CPLX1-Related Developmental and Epileptic Encephalopathy

Mendelian MONDO:0033372 Pathograph 23 Show in embeddings browser Neurodevelopmental Disorder Epileptic Encephalopathy

An autosomal recessive developmental and epileptic encephalopathy associated with biallelic CPLX1 variants. Complexin-1 regulates presynaptic SNARE-mediated neurotransmitter release. Founding reports described C-terminal truncating variants in two sibling pairs and p.Leu128Met in a third family; the missense allele remains disputed. Clinical findings include severe developmental impairment, hypotonia and drug-resistant myoclonic epilepsy, with overt seizure onset ranging from early infancy to two years in the 2017 series. Structural brain findings are variable. Experimental complexin depletion impairs evoked release, but spontaneous and asynchronous release effects depend on the model; the intervening human circuit mechanism remains unresolved.

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1
Inheritance
6
Pathophys.
30
Phenotypes
3
Gaps
23
Pathograph
1
Genes
4
Variants
4
Medical Actions
2
Differentials
5
Models
11
References
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Classifications

Harrison's Part
NEUROLOGIC GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal Recessive HP:0000007
Homozygous CPLX1 variants were identified in affected children of consanguineous families; the 2017 parents were unaffected heterozygotes. Confidence in disease attribution remains allele dependent.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:28422131 SUPPORT Human Clinical
"WES detected the homozygous nonsense variant chr4:g.786591G>T (GRCh38/hg38); NM_006651.2:c.315C>A; NP_006642.1:p.(Cys105Ter) in Exon 4 of CPLX1 in the affected sisters. The unaffected parents were found to be heterozygous for this variant."
The two affected sisters carry a C-terminal stop variant; protein abundance and patient-neuron release were not measured.
PMID:26539891 SUPPORT Human Clinical
"We identified a homozygous nonsense mutation (NM_006651:c.G322T:p.E108X) in the CPLX1 gene in two female siblings, BAB6167 and BAB6168, who presented with malignant migrating epilepsy and cortical atrophy."
The 2015 sibling pair had homozygous p.Glu108Ter, migrating epilepsy and cortical atrophy.
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Discussions and Knowledge Gaps

3
Complexin-1 both clamps spontaneous vesicle fusion and facilitates fast calcium-evoked release; which arm of this dual function, when lost in CPLX1 disease, dominates the pathogenic synaptic defect — disinhibited spontaneous release, failed evoked release, or both?
OPEN QUESTION OPEN gap_cplx1_clamp_versus_facilitator_dominant_lesion
Attached to
pathophysiology#Reduced Evoked Synaptic Vesicle Release
Evoked-release impairment is shared across dual-knockdown cortical cultures and single-knockout calyces, whereas resting spontaneous release changes in opposite directions. Poststimulus asynchronous release is a separate defect. The dominant lesion in patient-variant human neurons and its contribution to epilepsy remain unresolved. Available p.Glu2Lys iPSCs also carry an SCN9A deletion and have not yet supplied neuronal functional data.
Proposed experiments
CPLX1-null human neuron spontaneous-versus-evoked release dissection
electrophysiological release-mode dissection experiment Relation: this experiment is of type this experiment type This experiment is of type electrophysiological release-mode dissection experiment.
exp_cplx1_spontaneous_versus_evoked_release_dissection
In CPLX1-null human iPSC-derived neurons, quantify spontaneous (miniature) release frequency and fast calcium-evoked release amplitude, then rescue with wild-type complexin-1 versus separation-of-function mutants that selectively restore clamping or facilitation, to attribute the pathogenic defect to a specific arm.
Perturbations
CPLX1 knockout and separation-of-function rescue
pathophysiology#Reduced Evoked Synaptic Vesicle Release
Compare CPLX1-null neurons rescued with wild-type complexin-1 versus clamp-selective or facilitation-selective complexin-1 variants.
CPLX1 hgnc:2309 HUGO Gene Nomenclature Committee (hgnc) Relation: this perturbation targets this gene This perturbation targets CPLX1 (hgnc:2309). hgnc:2309 is a gene from the HUGO Gene Nomenclature Committee.
Readouts
Spontaneous and evoked release readouts
pathophysiology#Reduced Evoked Synaptic Vesicle Release
synaptic vesicle exocytosis GO:0016079 ↕ DYSREGULATED Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on dysregulated synaptic vesicle exocytosis (GO:0016079). GO:0016079 is a biological process from the Gene Ontology. calcium-dependent activation of synaptic vesicle fusion GO:0099502 ↕ DYSREGULATED Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on dysregulated calcium-dependent activation of synaptic vesicle fusion (GO:0099502). GO:0099502 is a biological process from the Gene Ontology.
patch-clamp electrophysiology Relation: this readout is measured by this assay This readout is measured by patch-clamp electrophysiology.
Direction: POSITIVE
Controls
Wild-type complexin-1 rescue
CPLX1-null neurons rescued with wild-type human complexin-1.
Isogenic wild-type neurons
Isogenic CPLX1-intact neurons from the same iPSC background.
Decision criterion
The clamp arm dominates if the pathogenic defect is a selective rise in spontaneous release rescued only by clamp-competent complexin-1; the facilitator arm dominates if the defect is a selective loss of evoked release rescued only by facilitation-competent complexin-1.
Would support
pathophysiology#Reduced Evoked Synaptic Vesicle Release
Show evidence (4 references)
PMID:19164751 SUPPORT In Vitro
"In contrast, the complexin knock-down decreased 3-4 fold the amplitude of excitatory postsynaptic currents (EPSCs) evoked by isolated action potentials"
Evoked release was reduced in the dual-knockdown cortical culture.
PMID:19164751 SUPPORT In Vitro
"The complexin knock-down increased 3-4 fold the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs), without altering the mEPSC amplitude"
Spontaneous release increased in the dual-knockdown cortical culture.
PMID:26019341 SUPPORT Model Organism
"We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx of Held synapse, and discovered a developmentally exacerbating phenotype of reduced spontaneous and evoked transmission but excessive asynchronous release after stimulation, compatible with combined facilitating..."
Single-gene knockout at a native auditory brainstem synapse reduces resting spontaneous release, unlike dual-knockdown cortical cultures.
+ 1 more reference
Is biallelic CPLX1 loss best defined as a developmental and epileptic encephalopathy, as a progressive neurodegenerative/movement disorder, or as a single spectrum encompassing both — and what determines which phenotype predominates in a given patient?
KNOWLEDGE GAP OPEN gap_cplx1_phenotype_boundary_dee_versus_neurodegeneration
Attached to
pathophysiology#Complexin-1 Loss of Function pathophysiology#Epileptiform Brain Activity
The original p.Glu108Ter siblings had cortical atrophy, whereas the 2017 cases did not. One later case had a localized cerebellar cleft that may be coincidental. Mouse thalamic/cerebellar changes and granule-cell loss were nonprogressive across sampled ages; they do not establish human neurodegeneration. Small case numbers and uncertain missense attribution limit genotype-phenotype conclusions.
Proposed experiments
CPLX1 natural-history and genotype-phenotype cohort
natural-history cohort study Relation: this experiment is of type this experiment type This experiment is of type natural-history cohort study.
exp_cplx1_natural_history_genotype_phenotype_cohort
Assemble an international cohort of biallelic CPLX1 cases with standardized longitudinal phenotyping (seizure semiology and course, motor/movement features, developmental trajectory, and serial neuroimaging) to test whether epileptic and neurodegenerative/movement features co-segregate or define distinct subgroups, and whether variant class predicts phenotype.
Readouts
Longitudinal phenotype and course readouts
pathophysiology#Epileptiform Brain Activity
chemical synaptic transmission GO:0007268 ⚠ ABNORMAL Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on abnormal chemical synaptic transmission (GO:0007268). GO:0007268 is a biological process from the Gene Ontology.
electroencephalography Relation: this readout is measured by this assay This readout is measured by electroencephalography. magnetic resonance imaging Relation: this readout is measured by this assay This readout is measured by magnetic resonance imaging.
Direction: POSITIVE
Controls
Other synaptic vesicle cycle disorders
Comparison cohorts with STXBP1, SNAP25, STX1B, or SYT1 disorders to contextualize the CPLX1 phenotype spectrum.
Decision criterion
A unified spectrum is supported if epileptic and movement/neurodegenerative features consistently co-occur across cases; a split is supported if distinct, variant-correlated subgroups emerge.
Would support
pathophysiology#Epileptiform Brain Activity
Show evidence (3 references)
PMID:26539891 SUPPORT Human Clinical
"We identified a homozygous nonsense mutation (NM_006651:c.G322T:p.E108X) in the CPLX1 gene in two female siblings, BAB6167 and BAB6168, who presented with malignant migrating epilepsy and cortical atrophy."
The 2015 sibling pair had homozygous p.Glu108Ter, migrating epilepsy and cortical atrophy.
PMID:28422131 SUPPORT Human Clinical
"All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed a cerebellar cleft in addition."
Clinical findings in the three individuals reported in 2017; this does not estimate population frequency.
PMID:22393426 SUPPORT Model Organism
"Finally, stereology was used to show that there was loss of cerebellar granule cells in Cplx1(-/-) mice when compared to Cplx1(+/+) animals."
The primary study reports granule-cell loss; its negative neuronal-loss result is restricted to the molecular layer.
How faithfully does the Cplx1-knockout mouse — dominated by ataxia and a movement phenotype with variable seizures — model the human CPLX1 epileptic encephalopathy, versus mainly recapitulating the motor arm of the disease?
HUMAN MODEL MISMATCH OPEN gap_cplx1_mouse_model_fidelity_to_human_encephalopathy
Attached to
pathophysiology#Epileptiform Brain Activity
Cplx1 knockout produces prominent mouse motor and cerebellar abnormalities, and native calyx experiments demonstrate disrupted release timing. Correspondence to the human cortical seizure mechanism remains unknown. Neither whole-gene knockout nor dual-isoform knockdown directly models the function of the reported human C-terminal or missense alleles.
Proposed experiments
CPLX1 cross-species network-excitability comparison
cross-species network-excitability comparison Relation: this experiment is of type this experiment type This experiment is of type cross-species network-excitability comparison.
exp_cplx1_cross_species_network_excitability_comparison
Directly compare cortical network excitability and seizure-like activity between Cplx1-knockout mouse cortical preparations and human CPLX1-null iPSC-derived cortical neurons/organoids, to test whether the human cortical hyperexcitability phenotype is reproduced by the mouse or is human-specific.
Perturbations
CPLX1 loss of function across species
pathophysiology#Epileptiform Brain Activity
Cplx1-knockout mouse cortex versus isogenic human CPLX1-null cortical neurons/organoids.
CPLX1 hgnc:2309 HUGO Gene Nomenclature Committee (hgnc) Relation: this perturbation targets this gene This perturbation targets CPLX1 (hgnc:2309). hgnc:2309 is a gene from the HUGO Gene Nomenclature Committee.
Readouts
Network hyperexcitability readouts
pathophysiology#Epileptiform Brain Activity
trans-synaptic signaling GO:0099537 ↕ DYSREGULATED Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on dysregulated trans-synaptic signaling (GO:0099537). GO:0099537 is a biological process from the Gene Ontology. chemical synaptic transmission GO:0007268 ⚠ ABNORMAL Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on abnormal chemical synaptic transmission (GO:0007268). GO:0007268 is a biological process from the Gene Ontology.
multielectrode array recording Relation: this readout is measured by this assay This readout is measured by multielectrode array recording.
Direction: POSITIVE
Controls
Isogenic wild-type human neurons
CPLX1-intact human neurons from the same iPSC background.
Wild-type mouse cortex
Cplx1 wild-type littermate cortical preparations.
Decision criterion
The mouse is a faithful model of the human seizure phenotype if Cplx1-null mouse cortex shows network hyperexcitability matching human CPLX1-null cortical neurons; a human-specific cortical phenotype is supported if hyperexcitability appears in human but not mouse preparations.
Would support
pathophysiology#Epileptiform Brain Activity
Show evidence (2 references)
PMID:22393426 SUPPORT Model Organism
"Finally, stereology was used to show that there was loss of cerebellar granule cells in Cplx1(-/-) mice when compared to Cplx1(+/+) animals."
The primary study reports granule-cell loss; its negative neuronal-loss result is restricted to the molecular layer.
PMID:26019341 SUPPORT Model Organism
"We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx of Held synapse, and discovered a developmentally exacerbating phenotype of reduced spontaneous and evoked transmission but excessive asynchronous release after stimulation, compatible with combined facilitating..."
Single-gene knockout at a native auditory brainstem synapse reduces resting spontaneous release, unlike dual-knockdown cortical cultures.
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Pathophysiology

6
Complexin-1 Loss of Function
C-terminal truncating CPLX1 variants are predicted to impair complexin-1 function. Complete protein absence, nonsense-mediated decay and the effects of the reported missense alleles have not been demonstrated in patient material. Complexin binds SNAREs, while C-terminal membrane interactions are supported by nonhuman recombinant and worm studies. Loss of SNARE binding itself is not established for the patient C-terminal alleles.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Genetic context CPLX1 hgnc:2309 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CPLX1 (hgnc:2309). hgnc:2309 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact: Predicted impairment for C-terminal stop variants; patient protein abundance and missense effects remain unmeasured.
SNARE binding GO:0000149 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves SNARE binding (GO:0000149). GO:0000149 is a molecular function from the Gene Ontology.
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Recombinant complexin membrane-binding assays OTHER Defines C-terminal membrane interactions that motivate the predicted consequences of human truncation.
Animal models
Cplx1 knockout mouse: brain anatomy Mouse (Mus musculus) perturbs Genetic deletion permits assessment of the neurological consequences of complexin-1 loss.
Downstream
Epileptiform Brain Activity
Global Developmental Delay
Intellectual Disability The clinical report associates this manifestation with biallelic CPLX1 variants; the intervening neuronal mechanism is unresolved.
Hypotonia The clinical report associates this manifestation with biallelic CPLX1 variants; the intervening neuronal mechanism is unresolved.
Absent Speech The clinical report associates this manifestation with biallelic CPLX1 variants; the intervening neuronal mechanism is unresolved.
Inability to Walk The clinical report associates this manifestation with biallelic CPLX1 variants; the intervening neuronal mechanism is unresolved.
Show evidence (4 references)
PMID:28422131 SUPPORT Human Clinical
"WES detected the homozygous nonsense variant chr4:g.786591G>T (GRCh38/hg38); NM_006651.2:c.315C>A; NP_006642.1:p.(Cys105Ter) in Exon 4 of CPLX1 in the affected sisters. The unaffected parents were found to be heterozygous for this variant."
The two affected sisters carry a C-terminal stop variant; protein abundance and patient-neuron release were not measured.
PMID:26539891 SUPPORT Human Clinical
"We identified a homozygous nonsense mutation (NM_006651:c.G322T:p.E108X) in the CPLX1 gene in two female siblings, BAB6167 and BAB6168, who presented with malignant migrating epilepsy and cortical atrophy."
The 2015 sibling pair had homozygous p.Glu108Ter, migrating epilepsy and cortical atrophy.
PMID:25229806 SUPPORT In Vitro
"Here we show that complexin's CTD is highly sensitive to membrane curvature, which it senses via tandem motifs, a C-terminal motif containing a mix of bulky hydrophobic and positively charged residues, and an adjacent amphipathic region that can bind membranes in either a disordered or a helical..."
Recombinant complexin/liposome experiments support a membrane-binding role for the C terminus, not direct functional validation of the human alleles.
+ 1 more reference
Reduced Evoked Synaptic Vesicle Release
Evoked synaptic release is reduced after dual complexin-1/2 knockdown in cultured cortical neurons and after single Cplx1 knockout at mature mouse calyces of Held. The calyx study found preserved calcium influx, readily releasable pool size and quantal size; increased EGTA sensitivity supports looser calcium-channel/vesicle coupling as a contributing inference. These are experimental findings, not measurements in affected children.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
calcium-dependent activation of synaptic vesicle fusion GO:0099502 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased calcium-dependent activation of synaptic vesicle fusion (GO:0099502). GO:0099502 is a biological process from the Gene Ontology. synaptic vesicle exocytosis GO:0016079 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased synaptic vesicle exocytosis (GO:0016079). GO:0016079 is a biological process from the Gene Ontology.
Experimental models
Dual complexin-1/2 knockdown cortical neurons PRIMARY CELL CULTURE Reduced evoked EPSC amplitude after dual knockdown.
Dual complexin-1/2 knockdown cortical neurons PRIMARY CELL CULTURE Wild-type complexin-1 rescues the evoked-release defect.
Animal models
Cplx1 knockout mouse: calyx of Held Mouse (Mus musculus) measures Evoked EPSCs are reduced after maturation.
Show evidence (2 references)
PMID:19164751 SUPPORT In Vitro
"In contrast, the complexin knock-down decreased 3-4 fold the amplitude of excitatory postsynaptic currents (EPSCs) evoked by isolated action potentials"
Evoked release was reduced in the dual-knockdown cortical culture.
PMID:26019341 SUPPORT Model Organism
"We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx of Held synapse, and discovered a developmentally exacerbating phenotype of reduced spontaneous and evoked transmission but excessive asynchronous release after stimulation, compatible with combined facilitating..."
Single-Cplx1 knockout reduces evoked transmission at the mouse calyx of Held. This is a native synapse model, not a measurement in affected children.
Increased Spontaneous Release in Dual-Knockdown Cortical Neurons
Spontaneous miniature EPSC frequency increases in cultured mouse cortical neurons depleted of both complexin-1 and complexin-2, with unchanged miniature amplitude. This direction is specific to this preparation: resting spontaneous transmission decreases in single-Cplx1-knockout calyces of Held.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
synaptic vesicle exocytosis GO:0016079 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased synaptic vesicle exocytosis (GO:0016079). GO:0016079 is a biological process from the Gene Ontology.
Experimental models
Dual complexin-1/2 knockdown cortical neurons PRIMARY CELL CULTURE Increased miniature EPSC frequency after dual knockdown.
Dual complexin-1/2 knockdown cortical neurons PRIMARY CELL CULTURE Wild-type complexin-1 rescues the spontaneous-release defect.
Show evidence (2 references)
PMID:19164751 SUPPORT In Vitro
"We knocked down complexin expression in cultured cortical neurons using an shRNA that targets both complexin-1 and -2, the only complexin isoforms significantly expressed in these neurons"
This is dual complexin-1/2 knockdown in mouse neuronal culture, not a patient-variant experiment.
PMID:19164751 SUPPORT In Vitro
"The complexin knock-down increased 3-4 fold the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs), without altering the mEPSC amplitude"
Spontaneous release increased in the dual-knockdown cortical culture.
Excessive Poststimulus Asynchronous Release
Single-Cplx1-knockout calyces of Held exhibit excessive delayed asynchronous transmitter release following stimulation. This is distinct from resting spontaneous release, which is reduced in the same preparation. The proposed instability of newly recruited vesicles is a mechanistic interpretation.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
synaptic vesicle exocytosis GO:0016079 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated synaptic vesicle exocytosis (GO:0016079). GO:0016079 is a biological process from the Gene Ontology.
Animal models
Cplx1 knockout mouse: calyx of Held Mouse (Mus musculus) measures Delayed asynchronous release is increased after stimulation.
Downstream
Mistimed Postsynaptic Firing in the Calyx Model
Show evidence (2 references)
PMID:26019341 SUPPORT Model Organism
"We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx of Held synapse, and discovered a developmentally exacerbating phenotype of reduced spontaneous and evoked transmission but excessive asynchronous release after stimulation, compatible with combined facilitating..."
Single-Cplx1 knockout increases asynchronous transmitter release after stimulation at the mouse calyx of Held, while reducing resting spontaneous and evoked transmission.
PMID:26019341 SUPPORT Model Organism
"We found further that the excessive asynchronous release in Cplx1-deficient calyces triggered aberrant action potentials in their target neurons, and slowed-down the recovery of EPSCs after depleting stimuli."
Excess delayed release causes mistimed postsynaptic firing in this model; a human cortical mechanism is not established.
Mistimed Postsynaptic Firing in the Calyx Model
Excessive asynchronous release triggers aberrant action potentials in postsynaptic target neurons of Cplx1-deficient mouse calyces. The auditory brainstem experiment does not demonstrate the circuit origin of human cortical seizures.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Animal models
Cplx1 knockout mouse: calyx of Held Mouse (Mus musculus) measures Asynchronous release triggers aberrant postsynaptic action potentials.
Show evidence (1 reference)
PMID:26019341 SUPPORT Model Organism
"We found further that the excessive asynchronous release in Cplx1-deficient calyces triggered aberrant action potentials in their target neurons, and slowed-down the recovery of EPSCs after depleting stimuli."
Excess delayed release causes mistimed postsynaptic firing in this model; a human cortical mechanism is not established.
Epileptiform Brain Activity
Generalized epileptiform EEG activity was documented in the 2017 cases. In patient 3, persistent abnormal EEG activity preceded overt clinical seizures. These observations establish abnormal brain activity without identifying a specific excitatory/inhibitory imbalance.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Epilepsy
Show evidence (2 references)
PMID:28422131 SUPPORT Human Clinical
"Electroencephalography (EEG) repeatedly showed generalized epileptiform activity and hyperexcitability."
Repeated EEG in patient 1 documents epileptiform activity; no excitatory/inhibitory cell-specific imbalance was measured.
PMID:28422131 SUPPORT Human Clinical
"Beginning from the first months postpartum, EEG revealed marked persistent generalized seizure activity despite the absence of overt clinical seizure episodes."
The p.Leu128Met patient had EEG abnormalities before overt seizures; prematurity and variant uncertainty limit attribution.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for CPLX1-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

30
Digestive 1
Feeding Difficulties 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 (1 reference)
PMID:28422131 SUPPORT Human Clinical
"He displayed infant respiratory distress syndrome, hypotonia and feeding difficulties (no sucking reflex)."
Patient 3 had neonatal feeding difficulty with no sucking reflex after preterm birth. The clinical table also records feeding difficulties in patient 2.
Ear 1
Conductive Hearing Impairment HP:0000405 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conductive hearing impairment (HP:0000405). HP:0000405 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://push-zb.helmholtz-munich.de/deliver.php?id=18934 SUPPORT Human Clinical
"Cleft palate −− + Internal abnormalities −−− Bilateral conductive hearing loss −− + Myopia −− + Strabismus −− + Hypothyreosis − + − Brain abnormalities Unilateral cerebellar cleft −−"
Bilateral conductive hearing loss was recorded in patient 3; this is a case-level association with disputed p.Leu128Met. Table 1 columns are patient 1, patient 2 and patient 3; plus and minus denote presence and absence.
Endocrine 1
Hypothyroidism HP:0000821 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypothyroidism (HP:0000821). HP:0000821 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://push-zb.helmholtz-munich.de/deliver.php?id=18934 SUPPORT Human Clinical
"Cleft palate −− + Internal abnormalities −−− Bilateral conductive hearing loss −− + Myopia −− + Strabismus −− + Hypothyreosis − + − Brain abnormalities Unilateral cerebellar cleft −−"
Hypothyroidism was recorded in patient 2 carrying p.Cys105Ter; prevalence and causal relationship are not established. Table 1 columns are patient 1, patient 2 and patient 3; plus and minus denote presence and absence.
Eye 3
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"Craniofacial dysmorphisms comprising hypertelorism, bowed eyebrows, flat midface and thin upper lip were noted"
Hypertelorism was described in the two p.Cys105Ter sisters.
Myopia HP:0000545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopia (HP:0000545). HP:0000545 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://push-zb.helmholtz-munich.de/deliver.php?id=18934 SUPPORT Human Clinical
"Cleft palate −− + Internal abnormalities −−− Bilateral conductive hearing loss −− + Myopia −− + Strabismus −− + Hypothyreosis − + − Brain abnormalities Unilateral cerebellar cleft −−"
Myopia was recorded in patient 3, with uncertain attribution to p.Leu128Met. Table 1 columns are patient 1, patient 2 and patient 3; plus and minus denote presence and absence.
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)
url:https://push-zb.helmholtz-munich.de/deliver.php?id=18934 SUPPORT Human Clinical
"Cleft palate −− + Internal abnormalities −−− Bilateral conductive hearing loss −− + Myopia −− + Strabismus −− + Hypothyreosis − + − Brain abnormalities Unilateral cerebellar cleft −−"
Strabismus was recorded in patient 3, with uncertain attribution to p.Leu128Met. Table 1 columns are patient 1, patient 2 and patient 3; plus and minus denote presence and absence.
Head and Neck 7
Microcephaly 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:28422131 SUPPORT Human Clinical
"height (110–112 cm, −2.68 SD) and OFC (48.5 cm, −3.11 SD) were decreased."
Reduced head circumference was documented at seven years in the p.Leu128Met patient after a normal birth head measurement. Prematurity and variant uncertainty complicate attribution.
Midface Retrusion HP:0011800 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Midface retrusion (HP:0011800). HP:0011800 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"Craniofacial dysmorphisms comprising hypertelorism, bowed eyebrows, flat midface and thin upper lip were noted"
A flat midface was described in the two p.Cys105Ter sisters.
Thin Upper Lip Thin upper lip vermilion HP:0000219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin upper lip vermilion (HP:0000219). HP:0000219 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"Patient 1 at the age of 25/12 years with hypertelorism, bowed eyebrows, flat midface, long philtrum with thin upper lip and full cheeks."
A thin upper lip was described in all three 2017 patients; the facial findings are variable rather than a validated diagnostic gestalt.
Long Philtrum HP:0000343 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long philtrum (HP:0000343). HP:0000343 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"Patient 1 at the age of 25/12 years with hypertelorism, bowed eyebrows, flat midface, long philtrum with thin upper lip and full cheeks."
A long philtrum was described in patients 1 and 3.
Full Cheeks HP:0000293 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Full cheeks (HP:0000293). HP:0000293 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"Patient 1 at the age of 25/12 years with hypertelorism, bowed eyebrows, flat midface, long philtrum with thin upper lip and full cheeks."
Full cheeks were described in patient 1.
Bulbous Nasal Tip Bulbous nose HP:0000414 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bulbous nose (HP:0000414). HP:0000414 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"Patient 3 at the age of seven years with marked eyebrows, large nose with bulbous tip, long philtrum with thin upper lip."
A bulbous nasal tip was described in patient 3; this single observation does not establish a characteristic feature of confirmed CPLX1 disease.
Cleft Palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://push-zb.helmholtz-munich.de/deliver.php?id=18934 SUPPORT Human Clinical
"Cleft palate −− + Internal abnormalities −−− Bilateral conductive hearing loss −− + Myopia −− + Strabismus −− + Hypothyreosis − + − Brain abnormalities Unilateral cerebellar cleft −−"
Cleft palate was recorded only in patient 3 in Table 1; attribution to p.Leu128Met remains uncertain. Table 1 columns are patient 1, patient 2 and patient 3; plus and minus denote presence and absence.
Musculoskeletal 2
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"Assessment at age 25/12 years showed massive hypotonia, normal measurements"
Marked hypotonia was documented in patient 1; neonatal hypotonia was also described in the premature p.Leu128Met patient.
Poor Head Control HP:0002421 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor head control (HP:0002421). HP:0002421 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"She was unable to sit unsupported, to crawl or to walk. No head control was achieved."
Patient 1 did not achieve head control.
Nervous System 12
Epilepsy Myoclonic seizure HP:0032794 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoclonic seizure (HP:0032794). HP:0032794 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed a cerebellar cleft in addition."
Migrating myoclonic epilepsy was reported in all three 2017 cases; seizure onset and additional seizure types varied.
Global Developmental Delay 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:28422131 SUPPORT Human Clinical
"All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed a cerebellar cleft in addition."
Marked developmental delay was reported in the 2017 series; in patient 3 it preceded overt seizures.
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:28422131 SUPPORT Human Clinical
"identified homozygous CPLX1 variants in three patients with ID from two unrelated families."
Intellectual disability was reported in all three 2017 cases. It was not documented in the original 2015 sibling report, which does not establish its absence.
Epileptic Spasms 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:28422131 SUPPORT Human Clinical
"The first clinical signs of the disease appeared when she was 6 weeks old. She first experienced epileptic spasms."
Patient 1 developed spasms at six weeks and patient 2 at two and a half months; spasms are not established in every case.
Tonic Seizures HP:0032792 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tonic seizure (HP:0032792). HP:0032792 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"During course of disease, seizures switched to alternately myoclonic, tonic and generalized seizures, which occurred >50 times a day."
Tonic seizures occurred in patient 3, whose p.Leu128Met attribution remains uncertain.
Generalized Seizures Generalized-onset seizure HP:0002197 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized-onset seizure (HP:0002197). HP:0002197 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"Beyond the progressive myoclonic seizures, the diagnosis of generalized epilepsy was established at the age of three years."
Generalized epilepsy was diagnosed in patient 1 at three years; generalized seizures were also described in patients 2 and 3.
Absent Speech HP:0001344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent speech (HP:0001344). HP:0001344 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"She was unable to sit unsupported, to crawl or to walk. No head control was achieved. Speech was absent."
Speech was absent in patient 1 and patient 2 at reported assessments; patient 3 had nearly absent speech.
Delayed Sitting Delayed ability to sit HP:0025336 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed ability to sit (HP:0025336). HP:0025336 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"All milestones of motor and speech development were delayed. He was able to sit at 36 months and to walk with support at age 6 years."
The p.Leu128Met patient sat at 36 months; the two truncating-variant sisters could not sit unsupported at their reported assessments.
Inability to Walk HP:0002540 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inability to walk (HP:0002540). HP:0002540 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"At physical examination at around 33 months, she was unable to sit unsupported, to crawl, to walk and to speak."
Patients 1 and 2 could not walk at the reported assessments. Patient 3 later walked with support, so inability to walk is not universal.
Cerebral Cortical Atrophy HP:0002120 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral cortical atrophy (HP:0002120). HP:0002120 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26539891 SUPPORT Human Clinical
"We identified a homozygous nonsense mutation (NM_006651:c.G322T:p.E108X) in the CPLX1 gene in two female siblings, BAB6167 and BAB6168, who presented with malignant migrating epilepsy and cortical atrophy."
Cortical atrophy occurred in the original p.Glu108Ter siblings. It was absent on reported scans of all three 2017 patients.
Cerebral Palsy HP:0100021 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral palsy (HP:0100021). HP:0100021 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"He experienced cerebral movement disorder and cerebral palsy."
A case-specific motor diagnosis in patient 3, not proof of a uniform CPLX1 phenotype.
Choreoathetosis in the iPSC Donor 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 (1 reference)
DOI:10.1007/s13577-023-01016-z SUPPORT Human Clinical
"The 7-year-old female patient was diagnosed with global developmental delay, seizers since in infancy, and choreo- athetotic movements."
This is the donor-specific clinical description; the co-occurring SCN9A variant limits causal attribution.
Growth 2
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"height (110–112 cm, −2.68 SD) and OFC (48.5 cm, −3.11 SD) were decreased."
Short stature was documented at seven years in the p.Leu128Met patient; the two sisters had normal height at reported examinations.
Low Body Weight Decreased body weight HP:0004325 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased body weight (HP:0004325). HP:0004325 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"her weight (9.4 kg) diminished relatively (−2.95 SD)."
Patient 2 had low weight at about 33 months despite normal height and head circumference.
Other 1
Cerebellar Cleft
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"MRI of the brain performed at age 12, 24 and 36 months showed a small cleft of lobule VIII of the left cerebellar hemisphere with malorientation of the adjacent cerebellar folia"
Serial MRI documents the localized cleft; it does not demonstrate causation by CPLX1.
🧬

Genetic Associations

1
CPLX1 (Biallelic variants associated with developmental and epileptic encephalopathy)
Gene: CPLX1 hgnc:2309 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CPLX1 (hgnc:2309). hgnc:2309 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal Recessive
Show evidence (2 references)
PMID:28422131 SUPPORT Human Clinical
"WES detected the homozygous nonsense variant chr4:g.786591G>T (GRCh38/hg38); NM_006651.2:c.315C>A; NP_006642.1:p.(Cys105Ter) in Exon 4 of CPLX1 in the affected sisters. The unaffected parents were found to be heterozygous for this variant."
The two affected sisters carry a C-terminal stop variant; protein abundance and patient-neuron release were not measured.
PMID:26539891 SUPPORT Human Clinical
"We identified a homozygous nonsense mutation (NM_006651:c.G322T:p.E108X) in the CPLX1 gene in two female siblings, BAB6167 and BAB6168, who presented with malignant migrating epilepsy and cortical atrophy."
The 2015 sibling pair had homozygous p.Glu108Ter, migrating epilepsy and cortical atrophy.
Variants (4)
NM_006651.2:c.315C>A (p.Cys105Ter)
Gene: CPLX1 hgnc:2309 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CPLX1 (hgnc:2309). hgnc:2309 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Homozygous C-terminal stop variant in the two 2017 sisters; healthy parents were heterozygous. Total protein absence was not assayed.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"WES detected the homozygous nonsense variant chr4:g.786591G>T (GRCh38/hg38); NM_006651.2:c.315C>A; NP_006642.1:p.(Cys105Ter) in Exon 4 of CPLX1 in the affected sisters. The unaffected parents were found to be heterozygous for this variant."
The two affected sisters carry a C-terminal stop variant; protein abundance and patient-neuron release were not measured.
NM_006651:c.322G>T (p.Glu108Ter)
Gene: CPLX1 hgnc:2309 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CPLX1 (hgnc:2309). hgnc:2309 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Homozygous nonsense allele reported in the original two siblings with migrating epilepsy and cortical atrophy.
Show evidence (1 reference)
PMID:26539891 SUPPORT Human Clinical
"We identified a homozygous nonsense mutation (NM_006651:c.G322T:p.E108X) in the CPLX1 gene in two female siblings, BAB6167 and BAB6168, who presented with malignant migrating epilepsy and cortical atrophy."
The 2015 sibling pair had homozygous p.Glu108Ter, migrating epilepsy and cortical atrophy.
NM_006651.2:c.382C>A (p.Leu128Met)
Gene: CPLX1 hgnc:2309 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CPLX1 (hgnc:2309). hgnc:2309 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Homozygous in patient 3, born prematurely. ClinVar VCV000523650.12 has conflicting classifications: one likely pathogenic and three uncertain-significance submissions contributing to the aggregate. Functional loss has not been demonstrated.
Show evidence (2 references)
PMID:28422131 SUPPORT Human Clinical
"WES identified homozygosity for the variant chr4:g.786,524G>T (GRCh38/hg38); NM_006651.2:c.382C>A; NP_006642.1:p.(Leu128Met) in exon 4 of CLPX1 in the patient and heterozygosity in the unaffected parents."
The article reports the missense allele and segregation, but no patient functional assay; CLPX1 is a source typographical error.
url:https://www.ncbi.nlm.nih.gov/clinvar/variation/523650/ SUPPORT Other
"Likely pathogenic (1); Uncertain significance (3)"
ClinVar VCV000523650.12 reports conflicting classifications: one likely pathogenic and three uncertain-significance submissions contributing to the aggregate.
NM_006651.4:c.4G>A (p.Glu2Lys)
Gene: CPLX1 hgnc:2309 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CPLX1 (hgnc:2309). hgnc:2309 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Homozygous variant in a patient labelled as having Dravet syndrome, with heterozygous SCN9A c.3332_3346del (p.Ser1111_Glu1115del). Attribution to CPLX1 alone and the functional effect remain unresolved.
Show evidence (1 reference)
DOI:10.1007/s13577-023-01016-z SUPPORT Human Clinical
"Further analysis unraveled homozygous variant c.4G > A p.(Glu2Lys) in the CPLX1 gene. This variant leads to an amino acid exchange in exon 1 (NM_006651.4)."
The donor carried homozygous p.Glu2Lys as well as a heterozygous SCN9A deletion; this establishes the genotype, not single-gene causation.
💊

Medical Actions

4
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
Platform: Small molecule
Antiseizure medications were used, but all three 2017 patients had persistent seizures despite treatment. The report does not identify the individual agents, so no drug-specific efficacy is established.
Target Phenotypes: Epilepsy HP:0032794 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Epilepsy, annotated with Myoclonic seizure (HP:0032794). HP:0032794 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:28422131 SUPPORT Human Clinical
"Seizures were pharmacoresistant and did not respond to ketogenic diet."
Patient 1 had drug-resistant epilepsy.
PMID:28422131 SUPPORT Human Clinical
"Epilepsy did not respond to antiepileptic drugs."
Patient 2 did not respond to antiseizure medication.
PMID:28422131 SUPPORT Human Clinical
"Treatment with distinct anticonvulsants showed no improvement of patient’s clinical signs."
Patient 3 did not improve with the anticonvulsants tried; agents were unnamed.
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
A ketogenic diet was tried in patient 1 without seizure response. The report does not establish benefit in CPLX1 disease.
Target Phenotypes: Epilepsy HP:0032794 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Epilepsy, annotated with Myoclonic seizure (HP:0032794). HP:0032794 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"Seizures were pharmacoresistant and did not respond to ketogenic diet."
Direct evidence of nonresponse in patient 1; not a general efficacy estimate.
Supportive and Developmental Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Developmental, motor, communication and feeding support are reasonable individualized responses to the documented disabilities. The cited report describes needs rather than a tested CPLX1-specific rehabilitation regimen.
Show evidence (1 reference)
PMID:28422131 SUPPORT INDIRECT Human Clinical
"All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed a cerebellar cleft in addition."
Developmental impairment motivates supportive care by clinical inference; the study did not test its efficacy.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Counseling addresses recessive inheritance and allele-specific uncertainty. When both parents carry the same established pathogenic allele, the Mendelian expectation is a 25% chance of an affected homozygous child per pregnancy; this is an inheritance calculation, not an observed recurrence estimate from this small series.
Show evidence (1 reference)
PMID:28422131 SUPPORT INDIRECT Human Clinical
"WES detected the homozygous nonsense variant chr4:g.786591G>T (GRCh38/hg38); NM_006651.2:c.315C>A; NP_006642.1:p.(Cys105Ter) in Exon 4 of CPLX1 in the affected sisters. The unaffected parents were found to be heterozygous for this variant."
Affected homozygous sisters and unaffected heterozygous parents support recessive segregation. The recurrence probability is derived under the stated pathogenic-allele assumption.
🔬

Diagnosis

3
CPLX1 Molecular Diagnosis
Exome sequencing with segregation analysis identified the reported homozygous variants. Diagnosis requires phenotype-aware pathogenicity assessment; homozygosity for an uncertain missense allele alone is insufficient.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic or likely pathogenic CPLX1 variants support diagnosis in the appropriate phenotype; interpret uncertain variants and competing genetic findings separately.
Show evidence (2 references)
PMID:28422131 SUPPORT Human Clinical
"we performed trio-based WES in 311 patients with unsolved ID and additional clinical features, and identified homozygous CPLX1 variants in three patients"
Whole-exome sequencing established the molecular diagnosis of homozygous CPLX1 variants.
PMID:28422131 SUPPORT Human Clinical
"Trio-based WES was performed as described in Kuechler et al.7 and Sanger sequencing was performed to verify the variants and to perform segregation analysis"
The clinical study used exome sequencing, Sanger confirmation and family segregation.
Electroencephalography
EEG characterizes epileptiform activity and may be abnormal before overt seizures, as in patient 3.
Electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"Electroencephalography (EEG) repeatedly showed generalized epileptiform activity and hyperexcitability."
Repeated EEG in patient 1 documents epileptiform activity; no excitatory/inhibitory cell-specific imbalance was measured.
Brain MRI
MRI may show cortical atrophy or a localized cerebellar cleft, but normal imaging was reported in patients 2 and 3 and does not exclude the disorder.
Magnetic Resonance Imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:28422131 SUPPORT Human Clinical
"An MRI scan of the brain at around 17 months of age was normal and no cortical atrophy was noted."
Patient 3 had normal MRI despite developmental impairment and epilepsy.
PMID:26539891 SUPPORT Human Clinical
"We identified a homozygous nonsense mutation (NM_006651:c.G322T:p.E108X) in the CPLX1 gene in two female siblings, BAB6167 and BAB6168, who presented with malignant migrating epilepsy and cortical atrophy."
The 2015 sibling pair had homozygous p.Glu108Ter, migrating epilepsy and cortical atrophy.
📈

Progression

2
Variable seizure onset and severe developmental impairment
In the 2017 series, the two sisters developed spasms in early infancy. Patient 3 had EEG abnormalities in infancy but first overt seizures at two years; developmental impairment preceded those seizures. This case also had prematurity and a disputed missense allele.
Show evidence (3 references)
PMID:28422131 SUPPORT Human Clinical
"The first clinical signs of the disease appeared when she was 6 weeks old. She first experienced epileptic spasms."
Patient 1 had early infantile onset.
PMID:28422131 SUPPORT Human Clinical
"The first seizure event was recognized in a non-febrile context at 2 years."
Patient 3 had later overt seizure onset.
PMID:28422131 SUPPORT Human Clinical
"patient 3 showed ID and developmental delay before onset of epilepsy."
Developmental impairment cannot all be assigned as a consequence of overt seizures.
Severe outcomes reported in individual cases
Patient 1 died at eight years, probably during a seizure in sleep. This single observation does not establish a general survival estimate or a definitive cause-of-death diagnosis.
Show evidence (1 reference)
PMID:28422131 SUPPORT Human Clinical
"She passed away at 8 years of age most likely due to a severe seizure episode during sleep."
The probable cause was reported clinically, not established as definite SUDEP.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from CPLX1-Related Developmental and Epileptic Encephalopathy:

Other causes of epilepsy of infancy with migrating focal seizures
Overlapping Features Migrating seizures of infancy are genetically heterogeneous (e.g. KCNT1, SCN2A); CPLX1 disease is distinguished by biallelic pathogenic CPLX1 variants and the recessive inheritance.
Distinguishing Features
  • Biallelic pathogenic CPLX1 variants favor this disorder.
  • A variant in another migrating-seizure gene (e.g. KCNT1) favors that diagnosis.
Show evidence (1 reference)
PMID:35715422 SUPPORT Human Clinical
"17/36 cases had causative variants across 11 genes, including 6 novel EIMFS genes: PCDH19, ALDH7A1, DOCK6, PRRT2, ALG1 and ATP7A."
Documents the genetic heterogeneity of migrating focal seizures of infancy, which is why molecular testing is required to separate these causes from CPLX1 disease.
Other synaptic vesicle cycle disorders
Overlapping Features Other synaptic vesicle cycle / SNAREopathy disorders (STXBP1, SNAP25, STX1B, VAMP2, SYT1) overlap through early-onset epilepsy and developmental impairment and are distinguished by molecular testing.
Distinguishing Features
  • Biallelic pathogenic CPLX1 variants favor this disorder.
  • A variant in another vesicle-cycle gene favors the corresponding disorder.
Show evidence (1 reference)
PMID:32559416 SUPPORT Other
"Human pathogenic mutations have now been reported for all eight core components, but patients are diagnosed with very different neurodevelopmental syndromes."
Establishes that every core component of the fusion machine carries pathogenic human variants presenting as distinct neurodevelopmental syndromes, which is why these disorders sit on the differential for each other and are separated by molecular testing.
🧫

Experimental Models

3
Dual complexin-1/2 knockdown cortical neurons PRIMARY_CELL_CULTURE
An shRNA targeting both complexin-1 and complexin-2 increases miniature release and reduces evoked EPSC amplitude. Wild-type rat complexin-1 rescues both changes, whereas an engineered SNARE-binding mutant does not. This is not selective CPLX1 depletion or a patient-allele assay.
Cell source
Cultured mouse cortical neurons
Pathograph links
Reduced Evoked Synaptic Vesicle Release measures fidelity: unknown Reduced evoked EPSC amplitude after dual knockdown.
Limitations: Patient-variant neuronal physiology has not been established.
Show evidence (2 references)
PMID:19164751 SUPPORT In Vitro
"We knocked down complexin expression in cultured cortical neurons using an shRNA that targets both complexin-1 and -2, the only complexin isoforms significantly expressed in these neurons"
This is dual complexin-1/2 knockdown in mouse neuronal culture, not a patient-variant experiment.
+ 1 more reference
Increased Spontaneous Release in Dual-Knockdown Cortical Neurons measures fidelity: unknown Increased miniature EPSC frequency after dual knockdown.
Limitations: Patient-variant neuronal physiology has not been established.
Show evidence (2 references)
PMID:19164751 SUPPORT In Vitro
"We knocked down complexin expression in cultured cortical neurons using an shRNA that targets both complexin-1 and -2, the only complexin isoforms significantly expressed in these neurons"
This is dual complexin-1/2 knockdown in mouse neuronal culture, not a patient-variant experiment.
+ 1 more reference
Reduced Evoked Synaptic Vesicle Release rescues fidelity: unknown Wild-type complexin-1 rescues the evoked-release defect.
Limitations: Patient-variant neuronal physiology has not been established.
Show evidence (1 reference)
PMID:19164751 SUPPORT In Vitro
"Both changes were rescued by wild-type but not by 4M-mutant complexin, confirming the specificity of the shRNA and the importance of SNARE binding."
Wild-type rat complexin-1 rescued both release defects; the engineered SNARE-binding-deficient mutant failed.
Increased Spontaneous Release in Dual-Knockdown Cortical Neurons rescues fidelity: unknown Wild-type complexin-1 rescues the spontaneous-release defect.
Limitations: Patient-variant neuronal physiology has not been established.
Show evidence (1 reference)
PMID:19164751 SUPPORT In Vitro
"Both changes were rescued by wild-type but not by 4M-mutant complexin, confirming the specificity of the shRNA and the importance of SNARE binding."
Wild-type rat complexin-1 rescued both release defects; the engineered SNARE-binding-deficient mutant failed.
Show evidence (4 references)
PMID:19164751 SUPPORT In Vitro
"We knocked down complexin expression in cultured cortical neurons using an shRNA that targets both complexin-1 and -2, the only complexin isoforms significantly expressed in these neurons"
This is dual complexin-1/2 knockdown in mouse neuronal culture, not a patient-variant experiment.
PMID:19164751 SUPPORT In Vitro
"In contrast, the complexin knock-down decreased 3-4 fold the amplitude of excitatory postsynaptic currents (EPSCs) evoked by isolated action potentials"
Evoked release was reduced in the dual-knockdown cortical culture.
PMID:19164751 SUPPORT In Vitro
"The complexin knock-down increased 3-4 fold the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs), without altering the mEPSC amplitude"
Spontaneous release increased in the dual-knockdown cortical culture.
+ 1 more reference
Recombinant complexin membrane-binding assays OTHER
NMR and circular-dichroism experiments with recombinant worm complexin and liposomes establish curvature-sensitive C-terminal binding and helix formation. Mouse complexin showed related curvature sensitivity. Engineered worm substitutions and deletions inform membrane interactions, but none is a direct assay of the human disease alleles.
Pathograph links
Complexin-1 Loss of Function measures fidelity: low Defines C-terminal membrane interactions that motivate the predicted consequences of human truncation.
Limitations: Recombinant nonhuman proteins and engineered substitutions; human variant function was not measured.
Show evidence (1 reference)
PMID:25229806 SUPPORT In Vitro
"Here we show that complexin's CTD is highly sensitive to membrane curvature, which it senses via tandem motifs, a C-terminal motif containing a mix of bulky hydrophobic and positively charged residues, and an adjacent amphipathic region that can bind membranes in either a disordered or a helical..."
Recombinant complexin/liposome experiments support a membrane-binding role for the C terminus, not direct functional validation of the human alleles.
Show evidence (1 reference)
PMID:25229806 SUPPORT In Vitro
"Here we show that complexin's CTD is highly sensitive to membrane curvature, which it senses via tandem motifs, a C-terminal motif containing a mix of bulky hydrophobic and positively charged residues, and an adjacent amphipathic region that can bind membranes in either a disordered or a helical..."
Recombinant complexin/liposome experiments support a membrane-binding role for the C terminus, not direct functional validation of the human alleles.
KAIMRCi003A and KAIMRCi003B patient iPSCs OTHER
Two integration-free iPSC clones were generated from one seven-year-old patient labelled with Dravet syndrome, developmental delay, infantile seizures and choreoathetotic movements. Both carry homozygous CPLX1 p.Glu2Lys and a heterozygous SCN9A in-frame deletion. Identity, normal female karyotype, pluripotency and trilineage differentiation were characterized. Disease-relevant neuronal physiology, isogenic correction and functional rescue were proposed future work, not reported results.
Cell source
Patient peripheral blood erythroid progenitors reprogrammed to iPSCs
An undifferentiated patient-derived resource, not yet a validated neuronal disease model. The co-occurring SCN9A variant prevents assigning cellular findings to CPLX1 without further experiments.
Show evidence (2 references)
DOI:10.1007/s13577-023-01016-z SUPPORT In Vitro
"Here, we established two DRVT-iPSC lines harboring a homozygous mutation in the CPLX1 gene and heterozygous mutation in SCN9A gene."
Two iPSC clones were derived from one donor carrying both variants; this is a resource-generation result.
DOI:10.1007/s13577-023-01016-z SUPPORT Human Clinical
"Further analysis unraveled homozygous variant c.4G > A p.(Glu2Lys) in the CPLX1 gene. This variant leads to an amino acid exchange in exon 1 (NM_006651.4)."
The donor carried homozygous p.Glu2Lys as well as a heterozygous SCN9A deletion; this establishes the genotype, not single-gene causation.
🐁

Animal Models

2
Cplx1 knockout mouse: brain anatomy
Cplx1 knockout mice show early ataxia, selective thalamic and cerebellar volume loss, molecular-layer atrophy and loss of granule cells in selected cerebellar lobules. The structural phenotype was nonprogressive across the sampled ages. Neuronal loss was not detected in the molecular layer. These anatomical findings are not uniform human disease features.
Species
Mouse (Mus musculus)
Genotype
Homozygous Cplx1 knockout
Pathograph links
Complexin-1 Loss of Function perturbs fidelity: unknown Genetic deletion permits assessment of the neurological consequences of complexin-1 loss.
Limitations: Whole-gene mouse knockout differs from human C-terminal and missense alleles; anatomy does not establish the human seizure mechanism.
Show evidence (1 reference)
PMID:22393426 SUPPORT Model Organism
"Finally, stereology was used to show that there was loss of cerebellar granule cells in Cplx1(-/-) mice when compared to Cplx1(+/+) animals."
The primary study reports granule-cell loss; its negative neuronal-loss result is restricted to the molecular layer.
Show evidence (2 references)
PMID:22393426 SUPPORT Model Organism
"Finally, stereology was used to show that there was loss of cerebellar granule cells in Cplx1(-/-) mice when compared to Cplx1(+/+) animals."
The primary study reports granule-cell loss; its negative neuronal-loss result is restricted to the molecular layer.
PMID:22393426 SUPPORT Model Organism
"This suggests that, as with the behavioural phenotype, the pathological phenotype is non-progressive."
The early/late cross-sectional comparison supports nonprogressive structural changes in this mouse model.
Cplx1 knockout mouse: calyx of Held
Acute brainstem slices reveal developmentally worsening loss of evoked and resting spontaneous transmission, but excessive poststimulus asynchronous release. Calcium influx, readily releasable pool size and quantal size were preserved. Elevated extracellular calcium rescued aspects of evoked release experimentally but is not a tested human therapy.
Species
Mouse (Mus musculus)
Genotype
Homozygous Cplx1 knockout
Pathograph links
Reduced Evoked Synaptic Vesicle Release measures fidelity: unknown Evoked EPSCs are reduced after maturation.
Limitations: Patient-variant neuronal physiology has not been established.
Show evidence (1 reference)
PMID:26019341 SUPPORT Model Organism
"We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx of Held synapse, and discovered a developmentally exacerbating phenotype of reduced spontaneous and evoked transmission but excessive asynchronous release after stimulation, compatible with combined facilitating..."
Single-Cplx1 knockout reduces evoked transmission at the mouse calyx of Held. This is a native synapse model, not a measurement in affected children.
Excessive Poststimulus Asynchronous Release measures fidelity: unknown Delayed asynchronous release is increased after stimulation.
Limitations: Patient-variant neuronal physiology has not been established.
Show evidence (1 reference)
PMID:26019341 SUPPORT Model Organism
"We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx of Held synapse, and discovered a developmentally exacerbating phenotype of reduced spontaneous and evoked transmission but excessive asynchronous release after stimulation, compatible with combined facilitating..."
Single-Cplx1 knockout increases asynchronous transmitter release after stimulation at the mouse calyx of Held, while reducing resting spontaneous and evoked transmission.
Mistimed Postsynaptic Firing in the Calyx Model measures fidelity: unknown Asynchronous release triggers aberrant postsynaptic action potentials.
Limitations: Patient-variant neuronal physiology has not been established.
Show evidence (1 reference)
PMID:26019341 SUPPORT Model Organism
"We found further that the excessive asynchronous release in Cplx1-deficient calyces triggered aberrant action potentials in their target neurons, and slowed-down the recovery of EPSCs after depleting stimuli."
Excess delayed release causes mistimed postsynaptic firing in this model; a human cortical mechanism is not established.
Show evidence (2 references)
PMID:26019341 SUPPORT Model Organism
"We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx of Held synapse, and discovered a developmentally exacerbating phenotype of reduced spontaneous and evoked transmission but excessive asynchronous release after stimulation, compatible with combined facilitating..."
Single-gene knockout at a native auditory brainstem synapse reduces resting spontaneous release, unlike dual-knockdown cortical cultures.
PMID:26019341 SUPPORT Model Organism
"We found further that the excessive asynchronous release in Cplx1-deficient calyces triggered aberrant action potentials in their target neurons, and slowed-down the recovery of EPSCs after depleting stimuli."
Excess delayed release causes mistimed postsynaptic firing in this model; a human cortical mechanism is not established.
{ }

Source YAML

click to show 
name: CPLX1-Related Developmental and Epileptic Encephalopathy
creation_date: '2026-07-06T00:00:00Z'
description: >-
  An autosomal recessive developmental and epileptic encephalopathy associated with biallelic
  CPLX1 variants. Complexin-1 regulates presynaptic SNARE-mediated neurotransmitter release.
  Founding reports described C-terminal truncating variants in two sibling pairs and p.Leu128Met
  in a third family; the missense allele remains disputed. Clinical findings include severe
  developmental impairment, hypotonia and drug-resistant myoclonic epilepsy, with overt seizure
  onset ranging from early infancy to two years in the 2017 series. Structural brain findings
  are variable. Experimental complexin depletion impairs evoked release, but spontaneous and
  asynchronous release effects depend on the model; the intervening human circuit mechanism
  remains unresolved.
category: Mendelian
parents:
- Neurodevelopmental Disorder
- Epileptic Encephalopathy
disease_term:
  preferred_term: CPLX1 developmental and epileptic encephalopathy
  term:
    id: MONDO:0033372
    label: developmental and epileptic encephalopathy, 63
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:28422131
      reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All displayed marked developmental delay and migrating myoclonic epilepsy, and one
        showed a cerebellar cleft in addition
      explanation: Myoclonic epilepsy and developmental impairment place this disorder in the neurologic Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:28422131
      reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: identified homozygous CPLX1 variants in three patients with ID from two unrelated families
      explanation: >-
        The disorder was defined by homozygous CPLX1 variants segregating in two unrelated
        families, so it is also a Mendelian single-gene disorder and takes the genetics Part
        alongside the neurologic one.
references:
- reference: DOI:10.1007/s13577-023-01016-z
  title: >-
    Generation of iPSC lines (KAIMRCi003A, KAIMRCi003B) from a Saudi patient with Dravet syndrome
    carrying homozygous mutation in the CPLX1 gene and heterozygous mutation in SCN9A
- reference: PMID:19164751
  title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
- reference: PMID:22393426
  title: Tensor-based morphometry and stereology reveal brain pathology in the complexin1 knockout mouse.
- reference: PMID:25229806
  title: Membrane curvature sensing by the C-terminal domain of complexin.
- reference: PMID:26019341
  title: >-
    Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion
    at the mouse calyx of held synapse.
- reference: PMID:26539891
  title: >-
    Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of
    Mendelian Neurologic Disease.
- reference: PMID:28422131
  title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
- reference: PMID:32559416
  title: 'SNAREopathies: Diversity in Mechanisms and Symptoms.'
- reference: PMID:35715422
  title: >-
    Analysis of clinical phenotypic and genotypic spectra in 36 children patients with Epilepsy
    of Infancy with Migrating Focal Seizures.
- reference: url:https://push-zb.helmholtz-munich.de/deliver.php?id=18934
  title: https://push-zb.helmholtz-munich.de/deliver.php?id=18934
- reference: url:https://www.ncbi.nlm.nih.gov/clinvar/variation/523650/
  title: VCV000523650.12 - ClinVar - NCBI
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Homozygous CPLX1 variants were identified in affected children of consanguineous families;
    the 2017 parents were unaffected heterozygotes. Confidence in disease attribution remains
    allele dependent.
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES detected the homozygous nonsense variant chr4:g.786591G>T (GRCh38/hg38); NM_006651.2:c.315C>A;
      NP_006642.1:p.(Cys105Ter) in Exon 4 of CPLX1 in the affected sisters. The unaffected
      parents were found to be heterozygous for this variant.
    explanation: >-
      The two affected sisters carry a C-terminal stop variant; protein abundance and patient-neuron
      release were not measured.
  - reference: PMID:26539891
    reference_title: >-
      Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of
      Mendelian Neurologic Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a homozygous nonsense mutation (NM_006651:c.G322T:p.E108X) in the CPLX1
      gene in two female siblings, BAB6167 and BAB6168, who presented with malignant migrating
      epilepsy and cortical atrophy.
    explanation: The 2015 sibling pair had homozygous p.Glu108Ter, migrating epilepsy and cortical atrophy.
pathophysiology:
- name: Complexin-1 Loss of Function
  description: >-
    C-terminal truncating CPLX1 variants are predicted to impair complexin-1 function. Complete
    protein absence, nonsense-mediated decay and the effects of the reported missense alleles
    have not been demonstrated in patient material. Complexin binds SNAREs, while C-terminal
    membrane interactions are supported by nonhuman recombinant and worm studies. Loss of
    SNARE binding itself is not established for the patient C-terminal alleles.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES detected the homozygous nonsense variant chr4:g.786591G>T (GRCh38/hg38); NM_006651.2:c.315C>A;
      NP_006642.1:p.(Cys105Ter) in Exon 4 of CPLX1 in the affected sisters. The unaffected
      parents were found to be heterozygous for this variant.
    explanation: >-
      The two affected sisters carry a C-terminal stop variant; protein abundance and patient-neuron
      release were not measured.
  - reference: PMID:26539891
    reference_title: >-
      Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of
      Mendelian Neurologic Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a homozygous nonsense mutation (NM_006651:c.G322T:p.E108X) in the CPLX1
      gene in two female siblings, BAB6167 and BAB6168, who presented with malignant migrating
      epilepsy and cortical atrophy.
    explanation: The 2015 sibling pair had homozygous p.Glu108Ter, migrating epilepsy and cortical atrophy.
  - reference: PMID:25229806
    reference_title: Membrane curvature sensing by the C-terminal domain of complexin.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we show that complexin's CTD is highly sensitive to membrane curvature, which it
      senses via tandem motifs, a C-terminal motif containing a mix of bulky hydrophobic and
      positively charged residues, and an adjacent amphipathic region that can bind membranes
      in either a disordered or a helical conformation.
    explanation: >-
      Recombinant complexin/liposome experiments support a membrane-binding role for the C
      terminus, not direct functional validation of the human alleles.
  - reference: PMID:19164751
    reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Both changes were rescued by wild-type but not by 4M-mutant complexin, confirming the
      specificity of the shRNA and the importance of SNARE binding.
    explanation: Wild-type rat complexin-1 rescued both release defects; the engineered SNARE-binding-deficient mutant failed.
  role: trigger
  conforms_to: synaptic_vesicle_cycle#Synaptic Vesicle Cycle Protein Deficiency
  genetic_context:
    gene:
      preferred_term: CPLX1
      term:
        id: hgnc:2309
        label: CPLX1
    zygosity: HOMOZYGOUS
    variant_origin: GERMLINE
    functional_impact: >-
      Predicted impairment for C-terminal stop variants; patient protein abundance and missense
      effects remain unmeasured.
  molecular_functions:
  - preferred_term: SNARE binding
    term:
      id: GO:0000149
      label: SNARE binding
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  downstream:
  - target: Epileptiform Brain Activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28422131
      reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All displayed marked developmental delay and migrating myoclonic epilepsy, and one
        showed a cerebellar cleft in addition.
      explanation: Clinical findings in the three individuals reported in 2017; this does not estimate population frequency.
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28422131
      reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All displayed marked developmental delay and migrating myoclonic epilepsy, and one
        showed a cerebellar cleft in addition.
      explanation: Clinical findings in the three individuals reported in 2017; this does not estimate population frequency.
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The clinical report associates this manifestation with biallelic CPLX1 variants; the intervening
      neuronal mechanism is unresolved.
    evidence:
    - reference: PMID:28422131
      reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: identified homozygous CPLX1 variants in three patients with ID from two unrelated families.
      explanation: >-
        Intellectual disability was reported in all three 2017 cases. It was not documented
        in the original 2015 sibling report, which does not establish its absence.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The clinical report associates this manifestation with biallelic CPLX1 variants; the intervening
      neuronal mechanism is unresolved.
    evidence:
    - reference: PMID:28422131
      reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Assessment at age 25/12 years showed massive hypotonia, normal measurements
      explanation: >-
        Marked hypotonia was documented in patient 1; neonatal hypotonia was also described
        in the premature p.Leu128Met patient.
  - target: Absent Speech
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The clinical report associates this manifestation with biallelic CPLX1 variants; the intervening
      neuronal mechanism is unresolved.
    evidence:
    - reference: PMID:28422131
      reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: She was unable to sit unsupported, to crawl or to walk. No head control was achieved. Speech was absent.
      explanation: Speech was absent in patient 1 and patient 2 at reported assessments; patient 3 had nearly absent speech.
  - target: Inability to Walk
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The clinical report associates this manifestation with biallelic CPLX1 variants; the intervening
      neuronal mechanism is unresolved.
    evidence:
    - reference: PMID:28422131
      reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        At physical examination at around 33 months, she was unable to sit unsupported, to crawl,
        to walk and to speak.
      explanation: >-
        Patients 1 and 2 could not walk at the reported assessments. Patient 3 later walked
        with support, so inability to walk is not universal.
- name: Reduced Evoked Synaptic Vesicle Release
  description: >-
    Evoked synaptic release is reduced after dual complexin-1/2 knockdown in cultured cortical
    neurons and after single Cplx1 knockout at mature mouse calyces of Held. The calyx study
    found preserved calcium influx, readily releasable pool size and quantal size; increased
    EGTA sensitivity supports looser calcium-channel/vesicle coupling as a contributing inference.
    These are experimental findings, not measurements in affected children.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:19164751
    reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In contrast, the complexin knock-down decreased 3-4 fold the amplitude of excitatory
      postsynaptic currents (EPSCs) evoked by isolated action potentials
    explanation: Evoked release was reduced in the dual-knockdown cortical culture.
  - reference: PMID:26019341
    reference_title: >-
      Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion
      at the mouse calyx of held synapse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx of
      Held synapse, and discovered a developmentally exacerbating phenotype of reduced spontaneous
      and evoked transmission but excessive asynchronous release after stimulation, compatible
      with combined facilitating and clamping functions of Cplx1.
    explanation: >-
      Single-Cplx1 knockout reduces evoked transmission at the mouse calyx of Held. This is a native synapse
      model, not a measurement in affected children.
  biological_processes:
  - preferred_term: calcium-dependent activation of synaptic vesicle fusion
    term:
      id: GO:0099502
      label: calcium-dependent activation of synaptic vesicle fusion
    modifier: DECREASED
  - preferred_term: synaptic vesicle exocytosis
    term:
      id: GO:0016079
      label: synaptic vesicle exocytosis
    modifier: DECREASED
  role: central_effector
  conforms_to: synaptic_vesicle_cycle#Impaired Calcium-Triggered SNARE-Mediated Vesicle Fusion
- name: Increased Spontaneous Release in Dual-Knockdown Cortical Neurons
  description: >-
    Spontaneous miniature EPSC frequency increases in cultured mouse cortical neurons depleted
    of both complexin-1 and complexin-2, with unchanged miniature amplitude. This direction
    is specific to this preparation: resting spontaneous transmission decreases in single-Cplx1-knockout
    calyces of Held.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:19164751
    reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We knocked down complexin expression in cultured cortical neurons using an shRNA that
      targets both complexin-1 and -2, the only complexin isoforms significantly expressed
      in these neurons
    explanation: This is dual complexin-1/2 knockdown in mouse neuronal culture, not a patient-variant experiment.
  - reference: PMID:19164751
    reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The complexin knock-down increased 3-4 fold the frequency of spontaneous miniature excitatory
      postsynaptic currents (mEPSCs), without altering the mEPSC amplitude
    explanation: Spontaneous release increased in the dual-knockdown cortical culture.
  biological_processes:
  - preferred_term: synaptic vesicle exocytosis
    term:
      id: GO:0016079
      label: synaptic vesicle exocytosis
    modifier: INCREASED
- name: Excessive Poststimulus Asynchronous Release
  description: >-
    Single-Cplx1-knockout calyces of Held exhibit excessive delayed asynchronous transmitter
    release following stimulation. This is distinct from resting spontaneous release, which
    is reduced in the same preparation. The proposed instability of newly recruited vesicles
    is a mechanistic interpretation.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:26019341
    reference_title: >-
      Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion
      at the mouse calyx of held synapse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx of
      Held synapse, and discovered a developmentally exacerbating phenotype of reduced spontaneous
      and evoked transmission but excessive asynchronous release after stimulation, compatible
      with combined facilitating and clamping functions of Cplx1.
    explanation: >-
      Single-Cplx1 knockout increases asynchronous transmitter release after stimulation at the mouse
      calyx of Held, while reducing resting spontaneous and evoked transmission.
  - reference: PMID:26019341
    reference_title: >-
      Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion
      at the mouse calyx of held synapse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found further that the excessive asynchronous release in Cplx1-deficient calyces
      triggered aberrant action potentials in their target neurons, and slowed-down the recovery
      of EPSCs after depleting stimuli.
    explanation: >-
      Excess delayed release causes mistimed postsynaptic firing in this model; a human cortical
      mechanism is not established.
  biological_processes:
  - preferred_term: synaptic vesicle exocytosis
    term:
      id: GO:0016079
      label: synaptic vesicle exocytosis
    modifier: DYSREGULATED
  downstream:
  - target: Mistimed Postsynaptic Firing in the Calyx Model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26019341
      reference_title: >-
        Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion
        at the mouse calyx of held synapse.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We found further that the excessive asynchronous release in Cplx1-deficient calyces
        triggered aberrant action potentials in their target neurons, and slowed-down the
        recovery of EPSCs after depleting stimuli.
      explanation: >-
        Excess delayed release causes mistimed postsynaptic firing in this model; a human
        cortical mechanism is not established.
- name: Mistimed Postsynaptic Firing in the Calyx Model
  description: >-
    Excessive asynchronous release triggers aberrant action potentials in postsynaptic target
    neurons of Cplx1-deficient mouse calyces. The auditory brainstem experiment does not demonstrate
    the circuit origin of human cortical seizures.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:26019341
    reference_title: >-
      Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion
      at the mouse calyx of held synapse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found further that the excessive asynchronous release in Cplx1-deficient calyces
      triggered aberrant action potentials in their target neurons, and slowed-down the recovery
      of EPSCs after depleting stimuli.
    explanation: >-
      Excess delayed release causes mistimed postsynaptic firing in this model; a human cortical
      mechanism is not established.
- name: Epileptiform Brain Activity
  description: >-
    Generalized epileptiform EEG activity was documented in the 2017 cases. In patient 3,
    persistent abnormal EEG activity preceded overt clinical seizures. These observations
    establish abnormal brain activity without identifying a specific excitatory/inhibitory
    imbalance.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Electroencephalography (EEG) repeatedly showed generalized epileptiform activity and hyperexcitability.
    explanation: >-
      Repeated EEG in patient 1 documents epileptiform activity; no excitatory/inhibitory
      cell-specific imbalance was measured.
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Beginning from the first months postpartum, EEG revealed marked persistent generalized
      seizure activity despite the absence of overt clinical seizure episodes.
    explanation: >-
      The p.Leu128Met patient had EEG abnormalities before overt seizures; prematurity and
      variant uncertainty limit attribution.
  role: effector
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  downstream:
  - target: Epilepsy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28422131
      reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All displayed marked developmental delay and migrating myoclonic epilepsy, and one
        showed a cerebellar cleft in addition.
      explanation: Clinical findings in the three individuals reported in 2017; this does not estimate population frequency.
phenotypes:
- name: Epilepsy
  category: Clinical
  description: >-
    Migrating myoclonic epilepsy was reported in all three 2017 cases; seizure onset and additional
    seizure types varied.
  phenotype_term:
    preferred_term: Myoclonic seizure
    term:
      id: HP:0032794
      label: Myoclonic seizure
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed
      a cerebellar cleft in addition.
    explanation: >-
      Migrating myoclonic epilepsy was reported in all three 2017 cases; seizure onset and
      additional seizure types varied.
- name: Global Developmental Delay
  category: Clinical
  description: Marked developmental delay was reported in the 2017 series; in patient 3 it preceded overt seizures.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed
      a cerebellar cleft in addition.
    explanation: Marked developmental delay was reported in the 2017 series; in patient 3 it preceded overt seizures.
- name: Intellectual Disability
  category: Clinical
  description: >-
    Intellectual disability was reported in all three 2017 cases. It was not documented in
    the original 2015 sibling report, which does not establish its absence.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: identified homozygous CPLX1 variants in three patients with ID from two unrelated families.
    explanation: >-
      Intellectual disability was reported in all three 2017 cases. It was not documented
      in the original 2015 sibling report, which does not establish its absence.
- name: Epileptic Spasms
  category: Clinical
  description: >-
    Patient 1 developed spasms at six weeks and patient 2 at two and a half months; spasms
    are not established in every case.
  phenotype_term:
    preferred_term: Epileptic spasm
    term:
      id: HP:0011097
      label: Epileptic spasm
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first clinical signs of the disease appeared when she was 6 weeks old. She first
      experienced epileptic spasms.
    explanation: >-
      Patient 1 developed spasms at six weeks and patient 2 at two and a half months; spasms
      are not established in every case.
- name: Tonic Seizures
  category: Clinical
  description: Tonic seizures occurred in patient 3, whose p.Leu128Met attribution remains uncertain.
  phenotype_term:
    preferred_term: Tonic seizure
    term:
      id: HP:0032792
      label: Tonic seizure
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During course of disease, seizures switched to alternately myoclonic, tonic and generalized
      seizures, which occurred >50 times a day.
    explanation: Tonic seizures occurred in patient 3, whose p.Leu128Met attribution remains uncertain.
- name: Generalized Seizures
  category: Clinical
  description: >-
    Generalized epilepsy was diagnosed in patient 1 at three years; generalized seizures were
    also described in patients 2 and 3.
  phenotype_term:
    preferred_term: Generalized-onset seizure
    term:
      id: HP:0002197
      label: Generalized-onset seizure
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Beyond the progressive myoclonic seizures, the diagnosis of generalized epilepsy was
      established at the age of three years.
    explanation: >-
      Generalized epilepsy was diagnosed in patient 1 at three years; generalized seizures
      were also described in patients 2 and 3.
- name: Hypotonia
  category: Clinical
  description: >-
    Marked hypotonia was documented in patient 1; neonatal hypotonia was also described in
    the premature p.Leu128Met patient.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Assessment at age 25/12 years showed massive hypotonia, normal measurements
    explanation: >-
      Marked hypotonia was documented in patient 1; neonatal hypotonia was also described
      in the premature p.Leu128Met patient.
- name: Absent Speech
  category: Clinical
  description: Speech was absent in patient 1 and patient 2 at reported assessments; patient 3 had nearly absent speech.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She was unable to sit unsupported, to crawl or to walk. No head control was achieved. Speech was absent.
    explanation: Speech was absent in patient 1 and patient 2 at reported assessments; patient 3 had nearly absent speech.
- name: Poor Head Control
  category: Clinical
  description: Patient 1 did not achieve head control.
  phenotype_term:
    preferred_term: Poor head control
    term:
      id: HP:0002421
      label: Poor head control
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She was unable to sit unsupported, to crawl or to walk. No head control was achieved.
    explanation: Patient 1 did not achieve head control.
- name: Delayed Sitting
  category: Clinical
  description: >-
    The p.Leu128Met patient sat at 36 months; the two truncating-variant sisters could not
    sit unsupported at their reported assessments.
  phenotype_term:
    preferred_term: Delayed ability to sit
    term:
      id: HP:0025336
      label: Delayed ability to sit
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All milestones of motor and speech development were delayed. He was able to sit at 36
      months and to walk with support at age 6 years.
    explanation: >-
      The p.Leu128Met patient sat at 36 months; the two truncating-variant sisters could not
      sit unsupported at their reported assessments.
- name: Inability to Walk
  category: Clinical
  description: >-
    Patients 1 and 2 could not walk at the reported assessments. Patient 3 later walked with
    support, so inability to walk is not universal.
  phenotype_term:
    preferred_term: Inability to walk
    term:
      id: HP:0002540
      label: Inability to walk
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At physical examination at around 33 months, she was unable to sit unsupported, to crawl,
      to walk and to speak.
    explanation: >-
      Patients 1 and 2 could not walk at the reported assessments. Patient 3 later walked
      with support, so inability to walk is not universal.
- name: Microcephaly
  category: Clinical
  description: >-
    Reduced head circumference was documented at seven years in the p.Leu128Met patient after
    a normal birth head measurement. Prematurity and variant uncertainty complicate attribution.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: height (110–112 cm, −2.68 SD) and OFC (48.5 cm, −3.11 SD) were decreased.
    explanation: >-
      Reduced head circumference was documented at seven years in the p.Leu128Met patient
      after a normal birth head measurement. Prematurity and variant uncertainty complicate
      attribution.
- name: Short Stature
  category: Clinical
  description: >-
    Short stature was documented at seven years in the p.Leu128Met patient; the two sisters
    had normal height at reported examinations.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: height (110–112 cm, −2.68 SD) and OFC (48.5 cm, −3.11 SD) were decreased.
    explanation: >-
      Short stature was documented at seven years in the p.Leu128Met patient; the two sisters
      had normal height at reported examinations.
- name: Low Body Weight
  category: Clinical
  description: Patient 2 had low weight at about 33 months despite normal height and head circumference.
  phenotype_term:
    preferred_term: Decreased body weight
    term:
      id: HP:0004325
      label: Decreased body weight
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: her weight (9.4 kg) diminished relatively (−2.95 SD).
    explanation: Patient 2 had low weight at about 33 months despite normal height and head circumference.
- name: Feeding Difficulties
  category: Clinical
  description: >-
    Patient 3 had neonatal feeding difficulty with no sucking reflex after preterm birth.
    The clinical table also records feeding difficulties in patient 2.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He displayed infant respiratory distress syndrome, hypotonia and feeding difficulties (no sucking reflex).
    explanation: >-
      Patient 3 had neonatal feeding difficulty with no sucking reflex after preterm birth.
      The clinical table also records feeding difficulties in patient 2.
- name: Hypertelorism
  category: Clinical
  description: Hypertelorism was described in the two p.Cys105Ter sisters.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Craniofacial dysmorphisms comprising hypertelorism, bowed eyebrows, flat midface and thin upper lip were noted
    explanation: Hypertelorism was described in the two p.Cys105Ter sisters.
- name: Midface Retrusion
  category: Clinical
  description: A flat midface was described in the two p.Cys105Ter sisters.
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Craniofacial dysmorphisms comprising hypertelorism, bowed eyebrows, flat midface and thin upper lip were noted
    explanation: A flat midface was described in the two p.Cys105Ter sisters.
- name: Thin Upper Lip
  category: Clinical
  description: >-
    A thin upper lip was described in all three 2017 patients; the facial findings are variable
    rather than a validated diagnostic gestalt.
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 1 at the age of 25/12 years with hypertelorism, bowed eyebrows, flat midface,
      long philtrum with thin upper lip and full cheeks.
    explanation: >-
      A thin upper lip was described in all three 2017 patients; the facial findings are variable
      rather than a validated diagnostic gestalt.
- name: Long Philtrum
  category: Clinical
  description: A long philtrum was described in patients 1 and 3.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 1 at the age of 25/12 years with hypertelorism, bowed eyebrows, flat midface,
      long philtrum with thin upper lip and full cheeks.
    explanation: A long philtrum was described in patients 1 and 3.
- name: Full Cheeks
  category: Clinical
  description: Full cheeks were described in patient 1.
  phenotype_term:
    preferred_term: Full cheeks
    term:
      id: HP:0000293
      label: Full cheeks
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 1 at the age of 25/12 years with hypertelorism, bowed eyebrows, flat midface,
      long philtrum with thin upper lip and full cheeks.
    explanation: Full cheeks were described in patient 1.
- name: Bulbous Nasal Tip
  category: Clinical
  description: >-
    A bulbous nasal tip was described in patient 3; this single observation does not establish
    a characteristic feature of confirmed CPLX1 disease.
  phenotype_term:
    preferred_term: Bulbous nose
    term:
      id: HP:0000414
      label: Bulbous nose
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 3 at the age of seven years with marked eyebrows, large nose with bulbous tip,
      long philtrum with thin upper lip.
    explanation: >-
      A bulbous nasal tip was described in patient 3; this single observation does not establish
      a characteristic feature of confirmed CPLX1 disease.
- name: Cerebral Cortical Atrophy
  category: Clinical
  description: >-
    Cortical atrophy occurred in the original p.Glu108Ter siblings. It was absent on reported
    scans of all three 2017 patients.
  phenotype_term:
    preferred_term: Cerebral cortical atrophy
    term:
      id: HP:0002120
      label: Cerebral cortical atrophy
  evidence:
  - reference: PMID:26539891
    reference_title: >-
      Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of
      Mendelian Neurologic Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a homozygous nonsense mutation (NM_006651:c.G322T:p.E108X) in the CPLX1
      gene in two female siblings, BAB6167 and BAB6168, who presented with malignant migrating
      epilepsy and cortical atrophy.
    explanation: >-
      Cortical atrophy occurred in the original p.Glu108Ter siblings. It was absent on reported
      scans of all three 2017 patients.
- name: Cleft Palate
  category: Clinical
  description: Cleft palate was recorded only in patient 3 in Table 1; attribution to p.Leu128Met remains uncertain.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: url:https://push-zb.helmholtz-munich.de/deliver.php?id=18934
    reference_title: https://push-zb.helmholtz-munich.de/deliver.php?id=18934
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft palate −− + Internal abnormalities −−− Bilateral conductive hearing loss −− +
      Myopia −− + Strabismus −− + Hypothyreosis − + − Brain abnormalities Unilateral cerebellar
      cleft −−
    explanation: >-
      Cleft palate was recorded only in patient 3 in Table 1; attribution to p.Leu128Met remains
      uncertain. Table 1 columns are patient 1, patient 2 and patient 3; plus and minus denote
      presence and absence.
- name: Conductive Hearing Impairment
  category: Clinical
  description: >-
    Bilateral conductive hearing loss was recorded in patient 3; this is a case-level association
    with disputed p.Leu128Met.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: url:https://push-zb.helmholtz-munich.de/deliver.php?id=18934
    reference_title: https://push-zb.helmholtz-munich.de/deliver.php?id=18934
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft palate −− + Internal abnormalities −−− Bilateral conductive hearing loss −− +
      Myopia −− + Strabismus −− + Hypothyreosis − + − Brain abnormalities Unilateral cerebellar
      cleft −−
    explanation: >-
      Bilateral conductive hearing loss was recorded in patient 3; this is a case-level association
      with disputed p.Leu128Met. Table 1 columns are patient 1, patient 2 and patient 3; plus
      and minus denote presence and absence.
- name: Myopia
  category: Clinical
  description: Myopia was recorded in patient 3, with uncertain attribution to p.Leu128Met.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: url:https://push-zb.helmholtz-munich.de/deliver.php?id=18934
    reference_title: https://push-zb.helmholtz-munich.de/deliver.php?id=18934
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft palate −− + Internal abnormalities −−− Bilateral conductive hearing loss −− +
      Myopia −− + Strabismus −− + Hypothyreosis − + − Brain abnormalities Unilateral cerebellar
      cleft −−
    explanation: >-
      Myopia was recorded in patient 3, with uncertain attribution to p.Leu128Met. Table 1
      columns are patient 1, patient 2 and patient 3; plus and minus denote presence and absence.
- name: Strabismus
  category: Clinical
  description: Strabismus was recorded in patient 3, with uncertain attribution to p.Leu128Met.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: url:https://push-zb.helmholtz-munich.de/deliver.php?id=18934
    reference_title: https://push-zb.helmholtz-munich.de/deliver.php?id=18934
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft palate −− + Internal abnormalities −−− Bilateral conductive hearing loss −− +
      Myopia −− + Strabismus −− + Hypothyreosis − + − Brain abnormalities Unilateral cerebellar
      cleft −−
    explanation: >-
      Strabismus was recorded in patient 3, with uncertain attribution to p.Leu128Met. Table
      1 columns are patient 1, patient 2 and patient 3; plus and minus denote presence and
      absence.
- name: Hypothyroidism
  category: Clinical
  description: >-
    Hypothyroidism was recorded in patient 2 carrying p.Cys105Ter; prevalence and causal relationship
    are not established.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: url:https://push-zb.helmholtz-munich.de/deliver.php?id=18934
    reference_title: https://push-zb.helmholtz-munich.de/deliver.php?id=18934
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft palate −− + Internal abnormalities −−− Bilateral conductive hearing loss −− +
      Myopia −− + Strabismus −− + Hypothyreosis − + − Brain abnormalities Unilateral cerebellar
      cleft −−
    explanation: >-
      Hypothyroidism was recorded in patient 2 carrying p.Cys105Ter; prevalence and causal
      relationship are not established. Table 1 columns are patient 1, patient 2 and patient
      3; plus and minus denote presence and absence.
- name: Cerebellar Cleft
  category: Clinical
  description: >-
    Patient 1 had a small left cerebellar lobule VIII cleft with abnormal folial orientation.
    The authors considered a coincidental prenatal disruptive lesion possible; this is not
    a defining malformation.
  phenotype_term:
    preferred_term: Cleft of cerebellar lobule VIII
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI of the brain performed at age 12, 24 and 36 months showed a small cleft of lobule
      VIII of the left cerebellar hemisphere with malorientation of the adjacent cerebellar
      folia
    explanation: Serial MRI documents the localized cleft; it does not demonstrate causation by CPLX1.
- name: Cerebral Palsy
  category: Clinical
  description: >-
    Cerebral palsy was described in the premature p.Leu128Met patient. The contribution of
    CPLX1 remains uncertain because of both variant interpretation and perinatal factors.
  phenotype_term:
    preferred_term: Cerebral palsy
    term:
      id: HP:0100021
      label: Cerebral palsy
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He experienced cerebral movement disorder and cerebral palsy.
    explanation: A case-specific motor diagnosis in patient 3, not proof of a uniform CPLX1 phenotype.
- name: Choreoathetosis in the iPSC Donor
  category: Clinical
  description: >-
    Choreoathetotic movements were reported in the donor carrying homozygous CPLX1 p.Glu2Lys
    and a heterozygous SCN9A deletion. Attribution to CPLX1 alone is unestablished.
  phenotype_term:
    preferred_term: Choreoathetosis
    term:
      id: HP:0001266
      label: Choreoathetosis
  evidence:
  - reference: DOI:10.1007/s13577-023-01016-z
    reference_title: >-
      Generation of iPSC lines (KAIMRCi003A, KAIMRCi003B) from a Saudi patient with Dravet
      syndrome carrying homozygous mutation in the CPLX1 gene and heterozygous mutation in
      SCN9A
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 7-year-old female patient was diagnosed with global developmental delay, seizers
      since in infancy, and choreo- athetotic movements.
    explanation: This is the donor-specific clinical description; the co-occurring SCN9A variant limits causal attribution.
genetic:
- name: CPLX1
  gene_term:
    preferred_term: CPLX1
    term:
      id: hgnc:2309
      label: CPLX1
  association: Biallelic variants associated with developmental and epileptic encephalopathy
  presence: Positive
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    description: >-
      Homozygous CPLX1 variants were identified in affected children of consanguineous families;
      the 2017 parents were unaffected heterozygotes. Confidence in disease attribution remains
      allele dependent.
    evidence:
    - reference: PMID:28422131
      reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        WES detected the homozygous nonsense variant chr4:g.786591G>T (GRCh38/hg38); NM_006651.2:c.315C>A;
        NP_006642.1:p.(Cys105Ter) in Exon 4 of CPLX1 in the affected sisters. The unaffected
        parents were found to be heterozygous for this variant.
      explanation: >-
        The two affected sisters carry a C-terminal stop variant; protein abundance and patient-neuron
        release were not measured.
    - reference: PMID:26539891
      reference_title: >-
        Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses
        of Mendelian Neurologic Disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified a homozygous nonsense mutation (NM_006651:c.G322T:p.E108X) in the CPLX1
        gene in two female siblings, BAB6167 and BAB6168, who presented with malignant migrating
        epilepsy and cortical atrophy.
      explanation: The 2015 sibling pair had homozygous p.Glu108Ter, migrating epilepsy and cortical atrophy.
  notes: >-
    Two C-terminal nonsense alleles have been reported in sibling pairs. The p.Leu128Met missense
    allele has conflicting ClinVar interpretations, and p.Glu2Lys was reported with a co-occurring
    SCN9A deletion in an iPSC donor. Neither missense allele has a demonstrated CPLX1-specific
    neuronal defect in these reports.
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES detected the homozygous nonsense variant chr4:g.786591G>T (GRCh38/hg38); NM_006651.2:c.315C>A;
      NP_006642.1:p.(Cys105Ter) in Exon 4 of CPLX1 in the affected sisters. The unaffected
      parents were found to be heterozygous for this variant.
    explanation: >-
      The two affected sisters carry a C-terminal stop variant; protein abundance and patient-neuron
      release were not measured.
  - reference: PMID:26539891
    reference_title: >-
      Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of
      Mendelian Neurologic Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a homozygous nonsense mutation (NM_006651:c.G322T:p.E108X) in the CPLX1
      gene in two female siblings, BAB6167 and BAB6168, who presented with malignant migrating
      epilepsy and cortical atrophy.
    explanation: The 2015 sibling pair had homozygous p.Glu108Ter, migrating epilepsy and cortical atrophy.
  relationship_type: CAUSATIVE
  variants:
  - name: NM_006651.2:c.315C>A (p.Cys105Ter)
    description: >-
      Homozygous C-terminal stop variant in the two 2017 sisters; healthy parents were heterozygous.
      Total protein absence was not assayed.
    gene:
      preferred_term: CPLX1
      term:
        id: hgnc:2309
        label: CPLX1
    variant_type: single nucleotide variant
    evidence:
    - reference: PMID:28422131
      reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        WES detected the homozygous nonsense variant chr4:g.786591G>T (GRCh38/hg38); NM_006651.2:c.315C>A;
        NP_006642.1:p.(Cys105Ter) in Exon 4 of CPLX1 in the affected sisters. The unaffected
        parents were found to be heterozygous for this variant.
      explanation: >-
        The two affected sisters carry a C-terminal stop variant; protein abundance and patient-neuron
        release were not measured.
  - name: NM_006651:c.322G>T (p.Glu108Ter)
    description: Homozygous nonsense allele reported in the original two siblings with migrating epilepsy and cortical atrophy.
    gene:
      preferred_term: CPLX1
      term:
        id: hgnc:2309
        label: CPLX1
    variant_type: single nucleotide variant
    evidence:
    - reference: PMID:26539891
      reference_title: >-
        Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses
        of Mendelian Neurologic Disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified a homozygous nonsense mutation (NM_006651:c.G322T:p.E108X) in the CPLX1
        gene in two female siblings, BAB6167 and BAB6168, who presented with malignant migrating
        epilepsy and cortical atrophy.
      explanation: The 2015 sibling pair had homozygous p.Glu108Ter, migrating epilepsy and cortical atrophy.
  - name: NM_006651.2:c.382C>A (p.Leu128Met)
    description: >-
      Homozygous in patient 3, born prematurely. ClinVar VCV000523650.12 has conflicting classifications:
      one likely pathogenic and three uncertain-significance submissions contributing to the
      aggregate. Functional loss has not been demonstrated.
    gene:
      preferred_term: CPLX1
      term:
        id: hgnc:2309
        label: CPLX1
    variant_type: single nucleotide variant
    evidence:
    - reference: PMID:28422131
      reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        WES identified homozygosity for the variant chr4:g.786,524G>T (GRCh38/hg38); NM_006651.2:c.382C>A;
        NP_006642.1:p.(Leu128Met) in exon 4 of CLPX1 in the patient and heterozygosity in
        the unaffected parents.
      explanation: >-
        The article reports the missense allele and segregation, but no patient functional
        assay; CLPX1 is a source typographical error.
    - reference: url:https://www.ncbi.nlm.nih.gov/clinvar/variation/523650/
      reference_title: VCV000523650.12 - ClinVar - NCBI
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Likely pathogenic (1); Uncertain significance (3)
      explanation: >-
        ClinVar VCV000523650.12 reports conflicting classifications: one likely pathogenic
        and three uncertain-significance submissions contributing to the aggregate.
  - name: NM_006651.4:c.4G>A (p.Glu2Lys)
    description: >-
      Homozygous variant in a patient labelled as having Dravet syndrome, with heterozygous
      SCN9A c.3332_3346del (p.Ser1111_Glu1115del). Attribution to CPLX1 alone and the functional
      effect remain unresolved.
    gene:
      preferred_term: CPLX1
      term:
        id: hgnc:2309
        label: CPLX1
    variant_type: single nucleotide variant
    evidence:
    - reference: DOI:10.1007/s13577-023-01016-z
      reference_title: >-
        Generation of iPSC lines (KAIMRCi003A, KAIMRCi003B) from a Saudi patient with Dravet
        syndrome carrying homozygous mutation in the CPLX1 gene and heterozygous mutation
        in SCN9A
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Further analysis unraveled homozygous variant c.4G > A p.(Glu2Lys) in the CPLX1 gene.
        This variant leads to an amino acid exchange in exon 1 (NM_006651.4).
      explanation: >-
        The donor carried homozygous p.Glu2Lys as well as a heterozygous SCN9A deletion; this
        establishes the genotype, not single-gene causation.
diagnosis:
- name: CPLX1 Molecular Diagnosis
  description: >-
    Exome sequencing with segregation analysis identified the reported homozygous variants.
    Diagnosis requires phenotype-aware pathogenicity assessment; homozygosity for an uncertain
    missense allele alone is insufficient.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: CPLX1
        term:
          id: hgnc:2309
          label: CPLX1
  results: >-
    Biallelic pathogenic or likely pathogenic CPLX1 variants support diagnosis in the appropriate
    phenotype; interpret uncertain variants and competing genetic findings separately.
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we performed trio-based WES in 311 patients with unsolved ID and additional clinical
      features, and identified homozygous CPLX1 variants in three patients
    explanation: Whole-exome sequencing established the molecular diagnosis of homozygous CPLX1 variants.
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Trio-based WES was performed as described in Kuechler et al.7 and Sanger sequencing
      was performed to verify the variants and to perform segregation analysis
    explanation: The clinical study used exome sequencing, Sanger confirmation and family segregation.
- name: Electroencephalography
  description: EEG characterizes epileptiform activity and may be abnormal before overt seizures, as in patient 3.
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Electroencephalography (EEG) repeatedly showed generalized epileptiform activity and hyperexcitability.
    explanation: >-
      Repeated EEG in patient 1 documents epileptiform activity; no excitatory/inhibitory
      cell-specific imbalance was measured.
  diagnosis_term:
    preferred_term: Electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
- name: Brain MRI
  description: >-
    MRI may show cortical atrophy or a localized cerebellar cleft, but normal imaging was
    reported in patients 2 and 3 and does not exclude the disorder.
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An MRI scan of the brain at around 17 months of age was normal and no cortical atrophy was noted.
    explanation: Patient 3 had normal MRI despite developmental impairment and epilepsy.
  - reference: PMID:26539891
    reference_title: >-
      Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of
      Mendelian Neurologic Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a homozygous nonsense mutation (NM_006651:c.G322T:p.E108X) in the CPLX1
      gene in two female siblings, BAB6167 and BAB6168, who presented with malignant migrating
      epilepsy and cortical atrophy.
    explanation: The 2015 sibling pair had homozygous p.Glu108Ter, migrating epilepsy and cortical atrophy.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
differential_diagnoses:
- name: Other causes of epilepsy of infancy with migrating focal seizures
  description: >-
    Migrating seizures of infancy are genetically heterogeneous (e.g. KCNT1, SCN2A); CPLX1
    disease is distinguished by biallelic pathogenic CPLX1 variants and the recessive inheritance.
  distinguishing_features:
  - Biallelic pathogenic CPLX1 variants favor this disorder.
  - A variant in another migrating-seizure gene (e.g. KCNT1) favors that diagnosis.
  evidence:
  - reference: PMID:35715422
    reference_title: >-
      Analysis of clinical phenotypic and genotypic spectra in 36 children patients with Epilepsy
      of Infancy with Migrating Focal Seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      17/36 cases had causative variants across 11 genes, including 6 novel EIMFS genes: PCDH19,
      ALDH7A1, DOCK6, PRRT2, ALG1 and ATP7A.
    explanation: >-
      Documents the genetic heterogeneity of migrating focal seizures of infancy, which is
      why molecular testing is required to separate these causes from CPLX1 disease.
- name: Other synaptic vesicle cycle disorders
  description: >-
    Other synaptic vesicle cycle / SNAREopathy disorders (STXBP1, SNAP25, STX1B, VAMP2, SYT1)
    overlap through early-onset epilepsy and developmental impairment and are distinguished
    by molecular testing.
  distinguishing_features:
  - Biallelic pathogenic CPLX1 variants favor this disorder.
  - A variant in another vesicle-cycle gene favors the corresponding disorder.
  evidence:
  - reference: PMID:32559416
    reference_title: 'SNAREopathies: Diversity in Mechanisms and Symptoms.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Human pathogenic mutations have now been reported for all eight core components, but
      patients are diagnosed with very different neurodevelopmental syndromes.
    explanation: >-
      Establishes that every core component of the fusion machine carries pathogenic human
      variants presenting as distinct neurodevelopmental syndromes, which is why these disorders
      sit on the differential for each other and are separated by molecular testing.
animal_models:
- name: 'Cplx1 knockout mouse: brain anatomy'
  species: Mouse (Mus musculus)
  genotype: Homozygous Cplx1 knockout
  description: >-
    Cplx1 knockout mice show early ataxia, selective thalamic and cerebellar volume loss, molecular-layer
    atrophy and loss of granule cells in selected cerebellar lobules. The structural phenotype was nonprogressive
    across the sampled ages. Neuronal loss was not detected in the molecular layer. These anatomical findings
    are not uniform human disease features.
  modeled_mechanisms:
  - target: Complexin-1 Loss of Function
    relationship: PERTURBS
    description: Genetic deletion permits assessment of the neurological consequences of complexin-1 loss.
    fidelity: UNKNOWN
    limitations: >-
      Whole-gene mouse knockout differs from human C-terminal and missense alleles; anatomy
      does not establish the human seizure mechanism.
    evidence:
    - reference: PMID:22393426
      reference_title: Tensor-based morphometry and stereology reveal brain pathology in the complexin1 knockout mouse.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Finally, stereology was used to show that there was loss of cerebellar granule cells
        in Cplx1(-/-) mice when compared to Cplx1(+/+) animals.
      explanation: >-
        The primary study reports granule-cell loss; its negative neuronal-loss result is
        restricted to the molecular layer.
  evidence:
  - reference: PMID:22393426
    reference_title: Tensor-based morphometry and stereology reveal brain pathology in the complexin1 knockout mouse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Finally, stereology was used to show that there was loss of cerebellar granule cells
      in Cplx1(-/-) mice when compared to Cplx1(+/+) animals.
    explanation: >-
      The primary study reports granule-cell loss; its negative neuronal-loss result is restricted
      to the molecular layer.
  - reference: PMID:22393426
    reference_title: Tensor-based morphometry and stereology reveal brain pathology in the complexin1 knockout mouse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: This suggests that, as with the behavioural phenotype, the pathological phenotype is non-progressive.
    explanation: The early/late cross-sectional comparison supports nonprogressive structural changes in this mouse model.
- name: 'Cplx1 knockout mouse: calyx of Held'
  species: Mouse (Mus musculus)
  genotype: Homozygous Cplx1 knockout
  description: >-
    Acute brainstem slices reveal developmentally worsening loss of evoked and resting spontaneous
    transmission, but excessive poststimulus asynchronous release. Calcium influx, readily
    releasable pool size and quantal size were preserved. Elevated extracellular calcium rescued
    aspects of evoked release experimentally but is not a tested human therapy.
  modeled_mechanisms:
  - target: Reduced Evoked Synaptic Vesicle Release
    relationship: MEASURES
    description: Evoked EPSCs are reduced after maturation.
    fidelity: UNKNOWN
    limitations: Patient-variant neuronal physiology has not been established.
    evidence:
    - reference: PMID:26019341
      reference_title: >-
        Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion
        at the mouse calyx of held synapse.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx
        of Held synapse, and discovered a developmentally exacerbating phenotype of reduced
        spontaneous and evoked transmission but excessive asynchronous release after stimulation,
        compatible with combined facilitating and clamping functions of Cplx1.
      explanation: >-
        Single-Cplx1 knockout reduces evoked transmission at the mouse calyx of Held. This is a native
        synapse model, not a measurement in affected children.
  - target: Excessive Poststimulus Asynchronous Release
    relationship: MEASURES
    description: Delayed asynchronous release is increased after stimulation.
    fidelity: UNKNOWN
    limitations: Patient-variant neuronal physiology has not been established.
    evidence:
    - reference: PMID:26019341
      reference_title: >-
        Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion
        at the mouse calyx of held synapse.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx
        of Held synapse, and discovered a developmentally exacerbating phenotype of reduced
        spontaneous and evoked transmission but excessive asynchronous release after stimulation,
        compatible with combined facilitating and clamping functions of Cplx1.
      explanation: >-
        Single-Cplx1 knockout increases asynchronous transmitter release after stimulation at the mouse
        calyx of Held, while reducing resting spontaneous and evoked transmission.
  - target: Mistimed Postsynaptic Firing in the Calyx Model
    relationship: MEASURES
    description: Asynchronous release triggers aberrant postsynaptic action potentials.
    fidelity: UNKNOWN
    limitations: Patient-variant neuronal physiology has not been established.
    evidence:
    - reference: PMID:26019341
      reference_title: >-
        Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion
        at the mouse calyx of held synapse.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We found further that the excessive asynchronous release in Cplx1-deficient calyces
        triggered aberrant action potentials in their target neurons, and slowed-down the
        recovery of EPSCs after depleting stimuli.
      explanation: >-
        Excess delayed release causes mistimed postsynaptic firing in this model; a human
        cortical mechanism is not established.
  evidence:
  - reference: PMID:26019341
    reference_title: >-
      Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion
      at the mouse calyx of held synapse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx of
      Held synapse, and discovered a developmentally exacerbating phenotype of reduced spontaneous
      and evoked transmission but excessive asynchronous release after stimulation, compatible
      with combined facilitating and clamping functions of Cplx1.
    explanation: >-
      Single-gene knockout at a native auditory brainstem synapse reduces resting spontaneous
      release, unlike dual-knockdown cortical cultures.
  - reference: PMID:26019341
    reference_title: >-
      Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion
      at the mouse calyx of held synapse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found further that the excessive asynchronous release in Cplx1-deficient calyces
      triggered aberrant action potentials in their target neurons, and slowed-down the recovery
      of EPSCs after depleting stimuli.
    explanation: >-
      Excess delayed release causes mistimed postsynaptic firing in this model; a human cortical
      mechanism is not established.
progression:
- phase: Variable seizure onset and severe developmental impairment
  notes: >-
    In the 2017 series, the two sisters developed spasms in early infancy. Patient 3 had EEG
    abnormalities in infancy but first overt seizures at two years; developmental impairment
    preceded those seizures. This case also had prematurity and a disputed missense allele.
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first clinical signs of the disease appeared when she was 6 weeks old. She first
      experienced epileptic spasms.
    explanation: Patient 1 had early infantile onset.
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The first seizure event was recognized in a non-febrile context at 2 years.
    explanation: Patient 3 had later overt seizure onset.
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: patient 3 showed ID and developmental delay before onset of epilepsy.
    explanation: Developmental impairment cannot all be assigned as a consequence of overt seizures.
- phase: Severe outcomes reported in individual cases
  notes: >-
    Patient 1 died at eight years, probably during a seizure in sleep. This single observation
    does not establish a general survival estimate or a definitive cause-of-death diagnosis.
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She passed away at 8 years of age most likely due to a severe seizure episode during sleep.
    explanation: The probable cause was reported clinically, not established as definite SUDEP.
treatments:
- name: Antiseizure Medication
  description: >-
    Antiseizure medications were used, but all three 2017 patients had persistent seizures
    despite treatment. The report does not identify the individual agents, so no drug-specific
    efficacy is established.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Seizures were pharmacoresistant and did not respond to ketogenic diet.
    explanation: Patient 1 had drug-resistant epilepsy.
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Epilepsy did not respond to antiepileptic drugs.
    explanation: Patient 2 did not respond to antiseizure medication.
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Treatment with distinct anticonvulsants showed no improvement of patient’s clinical signs.
    explanation: Patient 3 did not improve with the anticonvulsants tried; agents were unnamed.
  target_phenotypes:
  - preferred_term: Epilepsy
    term:
      id: HP:0032794
      label: Myoclonic seizure
- name: Ketogenic Diet
  description: >-
    A ketogenic diet was tried in patient 1 without seizure response. The report does not
    establish benefit in CPLX1 disease.
  target_phenotypes:
  - preferred_term: Epilepsy
    term:
      id: HP:0032794
      label: Myoclonic seizure
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Seizures were pharmacoresistant and did not respond to ketogenic diet.
    explanation: Direct evidence of nonresponse in patient 1; not a general efficacy estimate.
  treatment_term:
    preferred_term: Ketogenic Diet
    term:
      id: NCIT:C173168
      label: Ketogenic Diet
- name: Supportive and Developmental Care
  description: >-
    Developmental, motor, communication and feeding support are reasonable individualized
    responses to the documented disabilities. The cited report describes needs rather than
    a tested CPLX1-specific rehabilitation regimen.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed
      a cerebellar cleft in addition.
    explanation: Developmental impairment motivates supportive care by clinical inference; the study did not test its efficacy.
- name: Genetic Counseling
  description: >-
    Counseling addresses recessive inheritance and allele-specific uncertainty. When both
    parents carry the same established pathogenic allele, the Mendelian expectation is a 25%
    chance of an affected homozygous child per pregnancy; this is an inheritance calculation,
    not an observed recurrence estimate from this small series.
  evidence:
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES detected the homozygous nonsense variant chr4:g.786591G>T (GRCh38/hg38); NM_006651.2:c.315C>A;
      NP_006642.1:p.(Cys105Ter) in Exon 4 of CPLX1 in the affected sisters. The unaffected
      parents were found to be heterozygous for this variant.
    explanation: >-
      Affected homozygous sisters and unaffected heterozygous parents support recessive segregation.
      The recurrence probability is derived under the stated pathogenic-allele assumption.
    directness: INDIRECT
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
discussions:
- discussion_id: gap_cplx1_clamp_versus_facilitator_dominant_lesion
  prompt: >-
    Complexin-1 both clamps spontaneous vesicle fusion and facilitates fast calcium-evoked
    release; which arm of this dual function, when lost in CPLX1 disease, dominates the pathogenic
    synaptic defect — disinhibited spontaneous release, failed evoked release, or both?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Evoked Synaptic Vesicle Release
  rationale: >-
    Evoked-release impairment is shared across dual-knockdown cortical cultures and single-knockout
    calyces, whereas resting spontaneous release changes in opposite directions. Poststimulus
    asynchronous release is a separate defect. The dominant lesion in patient-variant human
    neurons and its contribution to epilepsy remain unresolved. Available p.Glu2Lys iPSCs
    also carry an SCN9A deletion and have not yet supplied neuronal functional data.
  evidence:
  - reference: PMID:19164751
    reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In contrast, the complexin knock-down decreased 3-4 fold the amplitude of excitatory
      postsynaptic currents (EPSCs) evoked by isolated action potentials
    explanation: Evoked release was reduced in the dual-knockdown cortical culture.
  - reference: PMID:19164751
    reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The complexin knock-down increased 3-4 fold the frequency of spontaneous miniature excitatory
      postsynaptic currents (mEPSCs), without altering the mEPSC amplitude
    explanation: Spontaneous release increased in the dual-knockdown cortical culture.
  - reference: PMID:26019341
    reference_title: >-
      Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion
      at the mouse calyx of held synapse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx of
      Held synapse, and discovered a developmentally exacerbating phenotype of reduced spontaneous
      and evoked transmission but excessive asynchronous release after stimulation, compatible
      with combined facilitating and clamping functions of Cplx1.
    explanation: >-
      Single-gene knockout at a native auditory brainstem synapse reduces resting spontaneous
      release, unlike dual-knockdown cortical cultures.
  - reference: DOI:10.1007/s13577-023-01016-z
    reference_title: >-
      Generation of iPSC lines (KAIMRCi003A, KAIMRCi003B) from a Saudi patient with Dravet
      syndrome carrying homozygous mutation in the CPLX1 gene and heterozygous mutation in
      SCN9A
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we established two DRVT-iPSC lines harboring a homozygous mutation in the CPLX1
      gene and heterozygous mutation in SCN9A gene.
    explanation: Two iPSC clones were derived from one donor carrying both variants; this is a resource-generation result.
  proposed_experiments:
  - experiment_id: exp_cplx1_spontaneous_versus_evoked_release_dissection
    name: CPLX1-null human neuron spontaneous-versus-evoked release dissection
    description: >-
      In CPLX1-null human iPSC-derived neurons, quantify spontaneous (miniature) release frequency
      and fast calcium-evoked release amplitude, then rescue with wild-type complexin-1 versus
      separation-of-function mutants that selectively restore clamping or facilitation, to
      attribute the pathogenic defect to a specific arm.
    experiment_type:
      preferred_term: electrophysiological release-mode dissection experiment
    perturbations:
    - name: CPLX1 knockout and separation-of-function rescue
      target: pathophysiology#Reduced Evoked Synaptic Vesicle Release
      genes:
      - preferred_term: CPLX1
        term:
          id: hgnc:2309
          label: CPLX1
      description: >-
        Compare CPLX1-null neurons rescued with wild-type complexin-1 versus clamp-selective
        or facilitation-selective complexin-1 variants.
    readouts:
    - name: Spontaneous and evoked release readouts
      target: pathophysiology#Reduced Evoked Synaptic Vesicle Release
      biological_processes:
      - preferred_term: synaptic vesicle exocytosis
        term:
          id: GO:0016079
          label: synaptic vesicle exocytosis
        modifier: DYSREGULATED
      - preferred_term: calcium-dependent activation of synaptic vesicle fusion
        term:
          id: GO:0099502
          label: calcium-dependent activation of synaptic vesicle fusion
        modifier: DYSREGULATED
      assays:
      - preferred_term: patch-clamp electrophysiology
      direction: POSITIVE
    controls:
    - name: Wild-type complexin-1 rescue
      description: CPLX1-null neurons rescued with wild-type human complexin-1.
    - name: Isogenic wild-type neurons
      description: Isogenic CPLX1-intact neurons from the same iPSC background.
    decision_criterion: >-
      The clamp arm dominates if the pathogenic defect is a selective rise in spontaneous
      release rescued only by clamp-competent complexin-1; the facilitator arm dominates if
      the defect is a selective loss of evoked release rescued only by facilitation-competent
      complexin-1.
    would_support:
    - pathophysiology#Reduced Evoked Synaptic Vesicle Release
- discussion_id: gap_cplx1_phenotype_boundary_dee_versus_neurodegeneration
  prompt: >-
    Is biallelic CPLX1 loss best defined as a developmental and epileptic encephalopathy,
    as a progressive neurodegenerative/movement disorder, or as a single spectrum encompassing
    both — and what determines which phenotype predominates in a given patient?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Complexin-1 Loss of Function
  - pathophysiology#Epileptiform Brain Activity
  rationale: >-
    The original p.Glu108Ter siblings had cortical atrophy, whereas the 2017 cases did not.
    One later case had a localized cerebellar cleft that may be coincidental. Mouse thalamic/cerebellar
    changes and granule-cell loss were nonprogressive across sampled ages; they do not establish
    human neurodegeneration. Small case numbers and uncertain missense attribution limit genotype-phenotype
    conclusions.
  evidence:
  - reference: PMID:26539891
    reference_title: >-
      Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of
      Mendelian Neurologic Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a homozygous nonsense mutation (NM_006651:c.G322T:p.E108X) in the CPLX1
      gene in two female siblings, BAB6167 and BAB6168, who presented with malignant migrating
      epilepsy and cortical atrophy.
    explanation: The 2015 sibling pair had homozygous p.Glu108Ter, migrating epilepsy and cortical atrophy.
  - reference: PMID:28422131
    reference_title: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed
      a cerebellar cleft in addition.
    explanation: Clinical findings in the three individuals reported in 2017; this does not estimate population frequency.
  - reference: PMID:22393426
    reference_title: Tensor-based morphometry and stereology reveal brain pathology in the complexin1 knockout mouse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Finally, stereology was used to show that there was loss of cerebellar granule cells
      in Cplx1(-/-) mice when compared to Cplx1(+/+) animals.
    explanation: >-
      The primary study reports granule-cell loss; its negative neuronal-loss result is restricted
      to the molecular layer.
  proposed_experiments:
  - experiment_id: exp_cplx1_natural_history_genotype_phenotype_cohort
    name: CPLX1 natural-history and genotype-phenotype cohort
    description: >-
      Assemble an international cohort of biallelic CPLX1 cases with standardized longitudinal
      phenotyping (seizure semiology and course, motor/movement features, developmental trajectory,
      and serial neuroimaging) to test whether epileptic and neurodegenerative/movement features
      co-segregate or define distinct subgroups, and whether variant class predicts phenotype.
    experiment_type:
      preferred_term: natural-history cohort study
    readouts:
    - name: Longitudinal phenotype and course readouts
      target: pathophysiology#Epileptiform Brain Activity
      biological_processes:
      - preferred_term: chemical synaptic transmission
        term:
          id: GO:0007268
          label: chemical synaptic transmission
        modifier: ABNORMAL
      assays:
      - preferred_term: electroencephalography
      - preferred_term: magnetic resonance imaging
      direction: POSITIVE
    controls:
    - name: Other synaptic vesicle cycle disorders
      description: >-
        Comparison cohorts with STXBP1, SNAP25, STX1B, or SYT1 disorders to contextualize
        the CPLX1 phenotype spectrum.
    decision_criterion: >-
      A unified spectrum is supported if epileptic and movement/neurodegenerative features
      consistently co-occur across cases; a split is supported if distinct, variant-correlated
      subgroups emerge.
    would_support:
    - pathophysiology#Epileptiform Brain Activity
- discussion_id: gap_cplx1_mouse_model_fidelity_to_human_encephalopathy
  prompt: >-
    How faithfully does the Cplx1-knockout mouse — dominated by ataxia and a movement phenotype
    with variable seizures — model the human CPLX1 epileptic encephalopathy, versus mainly
    recapitulating the motor arm of the disease?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Epileptiform Brain Activity
  rationale: >-
    Cplx1 knockout produces prominent mouse motor and cerebellar abnormalities, and native
    calyx experiments demonstrate disrupted release timing. Correspondence to the human cortical
    seizure mechanism remains unknown. Neither whole-gene knockout nor dual-isoform knockdown
    directly models the function of the reported human C-terminal or missense alleles.
  evidence:
  - reference: PMID:22393426
    reference_title: Tensor-based morphometry and stereology reveal brain pathology in the complexin1 knockout mouse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Finally, stereology was used to show that there was loss of cerebellar granule cells
      in Cplx1(-/-) mice when compared to Cplx1(+/+) animals.
    explanation: >-
      The primary study reports granule-cell loss; its negative neuronal-loss result is restricted
      to the molecular layer.
  - reference: PMID:26019341
    reference_title: >-
      Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion
      at the mouse calyx of held synapse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx of
      Held synapse, and discovered a developmentally exacerbating phenotype of reduced spontaneous
      and evoked transmission but excessive asynchronous release after stimulation, compatible
      with combined facilitating and clamping functions of Cplx1.
    explanation: >-
      Single-gene knockout at a native auditory brainstem synapse reduces resting spontaneous
      release, unlike dual-knockdown cortical cultures.
  proposed_experiments:
  - experiment_id: exp_cplx1_cross_species_network_excitability_comparison
    name: CPLX1 cross-species network-excitability comparison
    description: >-
      Directly compare cortical network excitability and seizure-like activity between Cplx1-knockout
      mouse cortical preparations and human CPLX1-null iPSC-derived cortical neurons/organoids,
      to test whether the human cortical hyperexcitability phenotype is reproduced by the
      mouse or is human-specific.
    experiment_type:
      preferred_term: cross-species network-excitability comparison
    perturbations:
    - name: CPLX1 loss of function across species
      target: pathophysiology#Epileptiform Brain Activity
      genes:
      - preferred_term: CPLX1
        term:
          id: hgnc:2309
          label: CPLX1
      description: Cplx1-knockout mouse cortex versus isogenic human CPLX1-null cortical neurons/organoids.
    readouts:
    - name: Network hyperexcitability readouts
      target: pathophysiology#Epileptiform Brain Activity
      biological_processes:
      - preferred_term: trans-synaptic signaling
        term:
          id: GO:0099537
          label: trans-synaptic signaling
        modifier: DYSREGULATED
      - preferred_term: chemical synaptic transmission
        term:
          id: GO:0007268
          label: chemical synaptic transmission
        modifier: ABNORMAL
      assays:
      - preferred_term: multielectrode array recording
      direction: POSITIVE
    controls:
    - name: Isogenic wild-type human neurons
      description: CPLX1-intact human neurons from the same iPSC background.
    - name: Wild-type mouse cortex
      description: Cplx1 wild-type littermate cortical preparations.
    decision_criterion: >-
      The mouse is a faithful model of the human seizure phenotype if Cplx1-null mouse cortex
      shows network hyperexcitability matching human CPLX1-null cortical neurons; a human-specific
      cortical phenotype is supported if hyperexcitability appears in human but not mouse
      preparations.
    would_support:
    - pathophysiology#Epileptiform Brain Activity
synonyms:
- Developmental and epileptic encephalopathy 63
- DEE63
- Early infantile epileptic encephalopathy 63
- EIEE63
notes: >-
  The 2015 and 2017 reports together describe five individuals from three families; this is
  a historical series count, not a population prevalence estimate. Additional iPSC lines were
  reported from one patient carrying homozygous CPLX1 p.Glu2Lys together with a heterozygous
  SCN9A deletion, without establishing the separate causal contributions. Findings confined
  to the p.Leu128Met patient require caution because of conflicting variant interpretations
  and substantial prematurity.
experimental_models:
- name: Dual complexin-1/2 knockdown cortical neurons
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Cultured mouse cortical neurons
  description: >-
    An shRNA targeting both complexin-1 and complexin-2 increases miniature release and reduces
    evoked EPSC amplitude. Wild-type rat complexin-1 rescues both changes, whereas an engineered
    SNARE-binding mutant does not. This is not selective CPLX1 depletion or a patient-allele
    assay.
  modeled_mechanisms:
  - target: Reduced Evoked Synaptic Vesicle Release
    relationship: MEASURES
    description: Reduced evoked EPSC amplitude after dual knockdown.
    fidelity: UNKNOWN
    limitations: Patient-variant neuronal physiology has not been established.
    evidence:
    - reference: PMID:19164751
      reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We knocked down complexin expression in cultured cortical neurons using an shRNA that
        targets both complexin-1 and -2, the only complexin isoforms significantly expressed
        in these neurons
      explanation: This is dual complexin-1/2 knockdown in mouse neuronal culture, not a patient-variant experiment.
    - reference: PMID:19164751
      reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In contrast, the complexin knock-down decreased 3-4 fold the amplitude of excitatory
        postsynaptic currents (EPSCs) evoked by isolated action potentials
      explanation: Evoked release was reduced in the dual-knockdown cortical culture.
  - target: Increased Spontaneous Release in Dual-Knockdown Cortical Neurons
    relationship: MEASURES
    description: Increased miniature EPSC frequency after dual knockdown.
    fidelity: UNKNOWN
    limitations: Patient-variant neuronal physiology has not been established.
    evidence:
    - reference: PMID:19164751
      reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We knocked down complexin expression in cultured cortical neurons using an shRNA that
        targets both complexin-1 and -2, the only complexin isoforms significantly expressed
        in these neurons
      explanation: This is dual complexin-1/2 knockdown in mouse neuronal culture, not a patient-variant experiment.
    - reference: PMID:19164751
      reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The complexin knock-down increased 3-4 fold the frequency of spontaneous miniature
        excitatory postsynaptic currents (mEPSCs), without altering the mEPSC amplitude
      explanation: Spontaneous release increased in the dual-knockdown cortical culture.
  - target: Reduced Evoked Synaptic Vesicle Release
    relationship: RESCUES
    description: Wild-type complexin-1 rescues the evoked-release defect.
    fidelity: UNKNOWN
    limitations: Patient-variant neuronal physiology has not been established.
    evidence:
    - reference: PMID:19164751
      reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Both changes were rescued by wild-type but not by 4M-mutant complexin, confirming
        the specificity of the shRNA and the importance of SNARE binding.
      explanation: Wild-type rat complexin-1 rescued both release defects; the engineered SNARE-binding-deficient mutant failed.
  - target: Increased Spontaneous Release in Dual-Knockdown Cortical Neurons
    relationship: RESCUES
    description: Wild-type complexin-1 rescues the spontaneous-release defect.
    fidelity: UNKNOWN
    limitations: Patient-variant neuronal physiology has not been established.
    evidence:
    - reference: PMID:19164751
      reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Both changes were rescued by wild-type but not by 4M-mutant complexin, confirming
        the specificity of the shRNA and the importance of SNARE binding.
      explanation: Wild-type rat complexin-1 rescued both release defects; the engineered SNARE-binding-deficient mutant failed.
  evidence:
  - reference: PMID:19164751
    reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We knocked down complexin expression in cultured cortical neurons using an shRNA that
      targets both complexin-1 and -2, the only complexin isoforms significantly expressed
      in these neurons
    explanation: This is dual complexin-1/2 knockdown in mouse neuronal culture, not a patient-variant experiment.
  - reference: PMID:19164751
    reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In contrast, the complexin knock-down decreased 3-4 fold the amplitude of excitatory
      postsynaptic currents (EPSCs) evoked by isolated action potentials
    explanation: Evoked release was reduced in the dual-knockdown cortical culture.
  - reference: PMID:19164751
    reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The complexin knock-down increased 3-4 fold the frequency of spontaneous miniature excitatory
      postsynaptic currents (mEPSCs), without altering the mEPSC amplitude
    explanation: Spontaneous release increased in the dual-knockdown cortical culture.
  - reference: PMID:19164751
    reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Both changes were rescued by wild-type but not by 4M-mutant complexin, confirming the
      specificity of the shRNA and the importance of SNARE binding.
    explanation: Wild-type rat complexin-1 rescued both release defects; the engineered SNARE-binding-deficient mutant failed.
- name: Recombinant complexin membrane-binding assays
  experimental_model_type: OTHER
  description: >-
    NMR and circular-dichroism experiments with recombinant worm complexin and liposomes establish
    curvature-sensitive C-terminal binding and helix formation. Mouse complexin showed related
    curvature sensitivity. Engineered worm substitutions and deletions inform membrane interactions,
    but none is a direct assay of the human disease alleles.
  modeled_mechanisms:
  - target: Complexin-1 Loss of Function
    relationship: MEASURES
    description: Defines C-terminal membrane interactions that motivate the predicted consequences of human truncation.
    fidelity: LOW
    limitations: Recombinant nonhuman proteins and engineered substitutions; human variant function was not measured.
    evidence:
    - reference: PMID:25229806
      reference_title: Membrane curvature sensing by the C-terminal domain of complexin.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here we show that complexin's CTD is highly sensitive to membrane curvature, which
        it senses via tandem motifs, a C-terminal motif containing a mix of bulky hydrophobic
        and positively charged residues, and an adjacent amphipathic region that can bind
        membranes in either a disordered or a helical conformation.
      explanation: >-
        Recombinant complexin/liposome experiments support a membrane-binding role for the
        C terminus, not direct functional validation of the human alleles.
  evidence:
  - reference: PMID:25229806
    reference_title: Membrane curvature sensing by the C-terminal domain of complexin.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we show that complexin's CTD is highly sensitive to membrane curvature, which it
      senses via tandem motifs, a C-terminal motif containing a mix of bulky hydrophobic and
      positively charged residues, and an adjacent amphipathic region that can bind membranes
      in either a disordered or a helical conformation.
    explanation: >-
      Recombinant complexin/liposome experiments support a membrane-binding role for the C
      terminus, not direct functional validation of the human alleles.
- name: KAIMRCi003A and KAIMRCi003B patient iPSCs
  experimental_model_type: OTHER
  cell_source: Patient peripheral blood erythroid progenitors reprogrammed to iPSCs
  description: >-
    Two integration-free iPSC clones were generated from one seven-year-old patient labelled
    with Dravet syndrome, developmental delay, infantile seizures and choreoathetotic movements.
    Both carry homozygous CPLX1 p.Glu2Lys and a heterozygous SCN9A in-frame deletion. Identity,
    normal female karyotype, pluripotency and trilineage differentiation were characterized.
    Disease-relevant neuronal physiology, isogenic correction and functional rescue were proposed
    future work, not reported results.
  evidence:
  - reference: DOI:10.1007/s13577-023-01016-z
    reference_title: >-
      Generation of iPSC lines (KAIMRCi003A, KAIMRCi003B) from a Saudi patient with Dravet
      syndrome carrying homozygous mutation in the CPLX1 gene and heterozygous mutation in
      SCN9A
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we established two DRVT-iPSC lines harboring a homozygous mutation in the CPLX1
      gene and heterozygous mutation in SCN9A gene.
    explanation: Two iPSC clones were derived from one donor carrying both variants; this is a resource-generation result.
  - reference: DOI:10.1007/s13577-023-01016-z
    reference_title: >-
      Generation of iPSC lines (KAIMRCi003A, KAIMRCi003B) from a Saudi patient with Dravet
      syndrome carrying homozygous mutation in the CPLX1 gene and heterozygous mutation in
      SCN9A
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further analysis unraveled homozygous variant c.4G > A p.(Glu2Lys) in the CPLX1 gene.
      This variant leads to an amino acid exchange in exon 1 (NM_006651.4).
    explanation: >-
      The donor carried homozygous p.Glu2Lys as well as a heterozygous SCN9A deletion; this
      establishes the genotype, not single-gene causation.
  notes: >-
    An undifferentiated patient-derived resource, not yet a validated neuronal disease model.
    The co-occurring SCN9A variant prevents assigning cellular findings to CPLX1 without further
    experiments.
📚

References & Deep Research

References

11
DOI:10.1007/s13577-023-01016-z
Generation of iPSC lines (KAIMRCi003A, KAIMRCi003B) from a Saudi patient with Dravet syndrome carrying homozygous mutation in the CPLX1 gene and heterozygous mutation in SCN9A
No top-level findings curated for this source.
PMID:19164751
Complexin controls the force transfer from SNARE complexes to membranes in fusion.
No top-level findings curated for this source.
PMID:22393426
Tensor-based morphometry and stereology reveal brain pathology in the complexin1 knockout mouse.
No top-level findings curated for this source.
PMID:25229806
Membrane curvature sensing by the C-terminal domain of complexin.
No top-level findings curated for this source.
PMID:26019341
Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion at the mouse calyx of held synapse.
No top-level findings curated for this source.
PMID:26539891
Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.
No top-level findings curated for this source.
PMID:28422131
Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.
No top-level findings curated for this source.
PMID:32559416
SNAREopathies: Diversity in Mechanisms and Symptoms.
No top-level findings curated for this source.
PMID:35715422
Analysis of clinical phenotypic and genotypic spectra in 36 children patients with Epilepsy of Infancy with Migrating Focal Seizures.
No top-level findings curated for this source.
url:https://push-zb.helmholtz-munich.de/deliver.php?id=18934
https://push-zb.helmholtz-munich.de/deliver.php?id=18934
No top-level findings curated for this source.
No top-level findings curated for this source.