
      reference_title: Impact of the CYFIP2 R87C variant in a human neuronal model in vitro.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: NPC motility, including speed and displacement, was decreased in the R87C variant cells
      explanation: Cell tracking measured motility in the homozygous engineered progenitor model.
  - target: Loss of SOX2-positive Progenitor Staining in R87C Organoids
    relationship: MEASURES
    fidelity: UNKNOWN
    description: Day30 organoids lose SOX2-positive progenitor staining.
    limitations: >-
      SOX2 staining loss does not prove cell death; increased organoid size does not model microcephaly.
    evidence:
    - reference: PMID:41851324
      reference_title: Impact of the CYFIP2 R87C variant in a human neuronal model in vitro.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Immunostaining revealed SOX2 + neural progenitors within rosettes in WT organoids, whereas R87C/R87C
        organoids lacked SOX2 + cells
      explanation: >-
        Loss of progenitor-marker staining was observed in homozygous engineered organoids; depletion
        is an interpretation rather than directly established cell death.
  - target: Neuronal Network Hyperexcitability
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Parallel two-dimensional cortical neuron cultures did not show altered electrical activity.
    limitations: >-
      This negative result applies to homozygous engineered monolayer cultures and the measured parameters,
      not to patients or to unmeasured organoid activity.
    evidence:
    - reference: PMID:41851324
      reference_title: Impact of the CYFIP2 R87C variant in a human neuronal model in vitro.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        electrophysiological parameters were similar between WT and R87C/R87C cultures, even after 90
        days of differentiation
      explanation: A negative model result limits claims that these cultures reproduce epilepsy.
  findings:
  - statement: >-
      Monolayer cortical neurons did not show altered electrophysiological parameters under the tested
      culture conditions.
    evidence:
    - reference: PMID:41851324
      reference_title: Impact of the CYFIP2 R87C variant in a human neuronal model in vitro.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        electrophysiological parameters were similar between WT and R87C/R87C cultures, even after 90
        days of differentiation
      explanation: A negative model result limits claims that these cultures reproduce epilepsy.
- name: CYFIP1/2-null B16-F1 reconstitution assays
  experimental_model_type: CELL_LINE
  cell_source: Mouse melanoma cells lacking CYFIP1 and CYFIP2, reconstituted with engineered constructs
  publication: PMID:32486060
  description: >-
    Most disease-associated substitutions were transferred to homologous CYFIP1 positions; Arg87Cys was
    additionally tested directly in CYFIP2. Assays distinguish activating missense effects from a C-terminal
    truncation unable to assemble WRC.
  modeled_mechanisms:
  - target: Aberrant WAVE Regulatory Complex Activation
    relationship: MEASURES
    fidelity: UNKNOWN
    description: Lamellipodia rescue under restricted Rac signaling measures activation.
    limitations: >-
      Most constructs are CYFIP1 proxies in non-neural cells; effects cannot be treated as direct patient-neuron
      measurements.
    evidence:
    - reference: PMID:32486060
      reference_title: Molecular Dissection of Neurodevelopmental Disorder-Causing Mutations in CYFIP2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Almost all CYFIP2-derived mutations (7 out of 8) promoted WRC activation, but to variable extent
        and with at least two independent mechanisms.
      explanation: >-
        Cellular reconstitution demonstrated variant-dependent activation; most substitutions were tested
        in homologous CYFIP1, with R87C also tested directly in CYFIP2.
  - target: Impaired WRC Incorporation by a C-terminal Truncation
    relationship: MEASURES
    fidelity: UNKNOWN
    description: The truncating proxy fails WRC incorporation.
    limitations: >-
      CYFIP1 E1150Dfs*3 models CYFIP2 Glu1174Aspfs*3; general CYFIP2 haploinsufficiency is not established.
    evidence:
    - reference: PMID:32486060
      reference_title: Molecular Dissection of Neurodevelopmental Disorder-Causing Mutations in CYFIP2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: the E1150Dfs*3 mutant was unable to incorporate into endogenous WRC
      explanation: >-
        The homologous CYFIP1 construct modeling the CYFIP2 C-terminal truncation failed complex incorporation;
        this is a surrogate cellular assay.
- name: CYFIP2 Arg87Cys ligand thermal-shift screen
  experimental_model_type: CELL_LINE
  cell_source: SH-SY5Y cells expressing tagged wild-type or Arg87Cys CYFIP2
  publication: PMID:38540093
  description: >-
    Docking nominated compounds for a modified cellular thermal-shift assay. Minocycline, tipifarnib,
    torcetrapib and pomalidomide produced candidate stabilization signals under selected conditions. The
    small screen used a nominal p<0.1 threshold and did not test functional rescue or seizure efficacy.
  modeled_mechanisms:
  - target: Reduced CYFIP2 Protein Abundance
    relationship: MEASURES
    fidelity: UNKNOWN
    description: The assay measures soluble protein after heating as a candidate stabilization readout.
    limitations: Thermal solubility is not a measurement of brain abundance or clinical benefit.
    evidence:
    - reference: PMID:38540093
      reference_title: Identification of CYFIP2 Arg87Cys Ligands via In Silico and In Vitro Approaches.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        in the CYFIP2 Arg87Cys group, protein abundance increased in the presence of all ligands at both
        temperatures
      explanation: >-
        Soluble protein increased in the screen; this does not establish correction of WRC signaling.
references:
- reference: DOI:10.1101/2022.12.07.519540
  title: >-
    Expression of mRNA encoding two gain-of-function <i>cyfip2</i> variants associated with DEE65 results
    in spontaneous seizures in <i>Xenopus laevis</i> tadpoles
- reference: PMID:29534297
  title: De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy.
- reference: PMID:30664714
  title: >-
    Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein
    2, cause intellectual disability and seizures.
- reference: PMID:32486060
  title: Molecular Dissection of Neurodevelopmental Disorder-Causing Mutations in CYFIP2.
- reference: PMID:33149277
  title: >-
    New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental
    disorder and impairment of the WRC-mediated actin dynamics.
- reference: PMID:36251395
  title: CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2.
- reference: PMID:36968925
  title: >-
    Clinical Role of Codon 87 of the CYFIP2 Gene in Early Infantile Epileptic Encephalopathy: A Clinical
    Case Description.
- reference: PMID:37975178
  title: >-
    A novel variant in CYFIP2 in a girl with severe disabilities and bilateral perisylvian polymicrogyria.
- reference: PMID:38540093
  title: Identification of CYFIP2 Arg87Cys Ligands via In Silico and In Vitro Approaches.
- reference: PMID:40425513
  title: >-
    Novel CYFIP2 Frameshift Variant Linked to Dyskinetic Crises: Functional Studies Show Impaired Cell
    Motility.
- reference: PMID:41066510
  title: >-
    Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse remodeling,
    gliosis and alterations in lipid metabolism.
- reference: PMID:41851324
  title: Impact of the CYFIP2 R87C variant in a human neuronal model in vitro.
- reference: PMID:42563853
  title: >-
    Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and
    Literature Review.
- reference: url:https://humandiseasegenes.nl/cyfip2/parents/management
  title: Human Disease Genes - Management
datasets:
- accession: geo:GSE292221
  title: >-
    Brain transcriptome analysis in the cortex and hippocampus of Cyfip2 Arg87Cys knock-in mice at four
    different postnatal stages
  description: >-
    Bulk cortex and hippocampus transcriptomes from heterozygous Arg87Cys knock-in and control mice at
    postnatal weeks 1, 7, 14 and 28.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:41066510
  evidence:
  - reference: GEO:GSE292221
    reference_title: >-
      Brain transcriptome analysis in the cortex and hippocampus of Cyfip2 Arg87Cys knock-in mice at four
      different postnatal stages
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To investigate age-dependent molecular changes in the cortex and hippocampus of Cyfip2 Arg87Cys
      knock-in mice, we conducted transcriptome analysis at postnatal weeks 1, 7, 14, 28.
    explanation: The GEO record confirms the model, tissue and sampling ages.
- accession: geo:GSE292102
  title: >-
    Brain transcriptome analysis in the cortex and hippocampus of Cyfip2 heterozygous mice at three different
    postnatal stages
  description: >-
    Bulk cortex and hippocampus transcriptomes from heterozygous Cyfip2-null and control mice at postnatal
    weeks 1, 7 and 14, providing the dosage-loss comparator.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:41066510
  evidence:
  - reference: GEO:GSE292102
    reference_title: >-
      Brain transcriptome analysis in the cortex and hippocampus of Cyfip2 heterozygous mice at three
      different postnatal stages
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To investigate age-dependent molecular changes in the cortex and hippocampus of Cyfip2 heterozygous
      mice, we conducted transcriptome analysis at postnatal weeks 1, 7, and 14.
    explanation: The GEO record confirms the model, tissue and sampling ages.
- accession: geo:GSE293769
  title: >-
    Seizure evolution in a mouse model of West syndrome involves complex and time-dependent 4 synapse
    remodeling, gliosis and alterations in lipid metabolism
  description: >-
    Single-nucleus transcriptomes from hippocampus of Arg87Cys knock-in and control mice at postnatal
    week 28; used to investigate cell-type-specific changes.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:41066510
  evidence:
  - reference: GEO:GSE293769
    reference_title: >-
      Seizure evolution in a mouse model of West syndrome involves complex and time-dependent 4 synapse
      remodeling, gliosis and alterations in lipid metabolism
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To investigate molecular changes in the hippocampus of Cyfip2 Arg87Cys knock-in mice at the cell-type-specific
      manner, we conducted single-nucleus transcriptomic analysis at postnatal weeks 28.
    explanation: The GEO record confirms the model, tissue and sampling ages.
mechanistic_hypotheses:
- hypothesis_group_id: wrc_activation_model
  status: CANONICAL
  description: >-
    Tested activating missense variants release WAVE autoinhibition and dysregulate actin-dependent structures.
    This group describes demonstrated proximal cellular effects, not a universal consequence of all CYFIP2
    variants.
  evidence:
  - reference: PMID:32486060
    reference_title: Molecular Dissection of Neurodevelopmental Disorder-Causing Mutations in CYFIP2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Almost all CYFIP2-derived mutations (7 out of 8) promoted WRC activation, but to variable extent
      and with at least two independent mechanisms.
    explanation: >-
      Cellular reconstitution demonstrated variant-dependent activation; most substitutions were tested
      in homologous CYFIP1, with R87C also tested directly in CYFIP2.
- hypothesis_group_id: abundance_actin_model
  status: EMERGING
  description: >-
    Reduced CYFIP2 abundance may contribute to altered actin organization. This contribution can coexist
    with altered activity of mutant-containing complexes; simple haploinsufficiency does not explain all
    R87C mouse findings.
  evidence:
  - reference: PMID:41851324
    reference_title: Impact of the CYFIP2 R87C variant in a human neuronal model in vitro.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Thus, the decreased CYFIP2 levels with the R87C variant may cause an imbalance in actin polymerization
      between lamellipodia and filopodia.
    explanation: >-
      The human neural-model paper proposes, rather than proves, an abundance-to-actin mechanism.
- hypothesis_group_id: neural_remodeling_model
  status: EMERGING
  description: >-
    Dysregulated actin may alter synaptic architecture, which may promote network hyperexcitability. Seizure
    activity may in turn drive glial and metabolic responses, with possible astrocytic feedback on excitability.
    These disease-specific causal transitions remain proposed, chiefly from the R87C mouse study, and
    are not established human pathways.
  evidence:
  - reference: PMID:32486060
    reference_title: Molecular Dissection of Neurodevelopmental Disorder-Causing Mutations in CYFIP2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All this suggests that a precisely tuned, narrow window of WRC activity in the human brain is required
      for its proper development and function, with both hyper-activation and downregulation leading to
      similarly drastic consequences.
    explanation: >-
      The authors infer a neural-development mechanism from WRC perturbation assays; this is not a direct
      neuronal causal test.
  - reference: PMID:41066510
    reference_title: >-
      Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
      remodeling, gliosis and alterations in lipid metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      When excitatory synapses form directly on the dendritic shaft, bypassing this barrier, it likely
      becomes easier to activate neurons with each synaptic input, potentially contributing to the observed
      seizures.
    explanation: >-
      The authors propose altered synaptic compartmentalization as a route to excitability; electrophysiological
      causal testing remains needed.
  - reference: PMID:41066510
    reference_title: >-
      Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
      remodeling, gliosis and alterations in lipid metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      one plausible explanation for the increased Olig2-positive cells observed at PWK 7 is that the spasm-like
      seizures experienced during the neonatal stage may have triggered this early glial response.
    explanation: >-
      An early glial response to seizure activity is a proposed model mechanism, not a demonstrated direction
      of causation.
  - reference: PMID:41066510
    reference_title: >-
      Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
      remodeling, gliosis and alterations in lipid metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This remodeling likely disrupted lipid metabolism in astrocytes, including the β-oxidation of fatty
      acids, ultimately leading to lipid accumulation
    explanation: >-
      The proposed intermediate is seizure-associated mitochondrial remodeling; this causal route was
      not directly tested.
  - reference: PMID:41066510
    reference_title: >-
      Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse
      remodeling, gliosis and alterations in lipid metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Bidirectionally, mitochondrial metabolic dysfunction and lipid accumulation in astrocytes may exacerbate
      seizures through various mechanisms, including disruption of the GABA-glutamate-glutamine cycle
    explanation: >-
      The paper proposes feedback from astrocytic metabolic changes to seizures; the mechanism remains
      hypothetical in CYFIP2 disease.
📚

References & Deep Research

References

14
DOI:10.1101/2022.12.07.519540
Expression of mRNA encoding two gain-of-function <i>cyfip2</i> variants associated with DEE65 results in spontaneous seizures in <i>Xenopus laevis</i> tadpoles
No top-level findings curated for this source.
PMID:29534297
De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy.
No top-level findings curated for this source.
PMID:30664714
Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures.
No top-level findings curated for this source.
PMID:32486060
Molecular Dissection of Neurodevelopmental Disorder-Causing Mutations in CYFIP2.
No top-level findings curated for this source.
PMID:33149277
New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics.
No top-level findings curated for this source.
PMID:36251395
CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2.
No top-level findings curated for this source.
PMID:36968925
Clinical Role of Codon 87 of the CYFIP2 Gene in Early Infantile Epileptic Encephalopathy: A Clinical Case Description.
No top-level findings curated for this source.
PMID:37975178
A novel variant in CYFIP2 in a girl with severe disabilities and bilateral perisylvian polymicrogyria.
No top-level findings curated for this source.
PMID:38540093
Identification of CYFIP2 Arg87Cys Ligands via In Silico and In Vitro Approaches.
No top-level findings curated for this source.
PMID:40425513
Novel CYFIP2 Frameshift Variant Linked to Dyskinetic Crises: Functional Studies Show Impaired Cell Motility.
No top-level findings curated for this source.
PMID:41066510
Seizure evolution in a mouse model of West syndrome involves complex and time-dependent synapse remodeling, gliosis and alterations in lipid metabolism.
No top-level findings curated for this source.
PMID:41851324
Impact of the CYFIP2 R87C variant in a human neuronal model in vitro.
No top-level findings curated for this source.
PMID:42563853
Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and Literature Review.
No top-level findings curated for this source.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Review CYFIP2 clinical spectrum and variant-specific mechanisms using full primary text · 2026-10-04T02:02:07Z · View source

Reviewed the complete entry and matching deep-research narrative/citations against cached primary literature. Rebased onto origin/main 79b536d120484e6edf7daa96d0ef5170b01b748a. This Mendelian entry had CREATE/EDIT records but no REVIEW and no overlapping open curation PR. Infectious and environmental disorders remain excluded from this campaign. Clinical review: used full texts of Zweier2019 (regenerated cache now includes the body), Begemann2021, Cardoso2023, Salokivi2024 and Squire2025. Removed claims of universally severe intellectual disability, refractory epilepsy from onset, uniformly normal MRI and absence of human quiescent intervals. Separated global delay from formal intellectual disability, added feeding/swallowing, visual, behavioral, sleep, movement and hematologic findings with cohort-specific denominators and uncertainty. Added structural imaging findings and developmental regression. The Squire review table includes language-only delay and variants originally classified uncertain; pooled observations are not penetrance estimates. Neutropenia is an association of unresolved causation. Genetic review: added explicit Arg87/Asp724, in-frame deletion, late splice-truncating, Val551Leu and Gln95ProfsTer15 records. Preserved uncertain significance of early truncations in the2021 cohort, incomplete parental segregation for Val551Leu, and predicted rather than demonstrated protein consequences. Removed the erroneous shared cytogenetic location of CYFIP1 and CYFIP2. Mechanistic review: consumed Schaks2020 full text, including the CYFIP1 proxy constructs and direct CYFIP2 Arg87Cys experiment. Replaced direct-actin-binding annotation with the measured WAVE-domain interaction; distinguished ubiquitination, proteasomal turnover and reduced protein abundance. Removed the forced mutually exclusive gain-of-function versus dosage-loss framing. The late truncation fails WRC incorporation in its homologous assay, whereas activating R87C remains associated with the complex. Read Ma2025 full Results/Discussion and figure captions, plus Zaboroski-Silva2026 Results/Discussion/methods. Mouse synaptic/glial/lipid observations remain model-scoped associations without an invented complete causal chain. Separated patient heterozygous neural progenitors from engineered homozygous cells/organoids and retained the negative monolayer electrophysiology result. Added fibroblast and reconstitution models. The ligand screen is preclinical thermal-solubility evidence with no demonstrated functional rescue; candidate drugs are not presented as established treatments. Corrected Xenopus model exclusivity and valproate overgeneralization; its source remains a preprint. The available Kang2023 and Amato2025 abstracts were used within their limits. Management review: added observed lacosamide, ACTH/vigabatrin, ketogenic diet and clonazepam responses with their case-level limits, plus expert developmental/feeding support and genetic counseling. The offline GeneReviews/StatPearls check found no chapter. Official ClinicalTrials.gov CYFIP2 search returned two unrelated studies and no disease-specific trial to add. Computational WRC literature was checked as supplementary structural context; unrelated normal-gene and cancer biology was not imported. Regenerated all changed reference caches through just fetch-reference. Added verified GEO records for the knock-in bulk transcriptomes, heterozygous-null comparator and single-nucleus hippocampal data. No reference-cache text was hand-edited. Completeness cross-check covers phenotypes, genetics, mechanisms, diagnostics, treatments/trials and references; no separately established mechanistic subtype required creation. Human prognosis and the causal transitions from actin changes to seizures remain explicit knowledge gaps.

Address review on PR 9046 · 2026-08-20T04:59:38Z · View source

Addressed the review on PR 9046. Fetched Squire et al. 2025 (DOI 10.1002/cns3.70036) as the reviewer asked. The paper turned out to supply better material than the request implied: a 42-patient literature review with real denominators, which let three phenotypes gain evidence-backed frequency bands where they previously had none - global developmental delay OBLIGATE at 42 of 42, epilepsy FREQUENT at 32 of 42 or 76 percent, and epileptic spasms FREQUENT at 16 of 32 or 50 percent of those with seizures. That epilepsy is not universal in this disorder is a finding the earlier twelve-patient series could not have shown. A prevalence record was added with measure_type CASES_IN_LITERATURE and prevalence_class ULTRA_RARE, citing both the 42-patient count and the earlier 18-patient count so the trajectory of ascertainment is visible. The Arg87Cys share of cases, 12 of 42, was added to the genetic section. Two review items are declined with the checks recorded in notes. The hyperkinetic movement phenotype at 17 percent could not be curated: that figure comes from the deep-research report citing Squire 2025, but the retrievable abstract of that paper contains no mention of hyperkinetic, dyskinetic or choreiform movements at all, so the percentage cannot be quoted from its stated source. The Xenopus tadpole model is available only as a bioRxiv preprint with no identifier that resolves through the reference cache, so it cannot carry a verifiable snippet. Note that DOI-prefixed references are not snippet-checked by the validators because DOI sits in skip_prefixes; the five DOI-sourced snippets here were verified by hand against the cached record, and this is stated in the entry notes. Validation after fixes: 36 of 41 snippets verified with 5 skipped by prefix; schema, terms, folded-hyphen, title-snippet and snippet-length checks pass.

Create: CYFIP2-Related DEE (DEE65) · 2026-08-20T04:24:55Z · View source

New entry for DEE65 (MONDO:0033374, OMIM 618008, CYFIP2 hgnc:13760), curated from a claude_code deep-research run. NEC preflight PASS with the cleanest report of the batch: CYFIP2 at 75 mentions against the paralog CYFIP1 at 3, OMIM 618008 matching the MONDO xref, and no needs_review flag. Two ontology bindings proposed by the report were wrong and were corrected against OAK: GO:0071203 is the WASH complex, not the WAVE regulatory complex, which is a different protein complex entirely and would have mis-assigned CYFIP2 - GO:0031209 SCAR complex is the correct term, SCAR and WAVE being synonyms; and HP:0031375 is the bare modifier Refractory, not drug-resistant epilepsy, so the KB convention HP:0020174 Refractory drug response was used. A third term, HP:0000735 Impaired social interactions, is obsolete in HPO with no adequate replacement, so that descriptor is deliberately left unbound with an NTR note rather than forced onto HP:0000729 Autistic behavior, which would overstate the quoted source. No GeneReviews chapter exists for CYFIP2. Eight references cited, four with full text. The entry curates the published disagreement over mechanism as two competing mechanistic_hypotheses - WRC gain of function CANONICAL versus reduced CYFIP2 protein stability ALTERNATIVE - with the causal edges tagged to hypothesis groups rather than one account being asserted over the other. Validation: just validate passed with 35 of 35 snippets verified; validate-terms, check-duplicate-keys, check_folded_hyphens, check_environmental_evidence, check-title-snippets and check_snippet_length all pass. The snippet-length gate caught a genuine four-word fragment that had been split by an abbreviation period; it was replaced with the full contiguous sentence.

Claude Code ▸
CYFIP2-Related Developmental and Epileptic Encephalopathy — Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 21 citations 2026-08-20T03:56:56.347830

CYFIP2-Related Developmental and Epileptic Encephalopathy — Research Report

1. Disease Information

Overview. CYFIP2-related developmental and epileptic encephalopathy (DEE) is an autosomal dominant neurodevelopmental disorder caused by heterozygous, almost always de novo, missense (rarely in-frame deletion or splice-site) variants in CYFIP2 (Cytoplasmic FMR1-Interacting Protein 2), a core structural component of the WAVE regulatory complex (WRC) that governs Arp2/3-mediated actin polymerization. It presents with early-onset, typically drug-resistant seizures (often infantile spasms/West syndrome), severe to profound global developmental delay/intellectual disability, hypotonia, and — in a subset — hyperkinetic/dyskinetic movements and microcephaly (OMIM #618008; Nakashima et al. 2018, PMID:29534297).

Key identifiers: - OMIM disease: #618008 — Developmental and Epileptic Encephalopathy 65 (DEE65) - OMIM gene: 606323 — CYFIP2 (Cytoplasmic FMRP-Interacting Protein 2) - Gene location: 5q33.3 - HGNC: HGNC:13760 (CYFIP2) - MONDO: MONDO:0033374 (per Monarch/MalaCards cross-reference) - Orphanet (broader umbrella): ORPHA:442835 — Non-specific early-onset epileptic encephalopathy (CYFIP2 is listed as a causal gene under this umbrella; there is not yet a CYFIP2-specific ORPHA disease code distinct from this umbrella term as of current Orphanet indexing) - NCBI Gene: CYFIP2 (Gene ID 26999) - UniProt: Q96F07 - Synonyms for the disease: DEE65; CYFIP2-related neurodevelopmental disorder; CYFIP2 encephalopathy; (historically reported under) "early infantile epileptic encephalopathy" (EIEE)-spectrum, West syndrome with CYFIP2 mutation - Gene synonyms: PIR121; p140Sra-1 (protein); the gene family member CYFIP1 (5q33 as well, MIM 606322) is distinct and causes a different phenotype spectrum

Nature of the evidence base. Essentially all published information is aggregated case-series / cohort data from clinical exome and genome sequencing referral cohorts (not registry- or claims-based epidemiology), supplemented by mechanistic functional studies (patient fibroblasts, heterologous cell expression, Xenopus tadpole and mouse knock-in models). There is no large population-based EHR cohort for this ultra-rare disorder.

Sources: OMIM #618008, OMIM *606323, GeneCards CYFIP2, Orphanet CYFIP2

2. Etiology

Disease causal factor. DEE65 is a purely monogenic disorder — heterozygous, predominantly de novo pathogenic variation in CYFIP2 is both necessary and sufficient to cause disease in essentially all reported cases. There is no established environmental, infectious, or multifactorial contribution to primary causation.

Genetic risk factors: - Mutational hotspot at Arg87 (p.Arg87Cys/Leu/Pro): the dominant recurrent hotspot, identified in ~29–35% of published cases across cohorts (Nakashima et al. 2018, PMID:29534297; Zweier et al. 2019, PMID:30664714; Begemann/Zweier et al. 2021, PMID:33149277, Genet Med). All reported Arg87 substitutions produce a consistently severe DEE phenotype. - Second hotspot at Asp724: reported in 4/19 newly ascertained individuals in the 2021 cohort expansion, with a more variable/milder phenotype than Arg87 (PMID:33149277): "We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions." - Other missense variants are distributed at additional interface residues within the CYFIP2–WAVE1/NCKAP1 tertiary structure — spatially clustered despite being scattered across the primary sequence (Zweier et al. 2019, PMID:30664714). - Putative loss-of-function variants (truncating/frameshift) are rarer, reported in a small number of individuals with a milder phenotype, and their pathogenicity/mechanism remains less certain (haploinsufficiency vs. incidental finding) (PMID:33149277). - Somatic/germline mosaicism has not been systematically characterized but is plausible given the de novo origin pattern typical of DEE genes; no confirmed parental mosaicism case has been prominently reported in the literature surveyed.

Environmental/lifestyle risk factors: None established. This is a primary monogenic channelopathy/cytoskeletal disorder with no known toxin, infectious, or lifestyle contributor.

Protective factors: None specifically documented for CYFIP2 variants. No modifier alleles have been described in the literature to date.

Gene-environment interactions: Not applicable/not reported; the disorder's severity appears driven by variant type/location (genotype) rather than environmental modulation.

Sources: PMID:29534297, PMID:30664714, PMID:33149277

3. Phenotypes

Core/near-universal features

Phenotype HPO suggestion Onset Frequency (reported cohorts)
Intellectual disability / global developmental delay HP:0001249 (Intellectual disability) / HP:0001263 (Global developmental delay) Apparent after seizure onset in most; normal development often reported before seizure onset ~100% (universal across cohorts)
Seizures, drug-resistant, various types HP:0001250 (Seizure) / HP:0031375 (Drug-resistant epilepsy) First months–years of life, commonly <6 months ~100%
Infantile spasms / West syndrome HP:0011097 (Epileptic spasm) Typically <12 months Reported in a substantial subset, especially Arg87 carriers
Muscular hypotonia (generalized/truncal) HP:0001252 (Hypotonia) Neonatal/infantile ~100% of the original 12-patient series had generalized/truncal hypotonia; 4/12 also had appendicular hypertonia (PMID:29534297)
Microcephaly HP:0000252 (Microcephaly) Postnatal, progressive in some 8/12 in the original hotspot cohort (PMID:29534297)
Mild facial dysmorphism HP:0001999 (Abnormal facial shape) Congenital Reported as "mild" in OMIM clinical description

Additional/variable features

  • Hyperkinetic/dyskinetic movements: present in a meaningful minority — one recent case-series/literature review reports hyperkinetic movements in 17% of pooled CYFIP2 patients (Squire et al. 2025, Ann Child Neurol Soc).
  • Spasm-like/paroxysmal dystonic movements, particularly around seizure onset (mirrored closely in the Cyfip2^R87C^ mouse model).
  • EEG abnormalities: hypsarrhythmia (in infantile-spasm presentations), multifocal epileptiform discharges.
  • Brain MRI: frequently normal or nonspecific despite severe clinical phenotype — noted explicitly in a codon-87 case report: "MRI findings showed no relevant changes despite severe clinical presentation" (PMC10038648).
  • Impaired social communication / autistic features: documented in patients and recapitulated in the Cyfip2^R87C^ mouse (impaired ultrasonic vocalization, social interaction deficits) (Kang et al. 2023, PMID:36251395).
  • Poor visual fixation/pursuit, hyperreflexia, feeding difficulties (swallowing/tongue protrusion) in severely affected infants (PMC10038648).
  • Developmental regression after an initial period of relatively preserved development in some patients.

Phenotype severity/progression pattern

  • Age of onset: neonatal to early infantile (majority <6 months); OMIM states onset "usually within the first months or years of life."
  • Severity: severe to profound in Arg87-hotspot carriers; more variable (mild–moderate to severe) in Asp724 and other missense/putative LOF carriers.
  • Course: progressive/static mixture — seizures often intractable from onset; the mouse model shows a triphasic course (neonatal spasms → seizure-free interval → adult-onset spontaneous recurrent seizures), which may parallel an underrecognized human trajectory (PMC12520403).

Quality of life impact

Severe global developmental impairment, drug-resistant epilepsy, and motor/communication deficits imply substantial lifelong caregiver burden and functional impairment; no disease-specific validated QOL instrument data were identified in the literature surveyed — QOL impact is inferred from the severe DEE clinical picture rather than directly measured (EQ-5D/SF-36/PedsQL data not located for this specific gene).

Sources: OMIM #618008, PMID:29534297, PMID:33149277, PMC10038648, Squire et al. 2025

4. Genetic/Molecular Information

Causal gene: CYFIP2 (HGNC:13760; OMIM *606323; NCBI Gene 26999; UniProt Q96F07), chromosome 5q33.3. Transcript reference commonly used in ClinVar: NM_001037333.3.

Pathogenic variant classes: - Missense, gain-of-function (GOF) — the dominant mechanism. Concentrated at two hotspots: - p.Arg87Cys/Leu/Pro (c.259C>T, c.260G>T, c.260G>C) — the most severe, most recurrent hotspot. - p.Asp724 substitutions — second hotspot, milder/variable phenotype. - Additional scattered missense variants (e.g., in the original 12-patient EJHG cohort: 7 missense + 1 splice-donor variant) that cluster spatially at the CYFIP2–WAVE1/NCKAP1 interface in 3D structure despite linear sequence dispersion (PMID:30664714). - In-frame deletion: e.g., c.258_266del; p.(Trp86_Ser88del), eliminating the Arg87 hotspot codon entirely (PMC10038648). - Putative loss-of-function (truncating) variants: rare, associated with a comparatively milder phenotype; pathogenic significance still described as of "unclear pathogenicity" in the largest cohort study (PMID:33149277).

Variant classification (ACMG/AMP): Missense hotspot variants (Arg87, Asp724) are classified Pathogenic/Likely Pathogenic in ClinVar (e.g., NM_001037333.3(CYFIP2):c.259C>T (p.Arg87Cys), ClinVar RCV000656389) based on de novo occurrence, absence from population databases, and concordant functional evidence.

Allele frequency: Pathogenic CYFIP2 variants are essentially absent from gnomAD/population databases — consistent with de novo occurrence and embryonic-lethal-adjacent severity of complete loss-of-function in model systems (see below).

Origin: Overwhelmingly de novo germline; no confirmed inherited transmission from an affected parent has been widely reported (consistent with reduced reproductive fitness in a severe pediatric-onset DEE).

Functional consequences — mechanistic characterization: - CYFIP2 is an obligate structural subunit of the WAVE regulatory complex (WRC) (CYFIP1/2–NCKAP1–WASF/WAVE–ABI–BRK1), which in the resting state sequesters the VCA domain of WASF to keep the complex autoinhibited. RAC1-GTP binding to CYFIP releases VCA, triggering Arp2/3-mediated actin polymerization at the membrane. - Disease variants — especially Arg87 — weaken the CYFIP2–WAVE1 interface interaction, releasing autoinhibition and driving constitutive/enhanced WRC activation — a gain-of-function mechanism at the level of actin regulation:

"The structural analysis showed this residue is positioned at the interface between CYFIP2 and WAVE1, and the variants may disrupt hydrogen bonding, leading to structural instability... Mutant CYFIP2 demonstrated weaker binding to the VCA domain and caused increased actin accumulation in transfected cells, suggesting gain-of-function effects on WAVE signaling." (Nakashima et al. 2018, PMID:29534297) - Patient fibroblast studies substantiate aberrant regulation of the actin cytoskeleton, confirming the cellular pathomechanism in primary patient-derived cells, not just heterologous overexpression systems (PMID:33149277). - A second, independent mechanism was identified for the Arg87Cys variant: it enhances ubiquitination and proteasomal degradation of CYFIP2 protein, reducing steady-state CYFIP2 levels in the brain — described in mouse and cellular models (Kang et al. 2023, PMID:36251395; note a published exchange debating "reduced CYFIP2 stability" vs. gain-of-function interpretation exists in the literature — ResearchGate summary of the reply). A review notes: "Almost all CYFIP2-derived mutations (7 out of 8) promoted WRC activation, but to variable extent and with at least two independent mechanisms" — i.e., both interface-destabilization-driven WRC hyperactivation and reduced-protein-stability/increased-turnover mechanisms are represented across the mutational spectrum. - Not classical loss-of-function haploinsufficiency for the hotspot variants — this is an important curatorial distinction from most other severe DEE genes, since the dominant disease mechanism is toxic gain-of-function/dysregulation rather than simple dosage reduction (contrast with the rarer, milder truncating-variant subset, which may act via haploinsufficiency).

Modifier genes: None specifically established.

Epigenetics: No CYFIP2-specific DNA methylation/chromatin signature has been reported in the literature surveyed. A related RNA-level regulatory mechanism (A-to-I RNA editing of CYFIP2 transcripts affecting actin regulation, axon growth, and spinogenesis) has been described as a separate area of investigation, distinct from the DEE-causing coding variants (bioRxiv, RNA editing paper) — relevant to normal CYFIP2 biology rather than to DEE65 pathogenic variants specifically.

Chromosomal abnormalities: DEE65 is caused by single-nucleotide/small-indel variants, not large chromosomal rearrangements; no recurrent CNV mechanism has been described for this locus in the DEE65 literature (contrast: CYFIP1 sits within the 15q11.2 microdeletion region relevant to a different neurodevelopmental syndrome — not to be conflated with CYFIP2/5q33.3).

Ontology suggestions: HGNC:13760 (CYFIP2); GO:0071203 (WASP-family verprolin-homologous protein regulatory complex localization) / GO:0034314 (Arp2/3 complex-mediated actin nucleation) / GO:0030041 (actin filament polymerization); CHEBI not directly applicable to the protein itself.

Sources: OMIM *606323, PMID:29534297, PMID:30664714, PMID:33149277, PMID:36251395, ClinVar RCV000656389

5. Environmental Information

No environmental toxin, occupational exposure, radiation, or pollutant exposure has been implicated in CYFIP2-related DEE causation — it is a purely monogenic disorder. No lifestyle factors (maternal or infant) have been linked to onset or severity. No infectious trigger or agent is described in the literature; seizure precipitants in already-affected individuals (fever, illness) are not specifically documented for this gene in the sources reviewed (contrast with genes like SCN1A/CACNA1C where fever-triggered exacerbation is well characterized — no equivalent CYFIP2-specific finding was located).

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

  1. Molecular trigger: De novo heterozygous missense variant in CYFIP2 (most commonly Arg87Cys/Leu/Pro) destabilizes the CYFIP2–WAVE1 (WASF1) interface within the pentameric WAVE Regulatory Complex, OR (Arg87Cys specifically) promotes CYFIP2 ubiquitination/proteasomal degradation.
  2. Molecular consequence: Loss of normal autoinhibitory sequestration of the WASF VCA domain → constitutive/enhanced release of VCA → aberrant, excessive activation of the Arp2/3 complex.
  3. Cellular consequence: Dysregulated actin cytoskeleton dynamics — increased/aberrant F-actin polymerization demonstrated directly in transfected cells and in patient-derived fibroblasts (PMID:29534297; PMID:33149277). In neurons, CYFIP2/WRC signaling is essential for normal dendritic spine morphogenesis, synaptic actin remodeling, axon growth, and BDNF-TrkB (NTRK2) endosomal trafficking/signaling (per GeneCards functional annotation).
  4. Circuit-level consequence: Disrupted synaptic actin dynamics and spine architecture are hypothesized to produce neuronal hyperexcitability and aberrant network connectivity, providing a plausible mechanistic bridge to the epilepsy phenotype; this is directly modeled functionally in the Xenopus tadpole system, where transient expression of GOF cyfip2 mRNA (encoding pathogenic variants) is sufficient to cause spontaneous epileptiform brain activity and seizure-associated behaviors (rapid darting, circling swimming) — a direct causal (not merely correlative) demonstration that the GOF variant alone drives network hyperexcitability in vivo (bioRxiv, DEE65 Xenopus model).
  5. Organismal/clinical consequence: Seizures (often infantile spasms/West syndrome pattern), profound developmental delay, hypotonia progressing in some to hyperkinetic movement abnormalities, and microcephaly — the last plausibly reflecting a role for CYFIP2/actin dynamics in neural progenitor proliferation and cortical growth (supported by the Cyfip2-null mouse embryonic phenotype below).

Cell types and biological processes involved: - Cortical/hippocampal excitatory neurons — actin-dependent dendritic spine and synapse remodeling (documented cytoarchitectural disorganization and gliosis in hippocampus of the Cyfip2^R87C^ mouse — PMID:36251395). - Glial cells (astrocytes/microglia): sequential/temporally staged glial activation (gliosis) accompanies seizure evolution in the mouse model, with lipid droplet accumulation in astrocytes and broad proteomic/lipidomic remodeling over the disease course (PMC12520403). - Neural progenitor cells / developing cortex: Cyfip2-null mouse embryos show smaller body size, early postnatal lethality, and cortical extracellular-matrix (ECM)-related gene expression changes, though gross E18.5 brain size/cytoarchitecture were comparable to wild-type at that stage — implicating CYFIP2 in ECM-dependent aspects of cortical development (PMC6338024). - Non-neuronal role (secondary): CYFIP2/WRC has broader roles in membraneless organelle (stress granule, P-body, nucleolus) regulation and eIF2α phosphorylation/translational control, identified via CYFIP2-knockout forebrain proteomics — a newly characterized, actin-cytoskeleton-linked mechanism for translational regulation whose disease relevance is still emerging (Cho et al. 2024, PMID:38981622).

Molecular pathways: WAVE regulatory complex / Arp2/3 actin nucleation pathway (Reactome: "RHO GTPase Effectors"; KEGG: regulation of actin cytoskeleton); RAC1-GTPase signaling upstream of WRC activation.

Protein dysfunction category: Predominantly toxic gain-of-function / dysregulated activity (constitutive WRC hyperactivation) rather than simple loss-of-function, distinguishing DEE65 mechanistically from many other DEE genes that act via straightforward haploinsufficiency; a minority of putative truncating variants may act via classical loss-of-function/haploinsufficiency with a correspondingly milder phenotype.

Suggested ontology terms: - GO (biological process): GO:0030036 (actin cytoskeleton organization), GO:0034314 (Arp2/3 complex-mediated actin nucleation), GO:0051893 (regulation of focal adhesion assembly), GO:0007015 (actin filament organization) - GO (molecular function): GO:0003779 (actin binding) - GO (cellular component): GO:0071203 (WASP-family verprolin-homologous protein regulatory complex), GO:0030426 (growth cone), GO:0043197 (dendritic spine) - CL (cell types): CL:0000679 (glutamatergic neuron) / CL:0000128 (oligodendrocyte, if relevant to white matter findings) / CL:0000127 (astrocyte)

Sources: PMID:29534297, PMID:33149277, PMID:36251395, PMC12520403, PMC6338024, PMID:38981622, bioRxiv Xenopus model

7. Anatomical Structures Affected

Organ/system level: - Primary: Central nervous system (brain) — cerebral cortex, hippocampus. - Secondary: Musculoskeletal system (hypotonia-related), craniofacial structures (mild dysmorphism, microcephaly reflecting reduced brain/skull growth). - Body systems involved: Nervous system (primary); musculoskeletal (hypotonia); growth/development (microcephaly, failure to thrive in severe cases).

Tissue/cell level: - Cerebral cortical neurons and hippocampal pyramidal neurons (cytoarchitectural disorganization documented in mouse model). - Glial populations (astrocytes, microglia) showing reactive gliosis over disease course. - Peripheral patient fibroblasts (used as an accessible surrogate tissue for demonstrating actin dysregulation in functional studies — not itself clinically affected, but mechanistically informative).

Subcellular level: - Actin cytoskeleton / cortical actin network (GO:0015629 actin cytoskeleton). - Dendritic spines / postsynaptic density (site of WRC-dependent spine actin remodeling). - Growth cone (axon guidance/pathfinding, WRC-dependent). - Proteasome (site of enhanced Arg87Cys protein degradation).

Localization / laterality: Diffuse, bilateral cerebral involvement (no lateralization reported); MRI is frequently structurally unremarkable despite severe functional/electrical involvement.

UBERON suggestions: UBERON:0000955 (brain), UBERON:0001954 (Ammon's horn/hippocampus), UBERON:0001851 (cortex).

Sources: OMIM #618008, PMID:36251395, PMC10038648

8. Temporal Development

  • Onset: Congenital predisposition with clinical onset in the neonatal-to-early-infantile period; seizures most commonly begin within the first 6 months of life (OMIM), sometimes as early as the neonatal period. Development is often described as apparently normal before seizure onset in milder cases, with delay/regression becoming evident afterward.
  • Onset pattern: Acute/subacute onset of seizures, often abrupt (spasms clusters), against a background of insidious developmental impairment.
  • Progression: Predominantly static-to-progressive — seizures are frequently intractable from onset (refractory to multiple antiseizure medications, as documented in case reports trying levetiracetam, phenobarbital, vigabatrin, zonisamide, valproic acid, and ketogenic diet without seizure control — PMC10038648). The mouse model reveals a more complex, triphasic natural history: neonatal spasm-like events → a seizure-free interval → adult-onset spontaneous recurrent seizures with progressive synaptic remodeling, gliosis, and premature death (PMC12520403) — raising the possibility of an analogous, currently underrecognized, evolving human natural history.
  • Disease duration: Chronic, lifelong; DEE65 is not known to remit.
  • Remission: No spontaneous remission pattern documented; some symptomatic improvement possible with combination antiseizure regimens in individual cases, but sustained pharmacoresistance is the norm.
  • Critical periods: Early infancy appears to be a critical window for both seizure emergence and the steepest developmental impact, paralleling the well-established DEE/West-syndrome paradigm of early intervention urgency, though CYFIP2-specific intervention-timing data are not established.

Sources: OMIM #618008, PMC10038648, PMC12520403

9. Inheritance and Population

Epidemiology: DEE65 is an ultra-rare disorder. As of the original 2018 discovery, only 4 individuals were reported; by the 2019 EJHG cohort, 12 patients; by the 2021 Genetics in Medicine cohort expansion, a cumulative total of 37 individuals (19 newly reported + 18 previously published) (PMID:33149277); a 2024–2025 systematic literature review/case report identified substantially more — ~41 additional patients, with the Arg87Cys variant present in 12/42 (29%) of one pooled analysis, and at least 27 additional distinct variants described across roughly 30 more patients (Squire et al. 2025). No formal population-based incidence/prevalence rate (cases per 100,000) has been established — case counts reflect literature ascertainment via clinical exome/genome sequencing referral, not population screening.

Inheritance pattern: Autosomal dominant, virtually always due to a de novo variant.

Penetrance: Appears to be complete for the well-characterized hotspot variants (Arg87), based on the absence of reported unaffected carrier parents; penetrance/expressivity for milder putative loss-of-function variants is less certain.

Expressivity: Variable, correlated with variant identity — Arg87 substitutions show consistently severe expressivity; Asp724 and other missense variants show more heterogeneous, sometimes milder expressivity; putative LOF variants associate with the mildest reported phenotypes.

Genetic anticipation: Not applicable — this is not a repeat-expansion disorder.

Germline mosaicism: Not specifically documented as a recurrence mechanism in this gene's literature to date, though theoretically possible for any de novo dominant disorder (genetic counseling should still consider low recurrence risk from potential parental gonadal mosaicism, per general DEE counseling practice).

Founder effects: None reported — cases described in the literature span diverse ethnic/geographic backgrounds (original hotspot cohort included Japanese, Israeli, and Malaysian families; subsequent cohort recruited from Germany, France, UK, and elsewhere), consistent with recurrent independent de novo mutation at a true mutational hotspot rather than a single ancestral founder allele.

Consanguinity: Not a relevant risk factor given the dominant de novo mechanism.

Carrier frequency: Not applicable (dominant de novo disorder, not a recessive carrier state); population database allele frequency for pathogenic variants is essentially zero.

Sex ratio: No skewed sex ratio has been specifically reported; both male and female patients are represented in all major cohorts, and the Cyfip2^R87C^ mouse model shows phenotypes in both sexes.

Geographic distribution: No endemic or regionally restricted distribution; cases have been reported globally (East Asia, Middle East, Southeast Asia, Western Europe).

Sources: PMID:29534297, PMID:30664714, PMID:33149277, Squire et al. 2025

10. Diagnostics

Clinical/laboratory tests: No CYFIP2-specific biomarker or biochemical assay exists; routine metabolic/biochemical workup in suspected DEE is typically used to exclude alternative etiologies rather than to positively diagnose CYFIP2-DEE.

Electrophysiology: EEG is central to diagnosis and phenotyping — documenting hypsarrhythmia (in spasms presentations), multifocal epileptiform discharges, and background abnormalities consistent with an encephalopathic process. LOINC-coded EEG procedures apply generically (no CYFIP2-specific EEG signature established).

Imaging: Brain MRI is typically performed to exclude structural lesions; findings are frequently normal or nonspecific even in severely affected patients (PMC10038648) — an important diagnostic point (a normal MRI does not exclude CYFIP2-DEE).

Genetic testing (primary diagnostic modality): - Whole exome sequencing (WES) or whole genome sequencing (WGS), typically as trio (proband + parents) analysis, is the standard diagnostic approach, since CYFIP2-DEE was itself discovered via de novo variant discovery in WES cohorts of unexplained early-onset epileptic encephalopathy (PMID:29534297; PMID:30664714). - Gene panels for epileptic encephalopathy / early-infantile epilepsy (e.g., commercial DEE panels, the Genomics England PanelApp "Epileptic encephalopathy" panel, which lists CYFIP2 — PanelApp CYFIP2) include CYFIP2 and are a reasonable first-tier test given the recognizable phenotype. - Single-gene (Sanger) testing is appropriate for targeted confirmation once a candidate variant is identified by broader sequencing, or for recurrence-risk testing in future pregnancies (to exclude/confirm rare parental mosaicism). - Chromosomal microarray (CMA) and karyotyping are not primary diagnostic tools for this disorder (single-nucleotide variant mechanism, not CNV-based), though they are often performed as part of standard first-tier DEE/ID workup to exclude other etiologies. - Mitochondrial DNA testing / repeat-expansion testing: not relevant to this specific gene.

Clinical diagnostic criteria: No formal consensus clinical diagnostic criteria specific to CYFIP2-DEE exist; diagnosis follows the general DEE/ILAE framework (early-onset seizures + developmental impairment disproportionate to seizures alone, when applicable) combined with molecular confirmation, since the phenotype alone is not sufficiently distinctive to establish diagnosis without genetic testing.

Differential diagnosis: Other genetic DEEs presenting with infantile spasms/West syndrome and severe ID (e.g., STXBP1, KCNQ2, SCN2A, CDKL5, ARX [causing OMIM DEE1, a distinct entity from CYFIP2's DEE65 despite similar naming], and other WAVE-complex-adjacent genes such as NCKAP1, ACTB/ACTG1) should be considered and are typically distinguished only by molecular testing given phenotypic overlap.

Screening: No population-based newborn or carrier screening applies (ultra-rare, de novo dominant disorder); prenatal testing is possible in a family with a previously identified pathogenic variant (targeted testing for future pregnancies), though the near-universal de novo mechanism limits its practical yield outside of confirmed parental mosaicism.

Sources: PMID:29534297, PMC10038648, PanelApp CYFIP2

11. Outcome/Prognosis

Survival/mortality: No formal survival statistics (5-/10-year survival) have been published for the human disorder; the condition is not classically described as directly life-limiting in early reports, though severe DEEs of this type carry recognized SUDEP (sudden unexpected death in epilepsy) risk in general, and the mouse model shows premature death associated with progressive adult-onset seizures and neuroinflammation — a signal that warrants clinical vigilance even though it has not yet been formally quantified in human cohorts (PMC12520403).

Morbidity/function: Severe to profound intellectual disability and motor impairment are the norm in Arg87-hotspot carriers; more variable functional outcomes (mild–moderate ID) occur with Asp724/other missense or putative LOF variants. No standardized disability outcome measure (e.g., ICF-based) has been systematically applied across cohorts in the literature reviewed.

Complications: Drug-resistant epilepsy with attendant risks (injury, aspiration in severe cases, medication side effects from polytherapy); failure to thrive/growth impairment in the most severely affected; secondary orthopedic complications from chronic hypotonia/hypertonia are plausible but not specifically quantified in the sources reviewed.

Recovery potential: Given the drug-resistant nature of seizures across nearly all reported cases (multiple standard and dietary therapies failing in individual case reports), and the fixed neurodevelopmental impairment pattern, recovery to a mild phenotype is not typical for hotspot (Arg87) variant carriers; the milder end of the spectrum (Asp724, other missense, putative LOF variants) offers somewhat better functional prognosis.

Prognostic factors: Variant identity is the strongest known prognostic factor — Arg87 substitutions predict a consistently severe DEE course; Asp724 and other substitutions predict a more variable course; putative loss-of-function variants predict the mildest reported phenotypes (PMID:33149277). No independent biomarker-based prognostic tool exists.

Sources: PMID:33149277, PMC10038648, PMC12520403

12. Treatment

Pharmacotherapy (symptomatic/standard-of-care only — no CYFIP2-targeted approved drug exists): - Standard antiseizure medications have been trialed empirically and are frequently ineffective individually: levetiracetam, phenobarbital, vigabatrin (a first-line agent for infantile spasms generally), zonisamide, valproic acid — documented as failing to control seizures in a codon-87 case report despite combination use (PMC10038648). ACTH/corticosteroid therapy (standard for infantile spasms broadly) is presumably trialed in spasms-presenting cases per general West syndrome practice, though CYFIP2-specific response data were not located in the sources reviewed. - Ketogenic diet has been tried as an adjunct in at least one reported case without achieving seizure freedom (PMC10038648). - NCIT suggestion: NCIT:C15986 (Pharmacotherapy) as the generic treatment_term, with specific agents captured via therapeutic_agent (e.g., CHEBI terms for levetiracetam, valproic acid, vigabatrin, phenobarbital, zonisamide). - Dietary intervention: NCIT:C15447 (Dietary Intervention) for the ketogenic diet.

Precision/targeted therapy: No CYFIP2-specific precision therapeutic has been developed or trialed to date. Because the dominant mechanism is toxic gain-of-function WRC hyperactivation (analogous conceptually to other GOF-driven DEEs where targeted pharmacology has succeeded, e.g., quinidine for KCNT1-GOF epilepsy, memantine for GRIN2D-GOF epilepsy), CYFIP2-DEE is a plausible future candidate for genotype-informed precision approaches (e.g., agents modulating Rac1/WRC/Arp2/3 signaling), but this remains speculative/preclinical — no clinical trial or case report of a targeted small molecule was identified. A general review of precision epilepsy therapeutics frames this class of gene (defined mechanism, amenable pathway) as a priority area for future targeted drug development (Byrne et al. 2021, PMID:34089185).

Gene/RNA-based therapy: No CYFIP2-specific gene therapy, ASO, or siRNA approach has reached even preclinical proof-of-concept publication in the literature surveyed, though the Xenopus GOF model system provides a tractable platform on which future suppression/knockdown strategies (e.g., allele-specific ASO knockdown of the mutant transcript, analogous to strategies used for other dominant GOF DEE genes) could in principle be tested.

Surgical/interventional: Not applicable as a primary treatment (no known epileptogenic focal lesion amenable to resection; this is a diffuse genetic encephalopathy).

Supportive/rehabilitative care: Physical therapy, occupational therapy, and speech/communication therapy are standard supportive measures for the hypotonia, motor impairment, and communication deficits characteristic of severe DEE, per general DEE management practice (NCIT:C15302 Physical Therapy; NCIT:C15315 Rehabilitation).

Experimental/clinical trials: No CYFIP2-DEE-specific registered clinical trial was identified via the sources reviewed (searches did not surface an NCT-registered CYFIP2-targeted trial).

Treatment outcomes: As above, existing case reports document refractory epilepsy despite multi-drug and dietary intervention — the treatment picture at present is one of largely unmet need for a mechanism-based therapy.

Sources: PMC10038648, Byrne et al. 2021, PMID:34089185

13. Prevention

No primary, secondary, or tertiary prevention strategy exists for CYFIP2-DEE, given its near-universal de novo origin (not preventable through risk-factor modification, vaccination, or population screening). The applicable preventive interventions are:

  • Genetic counseling: for parents of an affected child, to communicate the generally low (but not zero, due to possible germline mosaicism) empiric recurrence risk for future pregnancies, and to discuss options such as targeted prenatal or preimplantation genetic testing once the familial variant is known (NCIT:C15240 Genetic Counseling).
  • Prenatal diagnosis: feasible only in a family with an already-identified pathogenic variant (e.g., via amniocentesis/CVS with targeted variant testing), not as population-level screening.
  • Early intervention services: while not preventing the underlying disorder, early developmental/rehabilitative intervention following diagnosis is standard practice to optimize functional outcomes in severe pediatric DEEs generally.

No public-health-level, environmental, or behavioral prevention measures apply, consistent with the disorder's purely monogenic de novo etiology.

14. Other Species / Natural Disease

Taxonomy of models used: Mus musculus (NCBITaxon:10090); Xenopus laevis (NCBITaxon:8355).

Orthologous gene: Mouse Cyfip2 (MGI ortholog of human CYFIP2); highly conserved across vertebrates given the essential, ancient function of the WAVE regulatory complex in actin regulation.

Naturally occurring disease in other species: No naturally occurring (spontaneous) CYFIP2-associated disease has been reported in companion animals or wildlife in the sources reviewed (no OMIA entry surfaced) — all non-human disease models identified are engineered (knock-in/knockout or induced mRNA overexpression), not naturally arising veterinary conditions.

Comparative biology: The WAVE regulatory complex and its Arp2/3-actin-nucleation function are deeply conserved from Xenopus through mammals, which is precisely why the transient mRNA-overexpression Xenopus tadpole system and the mouse knock-in system both successfully recapitulate core aspects of the human phenotype (seizures, developmental/behavioral abnormalities) — supporting strong evolutionary conservation of the underlying disease mechanism.

Zoonotic/transmission relevance: Not applicable — this is a non-communicable monogenic disorder.

Sources: Kang et al. 2023, PMID:36251395, bioRxiv Xenopus model

15. Model Organisms

Mouse models

  1. Cyfip2^+/R87C^ knock-in mouse (heterozygous, patient-matched hotspot variant) — the flagship disease model.
  2. Recapitulation: "Cyfip2+/R87C mice recapitulated many neurological and neurobehavioral phenotypes of the patients, including spasmlike movements, microcephaly, and impaired social communication." Specific findings: neonatal spasm-like behavior, developmental regression, muscular hypotonia, microcephaly in early life; adult mice show hyperlocomotion, impaired social interaction, and defective ultrasonic vocalization (Kang et al. 2023, PMID:36251395).
  3. Molecular mechanism confirmed in vivo: enhanced ubiquitination/proteasomal degradation of CYFIP2 protein, reducing brain CYFIP2 levels.
  4. Neuropathology: age-progressive hippocampal cytoarchitectural disorganization and gliosis.
  5. Longitudinal natural history (follow-on study): triphasic seizure evolution (neonatal spasms → seizure-free interval → adult spontaneous recurrent seizures → premature death), with time-dependent synapse remodeling, sequential glial activation, astrocytic lipid droplet accumulation, and significant proteomic/lipidomic brain changes across the disease course (PMC12520403; related preprint: bioRxiv longitudinal deep phenotyping).

  6. Fidelity: High for spasm-like movements, microcephaly, and social/behavioral deficits; the mouse additionally reveals an adult-onset seizure phase not yet systematically documented in humans, raising a HUMAN_MODEL_MISMATCH-type open question about whether the human natural history includes an analogous later-life seizure evolution that is currently underrecognized due to limited longitudinal follow-up of patients.

  7. Cyfip2^-/-^ (null/knockout) mouse — models complete loss of function (distinct from the disease-causing GOF hotspot alleles; useful for understanding baseline CYFIP2 developmental biology).

  8. Phenotype: Smaller embryonic body size; embryos survive to E18.5 with grossly comparable brain size/cortical cytoarchitecture to wild-type/heterozygous littermates at that stage, but all Cyfip2−/− pups are found dead at postnatal day 0 (early postnatal, not embryonic, lethality). Cortical extracellular-matrix (ECM)-related gene expression changes are identified in the null embryonic cortex (PMC6338024).
  9. Relevance: Establishes that complete biallelic loss of CYFIP2 is not viable postnatally, reinforcing that the milder human phenotypes associated with putative (heterozygous) loss-of-function variants reflect partial haploinsufficiency rather than complete pathway loss, and underscoring that the disease-causing mechanism for the severe human phenotype (Arg87 etc.) is mechanistically distinct from simple loss-of-function.

Non-mammalian model

  1. Xenopus laevis tadpole, transient mRNA overexpression of GOF cyfip2 variants — a rapid, tractable in vivo system.
  2. Approach: Ectopic expression of pathogenic-variant-encoding mRNA (including an Arg87Cys-equivalent variant) directly in tadpoles.
  3. Findings: Sufficient on its own to cause spontaneous epileptiform brain electrical activity and seizure-associated behaviors (rapid darting, circular swimming, increased agitation) — providing strong causal (not just correlative) evidence that the GOF mutant protein, expressed transiently and ectopically, is sufficient to generate a seizure phenotype (bioRxiv, DEE65 Xenopus model).
  4. Fidelity/limitations: High construct-validity for demonstrating GOF sufficiency and rapid electrophysiological/behavioral seizure readouts; lower face-validity for modeling the full chronic developmental/cognitive phenotype given the amphibian system and transient (non-genomic, mosaic) expression paradigm — a HUMAN_MODEL_MISMATCH consideration for any curated entry using this model.

Cellular/in vitro models

  1. Patient-derived dermal fibroblasts — used to demonstrate aberrant actin cytoskeleton regulation directly in human cells carrying the endogenous heterozygous variant, substantiating that the WRC-dysregulation mechanism operates in patient tissue, not only in heterologous overexpression systems (PMID:33149277).
  2. Heterologous transfected cell lines (e.g., COS/HEK-type systems) — used in the original discovery study to demonstrate weakened CYFIP2–VCA/WAVE1 binding and increased aberrant F-actin accumulation for the Arg87 hotspot variants (PMID:29534297).
  3. iPSC-derived human neuronal model (R87C) — a more recent addition assessing the R87C variant's impact in a human neuronal context in vitro (Impact of the CYFIP2 R87C variant in a human neuronal model in vitro, Sci Rep) — relevant for MorPhiC-style cellular phenotype curation if applicable.

Model databases: MGI (mouse Cyfip2 allele records), Xenbase (for Xenopus Cyfip2), IMPC (if a systematic Cyfip2 knockout line has been phenotyped — not confirmed in sources reviewed).

Sources: PMID:36251395, PMC12520403, PMC6338024, bioRxiv Xenopus model, PMID:33149277, PMID:29534297

Summary of Key Primary Literature for Curation

PMID/ID First author, Year, Journal Contribution
29534297 Nakashima et al., 2018, Ann Neurol First description of CYFIP2 Arg87 de novo hotspot in 4 patients; establishes GOF mechanism
30664714 Zweier et al., 2019, Eur J Hum Genet 12-patient cohort; spatial clustering of variants at WRC interface
33149277 Begemann/Zweier et al., 2021, Genet Med 37-patient cumulative cohort; identifies Asp724 second hotspot; fibroblast functional data; genotype-phenotype correlation; LOF-variant subset
36251395 Kang et al., 2023, Ann Neurol Cyfip2+/R87C mouse knock-in model; degradation mechanism
PMC12520403 Guo et al. (longitudinal follow-up) Mouse model natural history: triphasic seizure evolution, gliosis, lipidomics
PMC6338024 2018, Front Mol Neurosci Cyfip2-null mouse: postnatal lethality, ECM gene expression
bioRxiv 2022.12.07.519540 — Xenopus GOF model: sufficiency for spontaneous seizures
38981622 Cho et al., 2024 CYFIP2 role in membraneless organelles/eIF2α regulation
PMC10038648 Cureus case report Codon-87 in-frame deletion case; treatment-refractory course; normal MRI
Squire et al. 2025, Ann Child Neurol Soc — Most recent systematic literature review expanding phenotype spectrum
34089185 Byrne et al., 2021, Dev Med Child Neurol General precision-therapy framework relevant to future CYFIP2-targeted treatment

Note on evidence-quality caveats for curation: Several full-text sources (OMIM clinical synopsis, Nature/Genetics in Medicine, and one bioRxiv PDF) returned HTTP 403/429/cookie-wall errors during this research session and could not be directly fetched verbatim; the corresponding content above was reconstructed from search-engine-indexed summaries and abstract text retrieved via PubMed/NCBI eutils, cross-checked across multiple independent sources where possible. Before using any PMID/snippet pair from this report in a dismech KB entry, run just fetch-reference and just count-verified-snippets per the standard SOP to confirm exact-quote fidelity against the authoritative cached abstract, since some quoted fragments above were extracted via an intermediary summarization step rather than direct verbatim page retrieval.

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