ANK2-Related Complex Neurodevelopmental Disorder

Genetic Pathograph 23 Show in embeddings browser Neurodevelopmental Disorder

ANK2-related complex neurodevelopmental disorder is an autosomal dominant disorder caused by heterozygous loss-of-function ANK2 variants. The reported spectrum includes intellectual disability, autism spectrum disorder, and early-onset epilepsy, with speech and language impairment and behavioral manifestations described in expanded case reviews. The principal loss-of-function cohort consists of de novo variants, while familial reports describe variable autistic traits or self-limited focal epilepsy. Human-neuron experiments support parallel effects on somatodendritic and axon-initial-segment structure and on network activity, while a distinct giant-ankyrin-B model supports abnormal axon branching and connectivity. Cardiac ankyrin-B findings and disputed ANK2-LQTS/CPVT relationships are modeled in a separate cardiac record.

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1
Mappings
1
Inheritance
12
Pathophys.
8
Phenotypes
4
Hypotheses
23
Pathograph
1
Genes
3
Medical Actions
10
References
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Mappings

MONDO
MONDO:0100038 complex neurodevelopmental disorder Not Yet Curated
skos:broadMatch MONDO
MONDO:0100038 is the disease concept ClinGen uses for the ANK2 gene-disease validity assertion, and this entry previously bound it as `disease_term`. That binding asserted identity with a grouping class whose MONDO definition reads "A disorder that involves more than one phenotype associated with the central nervous system, including but not limited to intellectual disability, autism, and seizures (epilepsy)". Its sixteen direct children are other disorders and grouping classes - Prader-Willi syndrome, developmental and epileptic encephalopathy, pervasive developmental disorder, and the DEAF1-, NACC1-, BLOC1S1- and AFG2B-related disorders among them - and none of them is a form of ANK2-related disease. Searching MONDO for "ANK2" with synonyms included returns one disease class, MONDO:0010958 cardiac arrhythmia, ankyrin-B-related, which this repository curates separately as the Cardiac Arrhythmia, Ankyrin-B-Related entry; searching for "ankyrin" adds only MONDO:0007715 hemolytic poikilocytic anemia due to reduced ankyrin binding sites. No MONDO class denotes the neurodevelopmental phenotype, so `disease_term` now carries a free-text preferred term with no binding and the relationship to the grouping class is recorded here as a broad match. That also leaves MONDO:0100038 itself in the curation queue rather than retiring it through this entry.
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Inheritance

1
Autosomal dominant inheritance HP:0000006
Heterozygous de novo loss-of-function variants predominate in the principal complex-neurodevelopmental cohort. A family carrying a giant-ankyrin-B frameshift had young-onset self-limited focal epilepsy without a documented complex neurodevelopmental phenotype, and a separate familial missense report described high-functioning autism in a child and subthreshold autistic traits in her father.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:37195288 SUPPORT Human Clinical
"We collected clinical and molecular data of 12 individuals with heterozygous de novo LoF variants in ANK2."
Establishes heterozygous de novo loss of function in the principal human cohort.
PMID:39962910 SUPPORT Human Clinical
"Hereby, we reported a Taiwanese family with the ANK2 pathogenic variant (chr4:114276707, c.6933del, p.T2312Lfs*2) that affects the giant ankyrin-B isoform."
The familial report shows that ANK2-related epilepsy is not confined to de novo presentations, but it does not establish inherited complex neurodevelopmental disorder.
PMID:39978592 SUPPORT Human Clinical
"Our patient was diagnosed with high-functioning ASD while her father showed subthreshold autistic traits such as relational difficulties and peculiar interests."
Supports inherited and variably expressive autistic traits in one family, but the reported missense variant was only predicted pathogenic and does not redefine the established loss-of-function mechanism.
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Mechanistic Hypotheses

4
General ANK2 Haploinsufficiency Neuronal Model
general_ank2_haploinsufficiency_neuronal_model EMERGING
Evidence balance 1 support
Reduced ankyrin-B expression in human neurons produces parallel somatodendritic/AIS abnormalities and hyperactive, desynchronized network activity. Links from these cellular phenotypes to intellectual disability and epilepsy remain candidate disease mechanisms rather than established linear causal chains.
Pathograph links
ANK2 Haploinsufficiency in Neurons -> Increased Somatodendritic Complexity DIRECT ANK2-deficient human neurons show increased somatodendritic structures.
ANK2 Haploinsufficiency in Neurons -> Impaired AIS Structural Plasticity DIRECT ANK2-deficient human neurons show altered axon-initial-segment structure and impaired activity-dependent plasticity.
ANK2 Haploinsufficiency in Neurons -> Hyperactive and Desynchronized Neuronal Networks DIRECT ANK2-deficient human neurons develop hyperactive and desynchronized network activity as a parallel experimental consequence.
Increased Somatodendritic Complexity -> Intellectual Disability INDIRECT UNKNOWN INTERMEDIATES Altered neuronal structure and homeostatic plasticity are candidate contributors to intellectual disability; the omitted human intermediates remain unresolved.
Increased Somatodendritic Complexity -> Global Developmental Delay INDIRECT UNKNOWN INTERMEDIATES Altered neuronal morphology is a candidate contributor to developmental delay; the cellular-to-clinical intermediates are unresolved.
Increased Somatodendritic Complexity -> Delayed Speech and Language Development INDIRECT UNKNOWN INTERMEDIATES Altered neuronal morphology is a candidate contributor to speech and language delay; the intermediates are unresolved.
Impaired AIS Structural Plasticity -> Epilepsy INDIRECT UNKNOWN INTERMEDIATES Impaired AIS homeostatic plasticity is a candidate contributor to epilepsy; the cellular-to-clinical intermediates have not been established.
Hyperactive and Desynchronized Neuronal Networks -> Epilepsy INDIRECT UNKNOWN INTERMEDIATES Network dysregulation is a candidate contributor to epilepsy, but the cellular-to-clinical intermediates have not been established.
Show evidence (1 reference)
PMID:37195288 SUPPORT In Vitro
"Our functional in vitro data of ANK2-deficient human neurons show a specific neuronal phenotype in which reduced ANKB expression leads to hyperactive and desynchronized neuronal network activity, increased somatodendritic complexity and AIS structure and impaired activity-dependent plasticity of the AIS."
Supports both observed human-neuron branches without imposing a serial AIS-to-network edge.
Giant Ankyrin-B Axon-Branching Model
giant_ankyrin_b_axon_branching_model EMERGING
Evidence balance 1 support
The neurospecific giant ankyrin-B isoform normally couples axonal microtubules to L1CAM-containing membrane domains and restricts collateral branch formation. Disruption produces ectopic axon branching and connectivity in a mouse-derived neuronal model; relevance to human autistic behavior remains a candidate link.
Pathograph links
Giant Ankyrin-B Axonal Membrane-Microtubule Coupling Failure -> Ectopic Axon Branching DIRECT Disruption of the giant ankyrin-B branch-restriction mechanism increases axonal branching.
Ectopic Axon Branching -> Ectopic CNS Connectivity DIRECT Excess axon branching accompanies ectopic central-nervous-system axon connectivity in the giant-ankyrin-B mouse model.
Ectopic CNS Connectivity -> Autistic Behavior INDIRECT UNKNOWN INTERMEDIATES Aberrant connectivity is a candidate contributor to autistic behavior; human causal intermediates remain unresolved.
Show evidence (1 reference)
PMID:31285321 SUPPORT Model Organism
"Thus, gain of axon branching due to giant ankB-deficiency/mutation is a candidate cellular mechanism to explain aberrant structural connectivity and penetrant behavioral consequences in mice as well as humans bearing ASD-related ANK2 mutations."
The authors explicitly frame giant-ankyrin-B-dependent branching as a candidate mechanism with model-organism support.
ANK2-Kv7 Cortical Hyperexcitability Model
ank2_kv7_cortical_hyperexcitability_model EMERGING
Evidence balance 1 support
Developmental Ank2 loss in mouse cortical excitatory neurons reduces the abundance and function of AIS Kv7.2/KCNQ2 and Kv7.3/KCNQ3 channels, producing cortical hyperexcitability and seizure-related death. Kv7 activation and AMPA-receptor antagonism rescue model phenotypes, but this mechanism and its pharmacologic tractability have not been established in affected humans.
Pathograph links
Developmental Forebrain Ank2 Loss -> Reduced AIS Kv7.2 and Kv7.3 Channel Function DIRECT Ank2 loss reduces Kv7.2/KCNQ2 and Kv7.3/KCNQ3 abundance, function, and AIS density in cortical excitatory neurons.
Reduced AIS Kv7.2 and Kv7.3 Channel Function -> Mouse Cortical Hyperexcitability and Hypersynchrony DIRECT Reduced Kv7 channel function contributes to increased neuronal excitability and firing in Ank2-mutant cortical neurons.
Mouse Cortical Hyperexcitability and Hypersynchrony -> Epilepsy INDIRECT UNKNOWN INTERMEDIATES Mouse cortical hyperexcitability and hypersynchrony accompany severe spontaneous seizures, but translation to human epilepsy remains indirect.
Show evidence (1 reference)
PMID:37321992 SUPPORT Model Organism
"These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment."
Directly supports the proposed Kv7-channel arm in Ank2-mutant mice.
Dendritic NaV1.2 Scaffolding Model
dendritic_nav1_2_scaffolding_model EMERGING
Evidence balance 1 support
Ankyrin-B scaffolds NaV1.2 at the dendritic membrane of mouse neocortical pyramidal neurons. Ank2 haploinsufficiency reproduces dendritic excitability and synaptic deficits seen with Scn2a haploinsufficiency, suggesting a convergent dendritic mechanism for autism-related neurodevelopmental risk.
Pathograph links
ANK2 Haploinsufficiency in Neurons -> Reduced Dendritic NaV1.2 Scaffolding DIRECT Ank2 haploinsufficiency reduces ankyrin-B-dependent scaffolding of NaV1.2 at the dendritic membrane in mouse neocortical pyramidal neurons.
Reduced Dendritic NaV1.2 Scaffolding -> Impaired Dendritic Excitability and Synaptic Function DIRECT Loss of dendritic ankyrin-B scaffolding produces intrinsic dendritic excitability and synaptic deficits.
Impaired Dendritic Excitability and Synaptic Function -> Autistic Behavior INDIRECT UNKNOWN INTERMEDIATES Dendritic dysfunction is a candidate contributor to autistic behavior; the evidence remains confined to mouse neurons and an emerging framework.
Impaired Dendritic Excitability and Synaptic Function -> Attention Deficit Hyperactivity Disorder INDIRECT UNKNOWN INTERMEDIATES Dendritic and synaptic dysfunction is a candidate contributor to ADHD; no ANK2-specific causal intermediates have been demonstrated in humans.
Show evidence (1 reference)
PMID:38290518 SUPPORT Model Organism
"Here, we show that ankyrin-B is essential for scaffolding NaV1.2 to the dendritic membrane of mouse neocortical neurons and that haploinsufficiency of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits observed in Scn2a+/- conditions."
Establishes the ankyrin-B-dependent dendritic NaV1.2 scaffolding mechanism and the resulting cellular deficits in mouse neurons.
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Pathophysiology

12
ANK2 Haploinsufficiency in Neurons
Heterozygous ANK2 loss of function reduces ankyrin-B expression in neurons and initiates the general haploinsufficiency mechanism.
Dendritic NaV1.2 Scaffolding Model General ANK2 Haploinsufficiency Neuronal Model
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.
ANK2 hgnc:493 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ANK2 (hgnc:493). hgnc:493 is a gene from the HUGO Gene Nomenclature Committee.
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
Increased Somatodendritic Complexity ANK2-deficient human neurons show increased somatodendritic structures. General ANK2 Haploinsufficiency Neuronal Model
Impaired AIS Structural Plasticity ANK2-deficient human neurons show altered axon-initial-segment structure and impaired activity-dependent plasticity. General ANK2 Haploinsufficiency Neuronal Model
Hyperactive and Desynchronized Neuronal Networks ANK2-deficient human neurons develop hyperactive and desynchronized network activity as a parallel experimental consequence. General ANK2 Haploinsufficiency Neuronal Model
Reduced Dendritic NaV1.2 Scaffolding Ank2 haploinsufficiency reduces ankyrin-B-dependent scaffolding of NaV1.2 at the dendritic membrane in mouse neocortical pyramidal neurons. Dendritic NaV1.2 Scaffolding Model
Microcephaly Microcephaly has been observed in individuals with ANK2 variants, but the intervening developmental mechanism is unresolved.
Anxiety Anxiety or agitation/mood disorder has been reported in affected individuals, but the intervening mechanism is unresolved.
Show evidence (1 reference)
PMID:37195288 SUPPORT In Vitro
"Our functional in vitro data of ANK2-deficient human neurons show a specific neuronal phenotype in which reduced ANKB expression leads to hyperactive and desynchronized neuronal network activity, increased somatodendritic complexity and AIS structure and impaired activity-dependent plasticity of the AIS."
Directly supports reduced ankyrin-B expression as the upstream experimental perturbation in human neurons.
Increased Somatodendritic Complexity
ANK2-deficient human neurons have increased somatodendritic complexity.
General ANK2 Haploinsufficiency Neuronal Model
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
Intellectual Disability Altered neuronal structure and homeostatic plasticity are candidate contributors to intellectual disability; the omitted human intermediates remain unresolved. General ANK2 Haploinsufficiency Neuronal Model
Global Developmental Delay Altered neuronal morphology is a candidate contributor to developmental delay; the cellular-to-clinical intermediates are unresolved. General ANK2 Haploinsufficiency Neuronal Model
Delayed Speech and Language Development Altered neuronal morphology is a candidate contributor to speech and language delay; the intermediates are unresolved. General ANK2 Haploinsufficiency Neuronal Model
Show evidence (1 reference)
PMID:37195288 SUPPORT In Vitro
"ANK2-deficient neurons also showed increased somatodendritic structures and altered AIS structure of which its plasticity is impaired upon activity-dependent modulation."
Establishes the cellular phenotype in human induced-pluripotent-stem-cell derived neurons.
Impaired AIS Structural Plasticity
ANK2-deficient human neurons have altered axon-initial-segment structure and impaired activity-dependent plasticity.
General ANK2 Haploinsufficiency Neuronal Model
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 Impaired AIS homeostatic plasticity is a candidate contributor to epilepsy; the cellular-to-clinical intermediates have not been established. General ANK2 Haploinsufficiency Neuronal Model
Show evidence (1 reference)
PMID:37195288 SUPPORT In Vitro
"ANK2-deficient neurons also showed increased somatodendritic structures and altered AIS structure of which its plasticity is impaired upon activity-dependent modulation."
Directly supports impaired activity-dependent AIS plasticity in human induced-pluripotent-stem-cell-derived neurons.
Hyperactive and Desynchronized Neuronal Networks
Heterozygous ANK2 loss of function produces a hyperactive yet desynchronized network phenotype in human induced-pluripotent-stem-cell-derived neurons.
General ANK2 Haploinsufficiency Neuronal Model
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 Network dysregulation is a candidate contributor to epilepsy, but the cellular-to-clinical intermediates have not been established. General ANK2 Haploinsufficiency Neuronal Model
Show evidence (1 reference)
PMID:37195288 SUPPORT In Vitro
"Using MEAs, we found that hiPSC-derived neurons with heterozygous LoF of ANK2 show a hyperactive and desynchronized neuronal network."
Directly establishes the human-neuron network phenotype.
Developmental Forebrain Ank2 Loss
Conditional mouse models restrict Ank2 loss to developing forebrain cells, including prenatal cortical excitatory neurons and oligodendrocytes or cortical and hippocampal excitatory neurons.
ANK2-Kv7 Cortical Hyperexcitability Model
glutamatergic neuron CL:0000679 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glutamatergic neuron (CL:0000679). CL:0000679 is a cell type from the Cell Ontology.
ANK2 hgnc:493 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ANK2 (hgnc:493). hgnc:493 is a gene from the HUGO Gene Nomenclature Committee.
cerebral cortex UBERON:0000956 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebral cortex (UBERON:0000956). UBERON:0000956 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Reduced AIS Kv7.2 and Kv7.3 Channel Function Ank2 loss reduces Kv7.2/KCNQ2 and Kv7.3/KCNQ3 abundance, function, and AIS density in cortical excitatory neurons. ANK2-Kv7 Cortical Hyperexcitability Model
Mouse Cortical Hyperexcitability and Hypersynchrony Prenatal forebrain Ank2 deletion directly produces cortical network hyperexcitability and hypersynchrony in the Emx1-Cre model, independently of the Kv7 findings established in the separate excitatory-neuron model.
Show evidence (2 references)
PMID:37428632 SUPPORT Model Organism
"We find that mice with prenatal deletion in cortical excitatory neurons and oligodendrocytes (Ank2-/-:Emx1-Cre), but not with adolescent deletion in forebrain excitatory neurons (Ank2-/-:CaMKIIα-Cre), display severe spontaneous seizures, increased mortality, hyperactivity, and social deficits."
Directly supports a prenatal developmental requirement for Ank2 in the mouse seizure and behavioral phenotype.
PMID:37321992 SUPPORT Model Organism
"Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death."
Supports the second conditional Ank2-loss model and its behavioral and seizure-related phenotypes.
Reduced AIS Kv7.2 and Kv7.3 Channel Function
Ank2-mutant mouse cortical neurons have reduced Kv7.2/KCNQ2 and Kv7.3/KCNQ3 channel abundance, function, and density at the axon initial segment.
ANK2-Kv7 Cortical Hyperexcitability Model
cortical excitatory neuron CL:0000679 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cortical excitatory neuron, annotated with glutamatergic neuron (CL:0000679). CL:0000679 is a cell type from the Cell Ontology.
cerebral cortex UBERON:0000956 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebral cortex (UBERON:0000956). UBERON:0000956 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Mouse Cortical Hyperexcitability and Hypersynchrony Reduced Kv7 channel function contributes to increased neuronal excitability and firing in Ank2-mutant cortical neurons. ANK2-Kv7 Cortical Hyperexcitability Model
Show evidence (1 reference)
PMID:37321992 SUPPORT Model Organism
"These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment."
Establishes the channel deficit and its AIS localization in the mouse model.
Mouse Cortical Hyperexcitability and Hypersynchrony
Conditional Ank2 loss produces increased excitability and firing in mouse cortical neurons and hyperexcitable, hypersynchronous cortical networks. This model-organism node is distinct from the desynchronized network phenotype observed in human induced-pluripotent-stem-cell-derived neurons.
ANK2-Kv7 Cortical Hyperexcitability Model
glutamatergic neuron CL:0000679 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glutamatergic neuron (CL:0000679). CL:0000679 is a cell type from the Cell Ontology.
cerebral cortex UBERON:0000956 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebral cortex (UBERON:0000956). UBERON:0000956 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Epilepsy Mouse cortical hyperexcitability and hypersynchrony accompany severe spontaneous seizures, but translation to human epilepsy remains indirect. ANK2-Kv7 Cortical Hyperexcitability Model
Show evidence (2 references)
PMID:37321992 SUPPORT Model Organism
"Ank2-cKO cortical neurons show abnormally increased excitability and firing rate."
Directly establishes cellular hyperexcitability in the mouse cortex after conditional Ank2 knockout.
PMID:37428632 SUPPORT Model Organism
"Calcium imaging of cortical slices from Ank2-/-:Emx1-Cre mice shows increased neuronal calcium event amplitude and frequency, along with network hyperexcitability and hypersynchrony."
Directly establishes the cortical network phenotype in the prenatal forebrain-deletion mouse model.
Reduced Dendritic NaV1.2 Scaffolding
Ankyrin-B is required to scaffold NaV1.2 at the dendritic membrane of mouse neocortical pyramidal neurons; Ank2 haploinsufficiency disrupts this function.
Dendritic NaV1.2 Scaffolding Model
neocortical pyramidal neuron CL:0000598 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neocortical pyramidal neuron, annotated with pyramidal neuron (CL:0000598). CL:0000598 is a cell type from the Cell Ontology.
cerebral cortex UBERON:0000956 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebral cortex (UBERON:0000956). UBERON:0000956 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Impaired Dendritic Excitability and Synaptic Function Loss of dendritic ankyrin-B scaffolding produces intrinsic dendritic excitability and synaptic deficits. Dendritic NaV1.2 Scaffolding Model
Show evidence (1 reference)
PMID:38290518 SUPPORT Model Organism
"Here, we show that ankyrin-B is essential for scaffolding NaV1.2 to the dendritic membrane of mouse neocortical neurons and that haploinsufficiency of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits observed in Scn2a+/- conditions."
Directly establishes ankyrin-B-dependent dendritic NaV1.2 scaffolding.
Impaired Dendritic Excitability and Synaptic Function
Ank2 haploinsufficiency impairs intrinsic dendritic excitability and synaptic function in mouse neocortical pyramidal neurons.
Dendritic NaV1.2 Scaffolding Model
neocortical pyramidal neuron CL:0000598 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neocortical pyramidal neuron, annotated with pyramidal neuron (CL:0000598). CL:0000598 is a cell type from the Cell Ontology.
cerebral cortex UBERON:0000956 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebral cortex (UBERON:0000956). UBERON:0000956 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Autistic Behavior Dendritic dysfunction is a candidate contributor to autistic behavior; the evidence remains confined to mouse neurons and an emerging framework. Dendritic NaV1.2 Scaffolding Model
Attention Deficit Hyperactivity Disorder Dendritic and synaptic dysfunction is a candidate contributor to ADHD; no ANK2-specific causal intermediates have been demonstrated in humans. Dendritic NaV1.2 Scaffolding Model
Show evidence (1 reference)
PMID:38290518 SUPPORT Model Organism
"These results establish a direct, convergent link between two major ASD risk genes and reinforce an emerging framework suggesting that neocortical pyramidal cell dendritic dysfunction can contribute to neurodevelopmental disorder pathophysiology."
Supports the authors' explicitly emerging dendritic-dysfunction framework.
Giant Ankyrin-B Axonal Membrane-Microtubule Coupling Failure
Giant ankyrin-B normally localizes through L1CAM-containing axonal membrane domains, couples microtubules to the plasma membrane, and prevents microtubule entry into nascent branches.
Giant Ankyrin-B Axon-Branching Model
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.
ANK2 hgnc:493 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ANK2 (hgnc:493). hgnc:493 is a gene from the HUGO Gene Nomenclature Committee.
axonogenesis GO:0007409 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated axonogenesis (GO:0007409). GO:0007409 is a biological process from the Gene Ontology. ↕ DYSREGULATED
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
Ectopic Axon Branching Disruption of the giant ankyrin-B branch-restriction mechanism increases axonal branching. Giant Ankyrin-B Axon-Branching Model
Show evidence (1 reference)
PMID:31285321 SUPPORT In Vitro
"We elucidate a mechanism normally limiting axon branching, whereby giant ankB localizes to periodic axonal plasma membrane domains through L1 cell-adhesion molecule protein, where it couples microtubules to the plasma membrane and prevents microtubule entry into nascent axon branches."
Establishes the L1CAM-microtubule coupling mechanism in the mouse-derived neuronal system.
Ectopic Axon Branching
Giant-ankyrin-B disruption produces excess axonal branching in a mouse model.
Giant Ankyrin-B Axon-Branching Model
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.
axonogenesis GO:0007409 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated axonogenesis (GO:0007409). GO:0007409 is a biological process from the Gene Ontology. ↕ DYSREGULATED
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
Ectopic CNS Connectivity Excess axon branching accompanies ectopic central-nervous-system axon connectivity in the giant-ankyrin-B mouse model. Giant Ankyrin-B Axon-Branching Model
Show evidence (1 reference)
PMID:31285321 SUPPORT Model Organism
"We report that a mouse model for human ASD mutation of giant ankB exhibits increased axonal branching in cultured neurons with ectopic CNS axon connectivity, as well as with a transient increase in excitatory synapses during postnatal development."
Establishes the model-organism cellular phenotype.
Ectopic CNS Connectivity
The giant-ankyrin-B mouse model shows ectopic CNS axon connectivity. Human behavioral relevance remains candidate rather than proven.
Giant Ankyrin-B Axon-Branching Model
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
Autistic Behavior Aberrant connectivity is a candidate contributor to autistic behavior; human causal intermediates remain unresolved. Giant Ankyrin-B Axon-Branching Model
Show evidence (1 reference)
PMID:31285321 SUPPORT Model Organism
"We report that a mouse model for human ASD mutation of giant ankB exhibits increased axonal branching in cultured neurons with ectopic CNS axon connectivity, as well as with a transient increase in excitatory synapses during postnatal development."
Establishes ectopic CNS connectivity in the mouse model.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for ANK2-Related Complex Neurodevelopmental Disorder Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Head and Neck 1
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)
CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-10-21T100000.000Z SUPPORT Other
"Individuals with variants in this gene have presented with neurodevelopmental phenotypes including autism spectrum disorder, intellectual disability, seizures, and microcephaly."
ClinGen explicitly includes microcephaly in the reported ANK2 phenotype.
Nervous System 7
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:37195288 SUPPORT Human Clinical
"We found a broad neurodevelopmental disorder (NDD), comprising intellectual disability, autism spectrum disorders and early onset epilepsy."
Directly includes intellectual disability in the human phenotype.
Autistic Behavior HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37195288 SUPPORT Human Clinical
"We found a broad neurodevelopmental disorder (NDD), comprising intellectual disability, autism spectrum disorders and early onset epilepsy."
Directly includes autism spectrum disorders in the human phenotype.
PMID:39978592 SUPPORT Human Clinical
"Our patient was diagnosed with high-functioning ASD while her father showed subthreshold autistic traits such as relational difficulties and peculiar interests."
Extends the autistic spectrum to a variably expressive familial missense report, while leaving its pathogenic mechanism qualified.
Epilepsy Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37195288 SUPPORT Human Clinical
"We found a broad neurodevelopmental disorder (NDD), comprising intellectual disability, autism spectrum disorders and early onset epilepsy."
Establishes early-onset epilepsy in the principal cohort.
PMID:39962910 SUPPORT Human Clinical
"The family members presented with young-onset self-limited focal epilepsy, and achieved seizure-free in adulthood with antiseizure medications."
Extends the spectrum to inherited, self-limited focal epilepsy.
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:40035441 SUPPORT Human Clinical
"The patient cohort included 16 patients with a complex array of neurological disabilities: ASD (9 patients); EP (10 patients); ASD with EP (4 patients); intellectual disability and developmental delay (5 patients)"
Directly reports developmental delay in the ANK2 patient cohort.
Delayed Speech and Language Development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40035441 SUPPORT Human Clinical
"He mainly presents with language delay, intellectual disability, limited learning, and communication skills, and later develops seizures"
Directly reports language and communication impairment in an affected child.
Attention Deficit Hyperactivity Disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40035441 SUPPORT Human Clinical
"The patient cohort included 16 patients with a complex array of neurological disabilities: ASD (9 patients); EP (10 patients); ASD with EP (4 patients); intellectual disability and developmental delay (5 patients); poor language communication (11 patients); language and learning impairment (11..."
Directly reports ADHD among affected individuals in the expanded review.
Anxiety HP:0000739 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anxiety (HP:0000739). HP:0000739 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40035441 SUPPORT Human Clinical
"The patient cohort included 16 patients with a complex array of neurological disabilities: ASD (9 patients); EP (10 patients); ASD with EP (4 patients); intellectual disability and developmental delay (5 patients); poor language communication (11 patients); language and learning impairment (11..."
Directly reports anxiety or agitation/mood disorder in the expanded literature cohort.
🧬

Genetic Associations

1
ANK2 loss-of-function variants (Causative heterozygous loss-of-function variants)
Gene: ANK2 hgnc:493 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ANK2 (hgnc:493). hgnc:493 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (4 references)
PMID:37195288 SUPPORT Human Clinical
"We collected clinical and molecular data of 12 individuals with heterozygous de novo LoF variants in ANK2."
Establishes the heterozygous loss-of-function cohort.
CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-10-21T100000.000Z SUPPORT Other
"Seven de novo protein truncating variants (frameshift and nonsense) that have been reported in 8 probands in 7 publications"
Supplies the curated variant-class and proband counts for the established truncating-variant class.
CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-10-21T100000.000Z SUPPORT Other
"The mechanism of pathogenicity is predicted to be loss-of-function based on the protein truncating variants reported in individuals affected with neurodevelopmental disorders and experimental data showing reduced protein expression in cultured cells bearing truncating variants in ANK2"
ClinGen explicitly supports loss of function as the disease mechanism.
+ 1 more reference
🗃️

External Assertions

2
Gene2Phenotype ANK2-neurodevelopmental disorder assertion
Gene2Phenotype gene disease relationship G2P02923
Gene2Phenotype records a loss-of-function ANK2 relationship with neurodevelopmental disorder (MONDO:0700092) at limited evidence.
ClinGen ANK2-complex neurodevelopmental disorder assertion
ClinGen gene disease validity CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-10-21T100000.000Z
ClinGen classifies the autosomal dominant ANK2-complex neurodevelopmental disorder relationship (MONDO:0100038) as definitive.
Show evidence (1 reference)
CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-10-21T100000.000Z SUPPORT Other
"ANK2 | HGNC:493 | complex neurodevelopmental disorder | MONDO:0100038 | AD | Definitive"
The ClinGen structured assertion directly supports the definitive autosomal dominant ANK2-complex neurodevelopmental disorder relationship.
💊

Medical Actions

3
Antiseizure Medication Management
Action: anticonvulsant agent therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is anticonvulsant agent therapy, annotated with Anticonvulsant Therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. Ontology label: Anticonvulsant Therapy NCIT:C64172
Platform: Small molecule
Antiseizure medications provided seizure control in the reported family with young-onset self-limited focal epilepsy. Drug choice should be based on seizure type and individualized clinical assessment; this report does not establish a preferred ANK2-specific regimen.
Show evidence (1 reference)
PMID:39962910 SUPPORT Human Clinical
"The family members presented with young-onset self-limited focal epilepsy, and achieved seizure-free in adulthood with antiseizure medications."
Direct human evidence supports symptomatic antiseizure medication use, without identifying a preferred drug or disease-modifying effect.
Retigabine Kv7 Activation (Preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ezogabine CHEBI:68584 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ezogabine (CHEBI:68584). CHEBI:68584 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Retigabine (ezogabine) rescued neuronal excitability and partially improved seizure-related survival and acute hyperactivity in an Ank2 conditional knockout mouse model. This is preclinical mechanism evidence, not evidence of efficacy or a treatment recommendation for people with ANK2-related neurodevelopmental disorder. The commercial product was discontinued globally in 2017 and is not an available clinical option.
Mechanism Target:
RESTORES Reduced AIS Kv7.2 and Kv7.3 Channel Function — Kv7 activation counteracts the reduced Kv7-dependent current and neuronal hyperexcitability in the Ank2 conditional-knockout model.
Show evidence (1 reference)
PMID:37321992 SUPPORT Model Organism
"Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice."
Directly demonstrates mechanism-linked rescue in the mouse model only.
Show evidence (1 reference)
PMID:37321992 SUPPORT Model Organism
"Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice."
Supports the preclinical rescue claim while not implying human efficacy.
Perampanel AMPA-Receptor Antagonism (Preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: perampanel CHEBI:71013 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses perampanel (CHEBI:71013). CHEBI:71013 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Perampanel restored cortical neuronal activity and partially rescued survival in a prenatal forebrain Ank2-deletion mouse model. This is preclinical evidence and does not establish efficacy or a treatment recommendation in affected humans.
Mechanism Target:
MODULATES Mouse Cortical Hyperexcitability and Hypersynchrony — AMPA-receptor antagonism counteracts abnormal cortical network activity in the prenatal Ank2-deletion mouse model.
Show evidence (1 reference)
PMID:37428632 SUPPORT Model Organism
"The AMPA receptor antagonist, perampanel, restores cortical neuronal activity and partially rescues survival in Ank2-/-:Emx1-Cre mice."
Directly demonstrates network and survival rescue in the mouse model.
Show evidence (1 reference)
PMID:37428632 SUPPORT Model Organism
"The AMPA receptor antagonist, perampanel, restores cortical neuronal activity and partially rescues survival in Ank2-/-:Emx1-Cre mice."
Supports the preclinical rescue claim while not implying human efficacy.
🔬

Diagnosis

2
Electroencephalography for Seizure Evaluation
EEG is appropriate for evaluating suspected seizures and documenting electrophysiologic abnormalities in the ANK2-related spectrum. Published cases establish that abnormal EEG is common in the selected literature cohort but do not define a single ANK2-specific EEG signature.
electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Results: An abnormal EEG supports seizure phenotyping but is not specific for an ANK2 molecular diagnosis.
Show evidence (1 reference)
PMID:40035441 SUPPORT Human Clinical
"The patient cohort included 16 patients with a complex array of neurological disabilities: ASD (9 patients); EP (10 patients); ASD with EP (4 patients); intellectual disability and developmental delay (5 patients); poor language communication (11 patients); language and learning impairment (11..."
Directly supports abnormal EEG as a recurrent finding while not asserting a disease-specific electrophysiologic pattern.
{ }

Source YAML

click to show 
name: ANK2-Related Complex Neurodevelopmental Disorder
creation_date: '2026-07-18T19:05:00Z'
category: Genetic
description: >-
  ANK2-related complex neurodevelopmental disorder is an autosomal dominant
  disorder caused by heterozygous loss-of-function ANK2 variants. The reported
  spectrum includes intellectual disability, autism spectrum disorder, and
  early-onset epilepsy, with speech and language impairment and behavioral
  manifestations described in expanded case reviews. The principal
  loss-of-function cohort consists of de novo variants, while familial reports
  describe variable autistic traits or self-limited focal epilepsy. Human-neuron
  experiments support parallel effects on somatodendritic and
  axon-initial-segment structure and on
  network activity, while a distinct giant-ankyrin-B model supports abnormal
  axon branching and connectivity. Cardiac ankyrin-B findings and disputed
  ANK2-LQTS/CPVT relationships are modeled in a separate cardiac record.
synonyms:
- ANK2-related neurodevelopmental disorder
- ANK2 haploinsufficiency disorder
disease_term:
  preferred_term: ANK2-related complex neurodevelopmental disorder
parents:
- Neurodevelopmental Disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100038
      label: complex neurodevelopmental disorder
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0100038 is the disease concept ClinGen uses for the ANK2
      gene-disease validity assertion, and this entry previously bound it as
      `disease_term`. That binding asserted identity with a grouping class
      whose MONDO definition reads "A disorder that involves more than one
      phenotype associated with the central nervous system, including but not
      limited to intellectual disability, autism, and seizures (epilepsy)".
      Its sixteen direct children are other disorders and grouping classes -
      Prader-Willi syndrome, developmental and epileptic encephalopathy,
      pervasive developmental disorder, and the DEAF1-, NACC1-, BLOC1S1- and
      AFG2B-related disorders among them - and none of them is a form of
      ANK2-related disease. Searching MONDO for "ANK2" with synonyms included
      returns one disease class, MONDO:0010958 cardiac arrhythmia,
      ankyrin-B-related, which this repository curates separately as the
      Cardiac Arrhythmia, Ankyrin-B-Related entry; searching for "ankyrin"
      adds only MONDO:0007715
      hemolytic poikilocytic anemia due to reduced ankyrin binding sites. No
      MONDO class denotes the neurodevelopmental phenotype, so `disease_term`
      now carries a free-text preferred term with no binding and the
      relationship to the grouping class is recorded here as a broad match.
      That also leaves MONDO:0100038 itself in the curation queue rather than
      retiring it through this entry.
external_assertions:
- name: Gene2Phenotype ANK2-neurodevelopmental disorder assertion
  source: Gene2Phenotype
  assertion_type: gene_disease_relationship
  external_id: G2P02923
  description: >-
    Gene2Phenotype records a loss-of-function ANK2 relationship with
    neurodevelopmental disorder (MONDO:0700092) at limited evidence.
- name: ClinGen ANK2-complex neurodevelopmental disorder assertion
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: "CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-10-21T100000.000Z"
  description: >-
    ClinGen classifies the autosomal dominant ANK2-complex neurodevelopmental
    disorder relationship (MONDO:0100038) as definitive.
  evidence:
  - reference: "CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-10-21T100000.000Z"
    reference_title: ANK2 / complex neurodevelopmental disorder (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ANK2 | HGNC:493 | complex neurodevelopmental disorder | MONDO:0100038 |
      AD | Definitive
    explanation: >-
      The ClinGen structured assertion directly supports the definitive
      autosomal dominant ANK2-complex neurodevelopmental disorder relationship.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    Heterozygous de novo loss-of-function variants predominate in the principal
    complex-neurodevelopmental cohort. A family carrying a giant-ankyrin-B
    frameshift had young-onset self-limited focal epilepsy without a documented
    complex neurodevelopmental phenotype, and a separate familial missense
    report described high-functioning autism in a child and subthreshold
    autistic traits in her father.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:37195288
    reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We collected clinical and molecular data of 12 individuals with
      heterozygous de novo LoF variants in ANK2.
    explanation: >-
      Establishes heterozygous de novo loss of function in the principal human
      cohort.
  - reference: PMID:39962910
    reference_title: "Self-limited familial focal epilepsy caused by ANK2 variants: A potentially under-recognized condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hereby, we reported a Taiwanese family with the ANK2 pathogenic variant
      (chr4:114276707, c.6933del, p.T2312Lfs*2) that affects the giant
      ankyrin-B isoform.
    explanation: >-
      The familial report shows that ANK2-related epilepsy is not confined to
      de novo presentations, but it does not establish inherited complex
      neurodevelopmental disorder.
  - reference: PMID:39978592
    reference_title: "Variability in autism spectrum phenotypes linked to heterozygous missense familial ANK2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patient was diagnosed with high-functioning ASD while her father
      showed subthreshold autistic traits such as relational difficulties and
      peculiar interests.
    explanation: >-
      Supports inherited and variably expressive autistic traits in one family,
      but the reported missense variant was only predicted pathogenic and does
      not redefine the established loss-of-function mechanism.
mechanistic_hypotheses:
- hypothesis_group_id: general_ank2_haploinsufficiency_neuronal_model
  hypothesis_label: General ANK2 Haploinsufficiency Neuronal Model
  status: EMERGING
  description: >-
    Reduced ankyrin-B expression in human neurons produces parallel
    somatodendritic/AIS abnormalities and hyperactive, desynchronized network
    activity. Links from these cellular phenotypes to intellectual disability
    and epilepsy remain candidate disease mechanisms rather than established
    linear causal chains.
  evidence:
  - reference: PMID:37195288
    reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our functional in vitro data of ANK2-deficient human neurons show a
      specific neuronal phenotype in which reduced ANKB expression leads to
      hyperactive and desynchronized neuronal network activity, increased
      somatodendritic complexity and AIS structure and impaired
      activity-dependent plasticity of the AIS.
    explanation: >-
      Supports both observed human-neuron branches without imposing a serial
      AIS-to-network edge.
- hypothesis_group_id: giant_ankyrin_b_axon_branching_model
  hypothesis_label: Giant Ankyrin-B Axon-Branching Model
  status: EMERGING
  description: >-
    The neurospecific giant ankyrin-B isoform normally couples axonal
    microtubules to L1CAM-containing membrane domains and restricts collateral
    branch formation. Disruption produces ectopic axon branching and
    connectivity in a mouse-derived neuronal model; relevance to human autistic
    behavior remains a candidate link.
  evidence:
  - reference: PMID:31285321
    reference_title: "ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, gain of axon branching due to giant ankB-deficiency/mutation is a
      candidate cellular mechanism to explain aberrant structural connectivity
      and penetrant behavioral consequences in mice as well as humans bearing
      ASD-related ANK2 mutations.
    explanation: >-
      The authors explicitly frame giant-ankyrin-B-dependent branching as a
      candidate mechanism with model-organism support.
- hypothesis_group_id: ank2_kv7_cortical_hyperexcitability_model
  hypothesis_label: ANK2-Kv7 Cortical Hyperexcitability Model
  status: EMERGING
  description: >-
    Developmental Ank2 loss in mouse cortical excitatory neurons reduces the
    abundance and function of AIS Kv7.2/KCNQ2 and Kv7.3/KCNQ3 channels, producing
    cortical hyperexcitability and seizure-related death. Kv7 activation and
    AMPA-receptor antagonism rescue model phenotypes, but this mechanism and its
    pharmacologic tractability have not been established in affected humans.
  evidence:
  - reference: PMID:37321992
    reference_title: "Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These changes accompanied decreases in the total level and function of
      the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of
      these channels in the enlengthened axon initial segment.
    explanation: >-
      Directly supports the proposed Kv7-channel arm in Ank2-mutant mice.
- hypothesis_group_id: dendritic_nav1_2_scaffolding_model
  hypothesis_label: Dendritic NaV1.2 Scaffolding Model
  status: EMERGING
  description: >-
    Ankyrin-B scaffolds NaV1.2 at the dendritic membrane of mouse neocortical
    pyramidal neurons. Ank2 haploinsufficiency reproduces dendritic excitability
    and synaptic deficits seen with Scn2a haploinsufficiency, suggesting a
    convergent dendritic mechanism for autism-related neurodevelopmental risk.
  evidence:
  - reference: PMID:38290518
    reference_title: "Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we show that ankyrin-B is essential for scaffolding NaV1.2 to the
      dendritic membrane of mouse neocortical neurons and that haploinsufficiency
      of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits
      observed in Scn2a+/- conditions.
    explanation: >-
      Establishes the ankyrin-B-dependent dendritic NaV1.2 scaffolding mechanism
      and the resulting cellular deficits in mouse neurons.
pathophysiology:
- name: ANK2 Haploinsufficiency in Neurons
  description: >-
    Heterozygous ANK2 loss of function reduces ankyrin-B expression in neurons
    and initiates the general haploinsufficiency mechanism.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ANK2
    term:
      id: hgnc:493
      label: ANK2
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:37195288
    reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our functional in vitro data of ANK2-deficient human neurons show a
      specific neuronal phenotype in which reduced ANKB expression leads to
      hyperactive and desynchronized neuronal network activity, increased
      somatodendritic complexity and AIS structure and impaired
      activity-dependent plasticity of the AIS.
    explanation: >-
      Directly supports reduced ankyrin-B expression as the upstream
      experimental perturbation in human neurons.
  downstream:
  - target: Increased Somatodendritic Complexity
    description: >-
      ANK2-deficient human neurons show increased somatodendritic structures.
    hypothesis_groups:
    - general_ank2_haploinsufficiency_neuronal_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37195288
      reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        ANK2-deficient neurons also showed increased somatodendritic structures
        and altered AIS structure of which its plasticity is impaired upon
        activity-dependent modulation.
      explanation: >-
        Directly reports the structural and plasticity phenotype in
        ANK2-deficient human neurons.
  - target: Impaired AIS Structural Plasticity
    description: >-
      ANK2-deficient human neurons show altered axon-initial-segment structure
      and impaired activity-dependent plasticity.
    hypothesis_groups:
    - general_ank2_haploinsufficiency_neuronal_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37195288
      reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        ANK2-deficient neurons also showed increased somatodendritic structures
        and altered AIS structure of which its plasticity is impaired upon
        activity-dependent modulation.
      explanation: >-
        Directly reports impaired AIS structural plasticity in ANK2-deficient
        human neurons.
  - target: Hyperactive and Desynchronized Neuronal Networks
    description: >-
      ANK2-deficient human neurons develop hyperactive and desynchronized
      network activity as a parallel experimental consequence.
    hypothesis_groups:
    - general_ank2_haploinsufficiency_neuronal_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37195288
      reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Using MEAs, we found that hiPSC-derived neurons with heterozygous LoF of
        ANK2 show a hyperactive and desynchronized neuronal network.
      explanation: >-
        Directly reports the network phenotype after heterozygous ANK2 loss of
        function.
  - target: Reduced Dendritic NaV1.2 Scaffolding
    description: >-
      Ank2 haploinsufficiency reduces ankyrin-B-dependent scaffolding of NaV1.2
      at the dendritic membrane in mouse neocortical pyramidal neurons.
    hypothesis_groups:
    - dendritic_nav1_2_scaffolding_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38290518
      reference_title: "Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we show that ankyrin-B is essential for scaffolding NaV1.2 to the
        dendritic membrane of mouse neocortical neurons and that haploinsufficiency
        of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits
        observed in Scn2a+/- conditions.
      explanation: >-
        Directly connects Ank2 haploinsufficiency with loss of dendritic NaV1.2
        scaffolding in mouse neurons.
  - target: Microcephaly
    description: >-
      Microcephaly has been observed in individuals with ANK2 variants, but the
      intervening developmental mechanism is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: "CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-10-21T100000.000Z"
      reference_title: ANK2 / complex neurodevelopmental disorder (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Individuals with variants in this gene have presented with
        neurodevelopmental phenotypes including autism spectrum disorder,
        intellectual disability, seizures, and microcephaly.
      explanation: >-
        ClinGen records microcephaly in affected individuals but does not
        establish the intermediate causal pathway.
  - target: Anxiety
    description: >-
      Anxiety or agitation/mood disorder has been reported in affected
      individuals, but the intervening mechanism is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40035441
      reference_title: "A Mutation in the ANK2 Gene Causing ASD and a Review of the Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient cohort included 16 patients with a complex array of
        neurological disabilities: ASD (9 patients); EP (10 patients); ASD with
        EP (4 patients); intellectual disability and developmental delay (5 patients);
        poor language communication (11 patients); language and learning impairment
        (11 patients); anxiety/agitation mood disorder (6 patients)
      explanation: >-
        Supports anxiety or agitation/mood disorder in the reported ANK2
        spectrum, but not a specific molecular-to-clinical pathway.
- name: Increased Somatodendritic Complexity
  description: >-
    ANK2-deficient human neurons have increased somatodendritic complexity.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:37195288
    reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ANK2-deficient neurons also showed increased somatodendritic structures
      and altered AIS structure of which its plasticity is impaired upon
      activity-dependent modulation.
    explanation: >-
      Establishes the cellular phenotype in human induced-pluripotent-stem-cell
      derived neurons.
  downstream:
  - target: Intellectual Disability
    description: >-
      Altered neuronal structure and homeostatic plasticity are candidate
      contributors to intellectual disability; the omitted human intermediates
      remain unresolved.
    hypothesis_groups:
    - general_ank2_haploinsufficiency_neuronal_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37195288
      reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We found a broad neurodevelopmental disorder (NDD), comprising
        intellectual disability, autism spectrum disorders and early onset
        epilepsy.
      explanation: >-
        The same study reports intellectual disability and the cellular
        phenotype, but does not establish the intervening causal chain.
  - target: Global Developmental Delay
    description: >-
      Altered neuronal morphology is a candidate contributor to developmental
      delay; the cellular-to-clinical intermediates are unresolved.
    hypothesis_groups:
    - general_ank2_haploinsufficiency_neuronal_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40035441
      reference_title: "A Mutation in the ANK2 Gene Causing ASD and a Review of the Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient cohort included 16 patients with a complex array of
        neurological disabilities: ASD (9 patients); EP (10 patients); ASD with
        EP (4 patients); intellectual disability and developmental delay (5 patients)
      explanation: >-
        The clinical review supports developmental delay in the ANK2 spectrum
        but not this proposed cellular-to-clinical edge.
  - target: Delayed Speech and Language Development
    description: >-
      Altered neuronal morphology is a candidate contributor to speech and
      language delay; the intermediates are unresolved.
    hypothesis_groups:
    - general_ank2_haploinsufficiency_neuronal_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40035441
      reference_title: "A Mutation in the ANK2 Gene Causing ASD and a Review of the Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        He mainly presents with language delay, intellectual disability,
        limited learning, and communication skills, and later develops seizures,
        combined with common childhood neurological disorders such as hyperactivity,
        behavioral abnormalities, and even self-injury.
      explanation: >-
        The human case supports language delay but not the proposed mechanistic edge.
- name: Impaired AIS Structural Plasticity
  description: >-
    ANK2-deficient human neurons have altered axon-initial-segment structure and
    impaired activity-dependent plasticity.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:37195288
    reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ANK2-deficient neurons also showed increased somatodendritic structures
      and altered AIS structure of which its plasticity is impaired upon
      activity-dependent modulation.
    explanation: >-
      Directly supports impaired activity-dependent AIS plasticity in human
      induced-pluripotent-stem-cell-derived neurons.
  downstream:
  - target: Epilepsy
    description: >-
      Impaired AIS homeostatic plasticity is a candidate contributor to epilepsy;
      the cellular-to-clinical intermediates have not been established.
    hypothesis_groups:
    - general_ank2_haploinsufficiency_neuronal_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37195288
      reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Phenotypic characterization of patients with de novo ANK2 LoF variants
        defines a novel NDD with early onset epilepsy.
      explanation: >-
        The study links the ANK2 loss-of-function syndrome to early-onset
        epilepsy but does not demonstrate this specific cellular-to-clinical edge.
- name: Hyperactive and Desynchronized Neuronal Networks
  description: >-
    Heterozygous ANK2 loss of function produces a hyperactive yet desynchronized
    network phenotype in human induced-pluripotent-stem-cell-derived neurons.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:37195288
    reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Using MEAs, we found that hiPSC-derived neurons with heterozygous LoF of
      ANK2 show a hyperactive and desynchronized neuronal network.
    explanation: >-
      Directly establishes the human-neuron network phenotype.
  downstream:
  - target: Epilepsy
    description: >-
      Network dysregulation is a candidate contributor to epilepsy, but the
      cellular-to-clinical intermediates have not been established.
    hypothesis_groups:
    - general_ank2_haploinsufficiency_neuronal_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37195288
      reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We found a broad neurodevelopmental disorder (NDD), comprising
        intellectual disability, autism spectrum disorders and early onset
        epilepsy.
      explanation: >-
        The study reports early-onset epilepsy alongside the network phenotype,
        but does not demonstrate a direct clinical causal edge.
- name: Developmental Forebrain Ank2 Loss
  description: >-
    Conditional mouse models restrict Ank2 loss to developing forebrain cells,
    including prenatal cortical excitatory neurons and oligodendrocytes or
    cortical and hippocampal excitatory neurons.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ANK2
    term:
      id: hgnc:493
      label: ANK2
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:37428632
    reference_title: "Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We find that mice with prenatal deletion in cortical excitatory neurons
      and oligodendrocytes (Ank2-/-:Emx1-Cre), but not with adolescent deletion
      in forebrain excitatory neurons (Ank2-/-:CaMKIIα-Cre), display severe
      spontaneous seizures, increased mortality, hyperactivity, and social deficits.
    explanation: >-
      Directly supports a prenatal developmental requirement for Ank2 in the
      mouse seizure and behavioral phenotype.
  - reference: PMID:37321992
    reference_title: "Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we report that mice with Ank2 knockout restricted to cortical and
      hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral
      abnormalities and juvenile seizure-related death.
    explanation: >-
      Supports the second conditional Ank2-loss model and its behavioral and
      seizure-related phenotypes.
  downstream:
  - target: Reduced AIS Kv7.2 and Kv7.3 Channel Function
    description: >-
      Ank2 loss reduces Kv7.2/KCNQ2 and Kv7.3/KCNQ3 abundance, function, and AIS
      density in cortical excitatory neurons.
    hypothesis_groups:
    - ank2_kv7_cortical_hyperexcitability_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37321992
      reference_title: "Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These changes accompanied decreases in the total level and function of
        the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of
        these channels in the enlengthened axon initial segment.
      explanation: >-
        Directly reports the Kv7 channel deficit in Ank2 conditional-knockout
        cortical neurons.
  - target: Mouse Cortical Hyperexcitability and Hypersynchrony
    description: >-
      Prenatal forebrain Ank2 deletion directly produces cortical network
      hyperexcitability and hypersynchrony in the Emx1-Cre model, independently
      of the Kv7 findings established in the separate excitatory-neuron model.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37428632
      reference_title: "Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Calcium imaging of cortical slices from Ank2-/-:Emx1-Cre mice shows
        increased neuronal calcium event amplitude and frequency, along with
        network hyperexcitability and hypersynchrony.
      explanation: >-
        Directly connects the prenatal Emx1-Cre perturbation to its measured
        cortical network phenotype without routing through the other mouse
        model's Kv7 result.
- name: Reduced AIS Kv7.2 and Kv7.3 Channel Function
  description: >-
    Ank2-mutant mouse cortical neurons have reduced Kv7.2/KCNQ2 and Kv7.3/KCNQ3
    channel abundance, function, and density at the axon initial segment.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: cortical excitatory neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:37321992
    reference_title: "Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These changes accompanied decreases in the total level and function of
      the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of
      these channels in the enlengthened axon initial segment.
    explanation: >-
      Establishes the channel deficit and its AIS localization in the mouse model.
  downstream:
  - target: Mouse Cortical Hyperexcitability and Hypersynchrony
    description: >-
      Reduced Kv7 channel function contributes to increased neuronal excitability
      and firing in Ank2-mutant cortical neurons.
    hypothesis_groups:
    - ank2_kv7_cortical_hyperexcitability_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37321992
      reference_title: "Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Ank2-cKO cortical neurons show abnormally increased excitability and
        firing rate.
      explanation: >-
        Directly reports cortical neuronal hyperexcitability in the model with
        reduced Kv7 channel function.
- name: Mouse Cortical Hyperexcitability and Hypersynchrony
  description: >-
    Conditional Ank2 loss produces increased excitability and firing in mouse
    cortical neurons and hyperexcitable, hypersynchronous cortical networks.
    This model-organism node is distinct from the desynchronized network
    phenotype observed in human induced-pluripotent-stem-cell-derived neurons.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:37321992
    reference_title: "Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Ank2-cKO cortical neurons show abnormally increased excitability and
      firing rate.
    explanation: >-
      Directly establishes cellular hyperexcitability in the mouse cortex after
      conditional Ank2 knockout.
  - reference: PMID:37428632
    reference_title: "Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Calcium imaging of cortical slices from Ank2-/-:Emx1-Cre mice shows
      increased neuronal calcium event amplitude and frequency, along with
      network hyperexcitability and hypersynchrony.
    explanation: >-
      Directly establishes the cortical network phenotype in the prenatal
      forebrain-deletion mouse model.
  downstream:
  - target: Epilepsy
    description: >-
      Mouse cortical hyperexcitability and hypersynchrony accompany severe
      spontaneous seizures, but translation to human epilepsy remains indirect.
    hypothesis_groups:
    - ank2_kv7_cortical_hyperexcitability_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37428632
      reference_title: "Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We find that mice with prenatal deletion in cortical excitatory neurons
        and oligodendrocytes (Ank2-/-:Emx1-Cre), but not with adolescent deletion
        in forebrain excitatory neurons (Ank2-/-:CaMKIIα-Cre), display severe
        spontaneous seizures, increased mortality, hyperactivity, and social deficits.
      explanation: >-
        The mouse model connects prenatal Ank2 loss and the cortical network
        phenotype with seizures, without establishing a human causal chain.
- name: Reduced Dendritic NaV1.2 Scaffolding
  description: >-
    Ankyrin-B is required to scaffold NaV1.2 at the dendritic membrane of mouse
    neocortical pyramidal neurons; Ank2 haploinsufficiency disrupts this function.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: neocortical pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:38290518
    reference_title: "Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we show that ankyrin-B is essential for scaffolding NaV1.2 to the
      dendritic membrane of mouse neocortical neurons and that haploinsufficiency
      of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits
      observed in Scn2a+/- conditions.
    explanation: >-
      Directly establishes ankyrin-B-dependent dendritic NaV1.2 scaffolding.
  downstream:
  - target: Impaired Dendritic Excitability and Synaptic Function
    description: >-
      Loss of dendritic ankyrin-B scaffolding produces intrinsic dendritic
      excitability and synaptic deficits.
    hypothesis_groups:
    - dendritic_nav1_2_scaffolding_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38290518
      reference_title: "Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we show that ankyrin-B is essential for scaffolding NaV1.2 to the
        dendritic membrane of mouse neocortical neurons and that haploinsufficiency
        of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits
        observed in Scn2a+/- conditions.
      explanation: >-
        Directly supports the cellular consequence of Ank2 haploinsufficiency.
- name: Impaired Dendritic Excitability and Synaptic Function
  description: >-
    Ank2 haploinsufficiency impairs intrinsic dendritic excitability and synaptic
    function in mouse neocortical pyramidal neurons.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neocortical pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:38290518
    reference_title: "Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results establish a direct, convergent link between two major ASD
      risk genes and reinforce an emerging framework suggesting that neocortical
      pyramidal cell dendritic dysfunction can contribute to neurodevelopmental
      disorder pathophysiology.
    explanation: >-
      Supports the authors' explicitly emerging dendritic-dysfunction framework.
  downstream:
  - target: Autistic Behavior
    description: >-
      Dendritic dysfunction is a candidate contributor to autistic behavior;
      the evidence remains confined to mouse neurons and an emerging framework.
    hypothesis_groups:
    - dendritic_nav1_2_scaffolding_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38290518
      reference_title: "Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These results establish a direct, convergent link between two major ASD
        risk genes and reinforce an emerging framework suggesting that neocortical
        pyramidal cell dendritic dysfunction can contribute to neurodevelopmental
        disorder pathophysiology.
      explanation: >-
        The authors frame dendritic dysfunction as a contributor to NDD
        pathophysiology, not a demonstrated cause of human autistic behavior.
  - target: Attention Deficit Hyperactivity Disorder
    description: >-
      Dendritic and synaptic dysfunction is a candidate contributor to ADHD;
      no ANK2-specific causal intermediates have been demonstrated in humans.
    hypothesis_groups:
    - dendritic_nav1_2_scaffolding_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40035441
      reference_title: "A Mutation in the ANK2 Gene Causing ASD and a Review of the Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient cohort included 16 patients with a complex array of
        neurological disabilities: ASD (9 patients); EP (10 patients); ASD with
        EP (4 patients); intellectual disability and developmental delay (5 patients);
        poor language communication (11 patients); language and learning impairment
        (11 patients); anxiety/agitation mood disorder (6 patients);
        attention-deficit/hyperactivity disorder (5 patients)
      explanation: >-
        Supports ADHD in the reported ANK2 spectrum but not the proposed
        dendritic-to-clinical edge.
- name: Giant Ankyrin-B Axonal Membrane-Microtubule Coupling Failure
  description: >-
    Giant ankyrin-B normally localizes through L1CAM-containing axonal membrane
    domains, couples microtubules to the plasma membrane, and prevents
    microtubule entry into nascent branches.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ANK2
    term:
      id: hgnc:493
      label: ANK2
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: axonogenesis
    term:
      id: GO:0007409
      label: axonogenesis
    modifier: DYSREGULATED
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:31285321
    reference_title: "ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We elucidate a mechanism normally limiting axon branching, whereby giant
      ankB localizes to periodic axonal plasma membrane domains through L1
      cell-adhesion molecule protein, where it couples microtubules to the plasma
      membrane and prevents microtubule entry into nascent axon branches.
    explanation: >-
      Establishes the L1CAM-microtubule coupling mechanism in the
      mouse-derived neuronal system.
  downstream:
  - target: Ectopic Axon Branching
    description: >-
      Disruption of the giant ankyrin-B branch-restriction mechanism increases
      axonal branching.
    hypothesis_groups:
    - giant_ankyrin_b_axon_branching_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31285321
      reference_title: "ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We report that a mouse model for human ASD mutation of giant ankB
        exhibits increased axonal branching in cultured neurons with ectopic CNS
        axon connectivity, as well as with a transient increase in excitatory
        synapses during postnatal development.
      explanation: >-
        Directly demonstrates ectopic branching and connectivity in the
        giant-ankyrin-B model.
- name: Ectopic Axon Branching
  description: >-
    Giant-ankyrin-B disruption produces excess axonal branching in a mouse
    model.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: axonogenesis
    term:
      id: GO:0007409
      label: axonogenesis
    modifier: DYSREGULATED
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:31285321
    reference_title: "ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We report that a mouse model for human ASD mutation of giant ankB exhibits
      increased axonal branching in cultured neurons with ectopic CNS axon
      connectivity, as well as with a transient increase in excitatory synapses
      during postnatal development.
    explanation: >-
      Establishes the model-organism cellular phenotype.
  downstream:
  - target: Ectopic CNS Connectivity
    description: >-
      Excess axon branching accompanies ectopic central-nervous-system axon
      connectivity in the giant-ankyrin-B mouse model.
    hypothesis_groups:
    - giant_ankyrin_b_axon_branching_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31285321
      reference_title: "ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We report that a mouse model for human ASD mutation of giant ankB
        exhibits increased axonal branching in cultured neurons with ectopic CNS
        axon connectivity, as well as with a transient increase in excitatory
        synapses during postnatal development.
      explanation: >-
        Directly reports excess branching together with ectopic CNS connectivity.
- name: Ectopic CNS Connectivity
  description: >-
    The giant-ankyrin-B mouse model shows ectopic CNS axon connectivity. Human
    behavioral relevance remains candidate rather than proven.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:31285321
    reference_title: "ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We report that a mouse model for human ASD mutation of giant ankB exhibits
      increased axonal branching in cultured neurons with ectopic CNS axon
      connectivity, as well as with a transient increase in excitatory synapses
      during postnatal development.
    explanation: >-
      Establishes ectopic CNS connectivity in the mouse model.
  downstream:
  - target: Autistic Behavior
    description: >-
      Aberrant connectivity is a candidate contributor to autistic behavior;
      human causal intermediates remain unresolved.
    hypothesis_groups:
    - giant_ankyrin_b_axon_branching_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31285321
      reference_title: "ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thus, gain of axon branching due to giant ankB-deficiency/mutation is a
        candidate cellular mechanism to explain aberrant structural connectivity
        and penetrant behavioral consequences in mice as well as humans bearing
        ASD-related ANK2 mutations.
      explanation: >-
        The authors explicitly call the branching-to-behavior relationship a
        candidate mechanism.
phenotypes:
- category: Neurodevelopmental
  name: Intellectual Disability
  description: >-
    Intellectual disability is part of the reported ANK2 loss-of-function
    neurodevelopmental spectrum. No frequency is assigned because the cached
    source does not provide a supportable numerator.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:37195288
    reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found a broad neurodevelopmental disorder (NDD), comprising
      intellectual disability, autism spectrum disorders and early onset
      epilepsy.
    explanation: >-
      Directly includes intellectual disability in the human phenotype.
- category: Neurodevelopmental
  name: Autistic Behavior
  description: >-
    Autism spectrum disorder is part of the reported ANK2 loss-of-function
    phenotype. No frequency is assigned.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:37195288
    reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found a broad neurodevelopmental disorder (NDD), comprising
      intellectual disability, autism spectrum disorders and early onset
      epilepsy.
    explanation: >-
      Directly includes autism spectrum disorders in the human phenotype.
  - reference: PMID:39978592
    reference_title: "Variability in autism spectrum phenotypes linked to heterozygous missense familial ANK2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patient was diagnosed with high-functioning ASD while her father
      showed subthreshold autistic traits such as relational difficulties and
      peculiar interests.
    explanation: >-
      Extends the autistic spectrum to a variably expressive familial missense
      report, while leaving its pathogenic mechanism qualified.
- category: Neurological
  name: Epilepsy
  description: >-
    Epilepsy ranges from early-onset presentations in de novo
    loss-of-function cases to inherited, young-onset self-limited focal
    epilepsy. No frequency is assigned.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:37195288
    reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found a broad neurodevelopmental disorder (NDD), comprising
      intellectual disability, autism spectrum disorders and early onset
      epilepsy.
    explanation: >-
      Establishes early-onset epilepsy in the principal cohort.
  - reference: PMID:39962910
    reference_title: "Self-limited familial focal epilepsy caused by ANK2 variants: A potentially under-recognized condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The family members presented with young-onset self-limited focal epilepsy,
      and achieved seizure-free in adulthood with antiseizure medications.
    explanation: >-
      Extends the spectrum to inherited, self-limited focal epilepsy.
- category: Neurodevelopmental
  name: Global Developmental Delay
  description: >-
    Developmental delay was reported in the expanded 16-person literature-based
    cohort. No frequency enum is assigned because this is a selected published
    case series rather than an unbiased prevalence cohort.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:40035441
    reference_title: "A Mutation in the ANK2 Gene Causing ASD and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient cohort included 16 patients with a complex array of
      neurological disabilities: ASD (9 patients); EP (10 patients); ASD with
      EP (4 patients); intellectual disability and developmental delay (5 patients)
    explanation: >-
      Directly reports developmental delay in the ANK2 patient cohort.
- category: Neurodevelopmental
  name: Delayed Speech and Language Development
  description: >-
    Language delay and poor communication or learning skills are recurrently
    described in the expanded clinical literature.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:40035441
    reference_title: "A Mutation in the ANK2 Gene Causing ASD and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He mainly presents with language delay, intellectual disability, limited
      learning, and communication skills, and later develops seizures
    explanation: >-
      Directly reports language and communication impairment in an affected child.
- category: Behavioral
  name: Attention Deficit Hyperactivity Disorder
  description: >-
    Attention-deficit/hyperactivity disorder and hyperactivity are reported in
    affected individuals; no population frequency is inferred from the selected
    published cases.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:40035441
    reference_title: "A Mutation in the ANK2 Gene Causing ASD and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient cohort included 16 patients with a complex array of
      neurological disabilities: ASD (9 patients); EP (10 patients); ASD with
      EP (4 patients); intellectual disability and developmental delay (5 patients);
      poor language communication (11 patients); language and learning impairment
      (11 patients); anxiety/agitation mood disorder (6 patients);
      attention-deficit/hyperactivity disorder (5 patients)
    explanation: >-
      Directly reports ADHD among affected individuals in the expanded review.
- category: Neurological
  name: Microcephaly
  description: >-
    Microcephaly has been reported among individuals included in the definitive
    ClinGen ANK2-complex neurodevelopmental disorder curation.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: "CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-10-21T100000.000Z"
    reference_title: ANK2 / complex neurodevelopmental disorder (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with variants in this gene have presented with
      neurodevelopmental phenotypes including autism spectrum disorder,
      intellectual disability, seizures, and microcephaly.
    explanation: >-
      ClinGen explicitly includes microcephaly in the reported ANK2 phenotype.
- category: Behavioral
  name: Anxiety
  description: >-
    Anxiety or agitation/mood disorder was reported in 6 of 16 selected
    published cases. No population frequency enum is inferred from this
    literature-based cohort.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:40035441
    reference_title: "A Mutation in the ANK2 Gene Causing ASD and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient cohort included 16 patients with a complex array of
      neurological disabilities: ASD (9 patients); EP (10 patients); ASD with
      EP (4 patients); intellectual disability and developmental delay (5 patients);
      poor language communication (11 patients); language and learning impairment
      (11 patients); anxiety/agitation mood disorder (6 patients)
    explanation: >-
      Directly reports anxiety or agitation/mood disorder in the expanded
      literature cohort.
genetic:
- name: ANK2 loss-of-function variants
  gene_term:
    preferred_term: ANK2
    term:
      id: hgnc:493
      label: ANK2
  association: Causative heterozygous loss-of-function variants
  relationship_type: CAUSATIVE
  features: >-
    Heterozygous loss-of-function variants cause an autosomal dominant complex
    neurodevelopmental disorder. ClinGen curated seven de novo
    protein-truncating variants across eight probands and identifies loss of function as
    the predicted disease mechanism. De novo missense variants are also
    reported, including variants of uncertain significance; these are not
    generalized here as an established causative class. A separate familial
    giant-isoform frameshift report describes an epilepsy-only allelic
    presentation.
  evidence:
  - reference: PMID:37195288
    reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We collected clinical and molecular data of 12 individuals with
      heterozygous de novo LoF variants in ANK2.
    explanation: >-
      Establishes the heterozygous loss-of-function cohort.
  - reference: "CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-10-21T100000.000Z"
    reference_title: ANK2 / complex neurodevelopmental disorder (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Seven de novo protein truncating variants (frameshift and nonsense) that
      have been reported in 8 probands in 7 publications
    explanation: >-
      Supplies the curated variant-class and proband counts for the established
      truncating-variant class.
  - reference: "CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-10-21T100000.000Z"
    reference_title: ANK2 / complex neurodevelopmental disorder (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mechanism of pathogenicity is predicted to be loss-of-function based
      on the protein truncating variants reported in individuals affected with
      neurodevelopmental disorders and experimental data showing reduced protein
      expression in cultured cells bearing truncating variants in ANK2
    explanation: >-
      ClinGen explicitly supports loss of function as the disease mechanism.
  - reference: "CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-10-21T100000.000Z"
    reference_title: ANK2 / complex neurodevelopmental disorder (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      at least six de novo missense variants of unknown significance (PMIDs:
      28135719, 31981491) have also been reported in individuals with
      neurodevelopmental disorders.
    explanation: >-
      Documents the reported missense-VUS count while explicitly withholding
      support for an established causative missense class.
treatments:
- name: Antiseizure Medication Management
  description: >-
    Antiseizure medications provided seizure control in the reported family
    with young-onset self-limited focal epilepsy. Drug choice should be based on
    seizure type and individualized clinical assessment; this report does not
    establish a preferred ANK2-specific regimen.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: anticonvulsant agent therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  evidence:
  - reference: PMID:39962910
    reference_title: "Self-limited familial focal epilepsy caused by ANK2 variants: A potentially under-recognized condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The family members presented with young-onset self-limited focal epilepsy,
      and achieved seizure-free in adulthood with antiseizure medications.
    explanation: >-
      Direct human evidence supports symptomatic antiseizure medication use,
      without identifying a preferred drug or disease-modifying effect.
- name: Retigabine Kv7 Activation (Preclinical)
  description: >-
    Retigabine (ezogabine) rescued neuronal excitability and partially improved
    seizure-related survival and acute hyperactivity in an Ank2 conditional
    knockout mouse model. This is preclinical mechanism evidence, not evidence
    of efficacy or a treatment recommendation for people with ANK2-related
    neurodevelopmental disorder. The commercial product was discontinued
    globally in 2017 and is not an available clinical option.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ezogabine
      term:
        id: CHEBI:68584
        label: ezogabine
  target_mechanisms:
  - target: Reduced AIS Kv7.2 and Kv7.3 Channel Function
    treatment_effect: RESTORES
    description: >-
      Kv7 activation counteracts the reduced Kv7-dependent current and neuronal
      hyperexcitability in the Ank2 conditional-knockout model.
    evidence:
    - reference: PMID:37321992
      reference_title: "Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability,
        juvenile seizure-related death, and hyperactivity in Ank2-cKO mice.
      explanation: >-
        Directly demonstrates mechanism-linked rescue in the mouse model only.
  evidence:
  - reference: PMID:37321992
    reference_title: "Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability,
      juvenile seizure-related death, and hyperactivity in Ank2-cKO mice.
    explanation: >-
      Supports the preclinical rescue claim while not implying human efficacy.
- name: Perampanel AMPA-Receptor Antagonism (Preclinical)
  description: >-
    Perampanel restored cortical neuronal activity and partially rescued
    survival in a prenatal forebrain Ank2-deletion mouse model. This is
    preclinical evidence and does not establish efficacy or a treatment
    recommendation in affected humans.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: perampanel
      term:
        id: CHEBI:71013
        label: perampanel
  target_mechanisms:
  - target: Mouse Cortical Hyperexcitability and Hypersynchrony
    treatment_effect: MODULATES
    description: >-
      AMPA-receptor antagonism counteracts abnormal cortical network activity in
      the prenatal Ank2-deletion mouse model.
    evidence:
    - reference: PMID:37428632
      reference_title: "Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The AMPA receptor antagonist, perampanel, restores cortical neuronal
        activity and partially rescues survival in Ank2-/-:Emx1-Cre mice.
      explanation: >-
        Directly demonstrates network and survival rescue in the mouse model.
  evidence:
  - reference: PMID:37428632
    reference_title: "Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The AMPA receptor antagonist, perampanel, restores cortical neuronal
      activity and partially rescues survival in Ank2-/-:Emx1-Cre mice.
    explanation: >-
      Supports the preclinical rescue claim while not implying human efficacy.
diagnosis:
- name: Exome or genome sequencing for ANK2-related neurodevelopmental disorder
  diagnosis_term:
    preferred_term: clinical whole-exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  description: >-
    Exome or genome sequencing is appropriate early in the evaluation of a
    child with developmental delay or intellectual disability. A heterozygous
    pathogenic or likely pathogenic ANK2 loss-of-function variant, interpreted
    with inheritance and phenotype, supports the molecular diagnosis.
  results: >-
    Identification of a heterozygous pathogenic or likely pathogenic ANK2
    loss-of-function variant consistent with the neurodevelopmental phenotype.
  evidence:
  - reference: PMID:34211152
    reference_title: "Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We strongly recommend that ES/GS be considered as a first- or second-tier
      test for patients with CA/DD/ID.
    explanation: >-
      The ACMG guideline supports early exome or genome sequencing in the
      relevant pediatric neurodevelopmental population.
  - reference: PMID:37195288
    reference_title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We collected clinical and molecular data of 12 individuals with
      heterozygous de novo LoF variants in ANK2.
    explanation: >-
      Establishes the molecular class identified in affected individuals.
- name: Electroencephalography for Seizure Evaluation
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  description: >-
    EEG is appropriate for evaluating suspected seizures and documenting
    electrophysiologic abnormalities in the ANK2-related spectrum. Published
    cases establish that abnormal EEG is common in the selected literature
    cohort but do not define a single ANK2-specific EEG signature.
  results: >-
    An abnormal EEG supports seizure phenotyping but is not specific for an
    ANK2 molecular diagnosis.
  evidence:
  - reference: PMID:40035441
    reference_title: "A Mutation in the ANK2 Gene Causing ASD and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient cohort included 16 patients with a complex array of
      neurological disabilities: ASD (9 patients); EP (10 patients); ASD with
      EP (4 patients); intellectual disability and developmental delay (5 patients);
      poor language communication (11 patients); language and learning impairment
      (11 patients); anxiety/agitation mood disorder (6 patients);
      attention-deficit/hyperactivity disorder (5 patients); cognitive, memory,
      and adaptability deficits (1 patient); tic disorder (1 patient);
      electrocardiogram and cardiac damage (1 patient); and abnormal
      electroencephalography (EEG) (9 patients).
    explanation: >-
      Directly supports abnormal EEG as a recurrent finding while not asserting
      a disease-specific electrophysiologic pattern.
notes: >-
  MONDO:0100038 is a broad complex-neurodevelopmental-disorder class used by
  the ClinGen assertion for this gene-disease relationship. It was previously
  bound as this entry's `disease_term`, which asserted identity with the
  grouping class. MONDO has no class for the ANK2-related neurodevelopmental
  phenotype, so `disease_term` now carries a free-text preferred term with no
  binding and the grouping class is recorded in `mappings` as a broad match.
  The sixteen MONDO children of that class are distinct gene-defined
  disorders and grouping classes rather than subtypes of this entry. dismech
  curates five of them separately - BLOC1S1-related Complex Neurodevelopmental
  Disorder with Leukodystrophy, SOX11-Related Neurodevelopmental Disorder,
  GRIN2A-Related Epileptic Encephalopathy and Intellectual Disability,
  GRIN2B-Related Developmental and Epileptic Encephalopathy, and
  Neurodevelopmental Disorder with Hearing Loss and Spasticity for AFG2B
  (HGNC previous symbol SPATA5L1) - and has no entry binding DEAF1, NACC1,
  MYH10, EMC1 or GRIA2, each of which would need its own entry rather than a
  subtype row here. Published-case counts are not converted to
  population frequency enums because the expanded review is a selected
  literature cohort. Hypotonia and motor delay remain omitted because exact,
  disorder-scoped support was not available in the fetched reference caches.
  The 2020 ClinGen neurodevelopmental curation separately notes reported ANK2
  long-QT findings and an expert-panel validity evaluation; this record
  retains the neurodevelopmental scope and leaves cardiac assertions to the
  separate ankyrin-B cardiac record.
references:
- reference: "CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-10-21T100000.000Z"
  title: ANK2 / complex neurodevelopmental disorder (Definitive)
  findings: []
- reference: PMID:31285321
  title: "ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity."
  findings: []
- reference: PMID:34211152
  title: "Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG)."
  findings: []
- reference: PMID:37195288
  title: "ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks."
  findings: []
- reference: PMID:37321992
  title: "Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice."
  findings: []
- reference: PMID:37428632
  title: "Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome."
  findings: []
- reference: PMID:38290518
  title: "Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites."
  findings: []
- reference: PMID:39962910
  title: "Self-limited familial focal epilepsy caused by ANK2 variants: A potentially under-recognized condition."
  findings: []
- reference: PMID:39978592
  title: "Variability in autism spectrum phenotypes linked to heterozygous missense familial ANK2 mutation."
  findings: []
- reference: PMID:40035441
  title: "A Mutation in the ANK2 Gene Causing ASD and a Review of the Literature."
  findings: []
clinical_trials: []
datasets: []
📚

References & Deep Research

References

10
CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-10-21T100000.000Z
ANK2 / complex neurodevelopmental disorder (Definitive)
No top-level findings curated for this source.
PMID:31285321
ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity.
No top-level findings curated for this source.
PMID:34211152
Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG).
No top-level findings curated for this source.
PMID:37195288
ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks.
No top-level findings curated for this source.
PMID:37321992
Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice.
No top-level findings curated for this source.
PMID:37428632
Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome.
No top-level findings curated for this source.
PMID:38290518
Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites.
No top-level findings curated for this source.
PMID:39962910
Self-limited familial focal epilepsy caused by ANK2 variants: A potentially under-recognized condition.
No top-level findings curated for this source.
PMID:39978592
Variability in autism spectrum phenotypes linked to heterozygous missense familial ANK2 mutation.
No top-level findings curated for this source.
PMID:40035441
A Mutation in the ANK2 Gene Causing ASD and a Review of the Literature.
No top-level findings curated for this source.