KIF2A-related Complex Cortical Dysplasia

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Inheritance

1

Autosomal dominant inheritance HP:0000006

Heterozygous missense variants, de novo in nearly all reported probands. One sibling pair carrying the same variant absent from both parents suggests parental germline mosaicism, which bears on recurrence risk.

Autosomal dominant inheritance

Show evidence (4 references)

PMID:33506645 SUPPORT Human Clinical

"Cortical dysplasia, complex, with other brain malformations 3 (CDCBM3) is a rare autosomal dominant syndrome caused by Kinesin family Member 2A (KIF2A) gene mutation."

Directly states the autosomal dominant mode of inheritance for CDCBM3.

PMID:27747449 SUPPORT Human Clinical

"Here, we detected two de novo p.Ser317Asn and p.His321Pro mutations in KIF2A in two patients with lissencephaly and microcephaly."

De novo heterozygous occurrence in independent probands.

url:https://www.ncbi.nlm.nih.gov/books/NBK350554/pdf/Bookshelf_NBK350554.pdf SUPPORT Other

"Microcephaly w/cortical malformations KIF2A Complex cortical dysplasia w/other brain malformations 3 (OMIM 615411) AD"

The GeneReviews Tubulinopathies Overview lists KIF2A-related CDCBM3 among the differential diagnoses with autosomal dominant inheritance.

+ 1 more reference

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Discussions and Knowledge Gaps

1

Do KIF2A disease variants impair cortical progenitor proliferation, given that conditional loss of Kif2a in mouse does not?

HUMAN MODEL MISMATCH OPEN gap_kif2a_progenitor_versus_null

Attached to

pathophysiology#Progenitor Ciliogenesis and Cell-Cycle Coupling Defect

In utero electroporation of patient variants reduces progenitor proliferation and alters ciliogenesis, but conditional inactivation of Kif2a in cortical progenitors leaves embryonic neurogenesis intact and instead causes postnatal neuronal maturation failure and degeneration. If the missense variants act dominant-negatively, they could impair progenitors in a way that removing the protein does not; alternatively the electroporation result may reflect overexpression. The answer decides whether microcephaly in this disease comes mainly from reduced progenitor output or from neuronal loss.

Show evidence (2 references)

PMID:29077851 SUPPORT Model Organism

"Using cellular and in utero electroporation approaches, we show here that KIF2A disease-causing variants disrupts projection neuron positioning and interneuron migration, as well as progenitors proliferation."

Variant electroporation reduces progenitor proliferation.

PMID:36343267 REFUTE Model Organism

"Here, we report that KIF2A is dispensable for embryogenic neurogenesis but critical in postnatal stages for maturation, connectivity, and maintenance of neurons."

Conditional loss of Kif2a does not impair embryonic neurogenesis, which argues against a simple loss-of-function route to reduced progenitor output.

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Pathophysiology

7

KIF2A Motor-Domain Nucleotide-Pocket Disruption

Pathogenic missense variants alter residues in or next to the nucleotide-binding pocket of the central KIF2A motor domain (recurrently Ser317 and His321, also Gly318, Thr320, Ser433 and Gly440). The altered motor domain is expected to bind or hydrolyse ATP poorly. Recombinant mutant motor domains are poorly soluble, consistent with misfolding, and mutant proteins mislocalize in cells. Because both alleles are expressed and KIF2A acts as a dimer, the original report considered the data consistent with a dominant-negative effect.

KIF2A hgnc:6318

Genetic context allele_type: missense variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE

Only heterozygous missense alleles in the motor domain are associated with CDCBM3. The dominant-negative call follows the authors' stated interpretation ("consistent with a dominant-negative effect") and has not been demonstrated directly, for example by mixing mutant and wild-type dimers.

ATP hydrolysis activity GO:0016887 ↓ DECREASED microtubule binding GO:0008017 ↕ DYSREGULATED

Downstream

Impaired Microtubule Depolymerization A motor domain that cannot bind or hydrolyse ATP cannot drive the ATP-dependent depolymerization of microtubule ends.

Show evidence (6 references)

PMID:23603762 SUPPORT Computational

"both conserved residues p.S317 and p.H321 are located around the nucleotide binding pocket, suggesting that the ability of KIF2A mutants to bind and/or hydrolyse ATP is likely to be impaired."

Structural mapping places the founding variants at the nucleotide-binding pocket and predicts impaired ATP binding or hydrolysis.

PMID:23603762 SUPPORT In Vitro

"These data imply that the mutations lead to substantially reduced solubility as a result of misfolding, and therefore at a minimum result in a reduced yield of functional protein."

Recombinant mutant motor domains are poorly soluble, indicating misfolding.

PMID:23603762 SUPPORT INDIRECT In Vitro

"In view of the fact that both KIF2A alleles are expressed in patient fibroblasts (Supplementary Fig. 4b) and that the KIF2A molecule functions as a dimer22, our in vitro and in vivo data are consistent with a dominant-negative effect of these mutations."

Basis for the dominant-negative functional-impact call, which the authors present as an interpretation rather than a direct measurement.

+ 3 more references

Impaired Microtubule Depolymerization

Loss of KIF2A depolymerase activity leaves microtubule ends less dynamic. In knock-in mice carrying the patient His321Asp variant, the cellular phenotypes are attributed to deficient microtubule-depolymerizing function, and Kif2a-null growth cones show reduced depolymerizing activity with abnormally behaving microtubules at the cell edge.

cortical neuron CL:0010012

microtubule depolymerization GO:0007019 ↓ DECREASED

Downstream

Defective Neuronal Migration and Positioning Migrating neurons need dynamic microtubules to polarize and move.

Progenitor Ciliogenesis and Cell-Cycle Coupling Defect Cilium disassembly and spindle function in dividing progenitors depend on microtubule depolymerization.

Increased Neuronal Apoptosis Expression of the mutant protein increases apoptosis in the developing cortex.

Interneuron Inhibitory Synapse Formation Defect Interneurons need KIF2A-dependent microtubule remodeling to build inhibitory synapses.

Show evidence (2 references)

PMID:31919497 SUPPORT Model Organism

"We further demonstrate that the observed cellular phenotypes are likely to be linked to deficiency in the microtubule depolymerizing function of KIF2A."

In a patient-variant knock-in mouse, the cellular defects are attributed to loss of depolymerase function.

PMID:12887924 SUPPORT INDIRECT Model Organism

"In kif2a(-/-) growth cones, microtubule-depolymerizing activity decreased."

Null-allele evidence that KIF2A is required for microtubule depolymerization in neurons; indirect because the human disease alleles are missense rather than null.

Defective Neuronal Migration and Positioning

Disease variants disrupt the positioning of radially migrating projection neurons and the tangential migration of interneurons. In the knock-in mouse, newborn neurons fail to make the normal multipolar-to-bipolar transition, the step that precedes locomotion through the cortical plate.

migrating cortical neuron CL:0010012 cortical interneuron CL:0000099

cerebral cortex radially oriented cell migration GO:0021799 ↓ DECREASED cerebral cortex tangential migration GO:0021800 ↓ DECREASED

Animal models

Kif2a H321D conditional knock-in mouse Mouse recapitulates Patient-variant knock-in reproducing the neuronal transition defect.

Downstream

Posterior-Predominant Classic Lissencephaly Neurons that fail to complete migration leave a thick, poorly gyrated cortex.

Show evidence (3 references)

PMID:29077851 SUPPORT Model Organism

"Using cellular and in utero electroporation approaches, we show here that KIF2A disease-causing variants disrupts projection neuron positioning and interneuron migration, as well as progenitors proliferation."

In utero electroporation of patient variants disrupts both radial positioning of projection neurons and interneuron migration.

PMID:31919497 SUPPORT Model Organism

"We show that the expression of the p.His321Asp pathogenic variant increases apoptosis and causes abnormal multipolar to bipolar transition in newborn neurons"

Localizes the migration defect to the multipolar-to-bipolar transition in a knock-in model of a patient variant.

PMID:36733270 SUPPORT INDIRECT Model Organism

"KIF2A is essential for tangential migration of cortical interneurons, their positioning in the cerebral cortex"

Interneuron-specific deletion confirms KIF2A is needed for tangential migration; indirect because the allele is a null.

Progenitor Ciliogenesis and Cell-Cycle Coupling Defect

In cortical progenitors, disease variants reduce proliferation and alter the regulation of primary cilium assembly and disassembly across the cell cycle. The authors propose that uncoupling ciliogenesis from cell-cycle progression contributes to the brain malformation, and the reduced progenitor output is a plausible contributor to microcephaly. This node rests on electroporation of patient variants; conditional Kif2a knockout in mouse did not impair embryonic neurogenesis, an inconsistency recorded as an open discussion.

cortical neural progenitor cell CL:0011020

cilium disassembly GO:0061523 ↕ DYSREGULATED neural precursor cell proliferation GO:0061351 ↓ DECREASED

Downstream

Microcephaly Reduced progenitor proliferation lowers neuronal output and brain size.

Show evidence (2 references)

PMID:29077851 SUPPORT Model Organism

"Interestingly, further dissection of this latter process revealed that ciliogenesis regulation is also altered during progenitors cell cycle."

Shows altered ciliogenesis regulation during the progenitor cell cycle.

PMID:29077851 SUPPORT Model Organism

"Altogether, our data suggest that deregulation of the coupling between ciliogenesis and cell cycle might contribute to the pathogenesis of KIF2A-related brain malformations."

The authors' proposed link from the progenitor defect to the malformation, stated as a suggestion.

Increased Neuronal Apoptosis

Expression of the His321Asp variant increases apoptosis in the developing cortex, and kif2a-null zebrafish show increased apoptosis with microcephaly. Cell loss is one plausible route to the small brain.

cortical neuron CL:0010012

neuron apoptotic process GO:0051402 ↑ INCREASED

Animal models

Kif2a H321D conditional knock-in mouse Mouse recapitulates

kif2a knockout zebrafish Zebrafish partially recapitulates Reproduces apoptosis and microcephaly through loss of function.

Downstream

Microcephaly Loss of neurons and progenitors reduces brain size.

Show evidence (2 references)

PMID:31919497 SUPPORT Model Organism

"We show that the expression of the p.His321Asp pathogenic variant increases apoptosis"

Patient-variant knock-in mice show increased apoptosis.

PMID:34404749 SUPPORT INDIRECT Model Organism

"Here, we present a novel kif2a knock-out zebrafish model, showing hypoactivity, habituation deficits, pentylenetetrazole-induced seizure susceptibility and microcephaly, as well as neuronal cell proliferation defects and increased apoptosis."

A null zebrafish model shows increased apoptosis alongside microcephaly; indirect because the allele class differs from the human missense variants.

Interneuron Inhibitory Synapse Formation Defect

Beyond migration, KIF2A is needed in cortical GABAergic interneurons for the formation of inhibitory synapses. Forebrain interneuron-specific Kif2a deletion in mouse impairs inhibitory synapse formation and increases epilepsy susceptibility, offering a route to seizures that is separate from the gross malformation. The evidence is from a null allele in mouse, not from a patient variant.

cortical GABAergic interneuron CL:0010011

inhibitory synapse assembly GO:1904862 ↓ DECREASED

Downstream

Seizures Reduced inhibitory synapse formation lowers cortical inhibition and favours seizures.

Show evidence (2 references)

PMID:36733270 SUPPORT INDIRECT Model Organism

"KIF2A is essential for tangential migration of cortical interneurons, their positioning in the cerebral cortex, and for formation of inhibitory synapses in vivo."

Conditional interneuron deletion shows KIF2A is required for inhibitory synapse formation; indirect because the allele is a null.

PMID:36733270 SUPPORT INDIRECT Model Organism

"We report that adult mice with specific deletion of KIF2A in GABAergic interneurons display abnormal behavior and increased susceptibility to epilepsy."

Links the interneuron defect to epilepsy susceptibility.

Posterior-Predominant Classic Lissencephaly

The cortical malformation is classic lissencephaly with a posterior-to-anterior gradient (posterior agyria or pachygyria), close to the LIS1/PAFAH1B1 pattern, sometimes with anterior subcortical band heterotopia and a dysplastic corpus callosum. This malformed cortex is the substrate for the epilepsy and the neurodevelopmental impairment.

cerebral cortex radially oriented cell migration GO:0021799 ↓ DECREASED

Downstream

Lissencephaly The malformation itself, as seen on MRI.

Anterior Subcortical Band Heterotopia Arrested migration can leave a band of neurons beneath the cortex.

Seizures The malformed cortex is epileptogenic.

Infantile Spasms The malformed cortex is epileptogenic.

Global Developmental Delay Disorganized cortex underlies the motor and cognitive impairment.

Intellectual Disability Disorganized cortex underlies the cognitive impairment in milder cases.

Absent Speech Disorganized cortex underlies the severe language impairment.

Spastic Tetraplegia Malformed motor cortex and its descending projections produce the spastic tetraplegia.

Hypotonia Central (axial) hypotonia accompanies the cortical malformation.

Cortical Blindness The posterior-predominant malformation involves visual cortex.

Frontal Pachygyria The anterior end of the posterior-to-anterior migration gradient.

Show evidence (2 references)

PMID:27747449 SUPPORT Human Clinical

"Both mutations lead to a classic form of lissencephaly, with a posterior to anterior gradient, almost indistinguishable from LIS1-related lissencephaly."

Defines the cortical malformation and its gradient in four patients with hotspot variants.

PMID:33506645 SUPPORT Human Clinical

"Patients with CDCBM3 exhibit posterior dominant agyria/pachygyria with severe motor dysfunction."

Summarizes the posterior-dominant agyria/pachygyria of CDCBM3.

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Pathograph

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Phenotypes

20

Eye 4

Nystagmus HP:0000639

Show evidence (1 reference)

PMID:27896282 SUPPORT Human Clinical

"The patient presented with microcephaly, profound global developmental delay, nystagmus, and hypotonia, similar to a previous report"

Nystagmus in a KIF2A patient.

Microphthalmia HP:0000568

Show evidence (1 reference)

PMID:27896282 SUPPORT Human Clinical

"Our patient additionally had microphthalmia and PHPV, which were not previously described, and may represent a slight expansion of the phenotypic spectrum of this disorder."

Reports microphthalmia in one patient as a possible expansion of the phenotype.

Persistent Hyperplastic Primary Vitreous Remnants of the hyaloid vascular system HP:0007968

Show evidence (1 reference)

PMID:27896282 SUPPORT Human Clinical

"MRI of the orbits (not shown) demonstrated bilateral PHPV with decreased size of the left globe and thin optic nerves bilaterally."

Bilateral PHPV on orbital MRI.

Cortical Blindness 2/9 Cerebral visual impairment HP:0100704

Show evidence (1 reference)

PMID:37331001 SUPPORT Human Clinical

"| 4 | CDCBM3 | F | 8 y | Profound | – | Seizures, spastic tetraplegia, and cortical blindness |"

Cortical blindness recorded for patient 4 (also patient 3).

Head and Neck 2

Microcephaly 3/4 HP:0000252

Show evidence (2 references)

PMID:27747449 SUPPORT Human Clinical

"However, three fourths of patients also showed variable congenital and postnatal microcephaly, up to -5 SD."

Gives the frequency (three of four) and severity of microcephaly.

PMID:23603762 SUPPORT Human Clinical

"identified a second de novo KIF2A missense variation, c.950G>A, p.S317N (P147: Table 1 and Fig. 2a and 2b) in a girl affected by congenital microcephaly and posterior predominant agyria"

Congenital microcephaly with posterior agyria in the second original patient.

Thin Lips 2/9 Thin vermilion border HP:0000233

Show evidence (2 references)

PMID:37331001 SUPPORT Human Clinical

"| 6 | CDCBM3 | F | 0.8 y | Profound | – | Absent seizures, spastic tetraplegia, and axial hypotonia | Microcephaly, round face, subtle synophrys, and thin and tented lips |"

Thin and tented lips in patient 6 (also patient 3).

PMID:33506645 SUPPORT Human Clinical

"The clinical findings of patients with KIF2A variants appear restricted to the central nervous system and facial anomalies."

States that facial anomalies are part of the KIF2A phenotype.

Musculoskeletal 3

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:27896282 SUPPORT Human Clinical

"There was significant central hypotonia with poor head control"

Central hypotonia in a KIF2A patient.

Spastic Tetraplegia 4/9 HP:0002510

Show evidence (3 references)

PMID:37331001 SUPPORT Human Clinical

"| 4 | CDCBM3 | F | 8 y | Profound | – | Seizures, spastic tetraplegia, and cortical blindness |"

One of the four Table 1 rows recording spastic tetraplegia (patients 3, 4, 6 and 7).

PMID:37331001 SUPPORT Human Clinical

"| 7 | CDCBM3 | M | 13 y | Profound | – | Seizures, spastic tetraplegia, axial hypotonia, and nystagmus |"

A second row recording spastic tetraplegia, here with axial hypotonia and nystagmus.

PMID:37331001 SUPPORT Human Clinical

"including corpus callosum hypoplasia, spastic tetraplegia, cortical dysplasia, anencephaly, and subcortical banding heterotopia"

The authors list spastic tetraplegia among the features of CDCBM3.

Scoliosis 3/9 HP:0002650

Show evidence (2 references)

PMID:37331001 SUPPORT Human Clinical

"| 7 | CDCBM3 | M | 13 y | Profound | – | Seizures, spastic tetraplegia, axial hypotonia, and nystagmus | Mild growth retardation and scoliosis |"

One of the three Table 1 rows recording scoliosis (patients 3, 7 and 10).

PMID:37331001 SUPPORT Human Clinical

"| 10 | CDCBM3 | M | 7 y | Profound, standing without assistance at age 8 | – | Seizures, hypotonia | Growth retardation, microcephaly, and scoliosis |"

Scoliosis in the Ser433Tyr patient.

Nervous System 9

Lissencephaly 4/4 HP:0001339

Show evidence (2 references)

PMID:27747449 SUPPORT Human Clinical

"Both mutations lead to a classic form of lissencephaly, with a posterior to anterior gradient, almost indistinguishable from LIS1-related lissencephaly."

Lissencephaly in the four patients carrying the two hotspot variants.

PMID:27896282 SUPPORT Human Clinical

"MRI of the brain revealed lissencephaly, perhaps with a slight posterior predominance, with a dysplastic corpus callosum, and slightly diminutive brainstem"

Lissencephaly in an independent patient with a Thr320Ile variant.

Anterior Subcortical Band Heterotopia Anterior predominant subcortical band heterotopia HP:0032412

Show evidence (1 reference)

PMID:23603762 SUPPORT Human Clinical

"we found a single de novo missense change in KIF2A (c.961C>G, p.H321D) in a female patient (P462, Table 1) with frontal band heterotopia and posterior predominant pachygyria, severe congenital microcephaly and neonatal onset seizures"

Documents frontal band heterotopia in a KIF2A patient.

Seizures HP:0001250

Show evidence (1 reference)

PMID:23603762 SUPPORT Human Clinical

"with frontal band heterotopia and posterior predominant pachygyria, severe congenital microcephaly and neonatal onset seizures"

Neonatal-onset seizures in a KIF2A patient.

Infantile Spasms HP:0012469

Show evidence (1 reference)

PMID:27896282 SUPPORT Human Clinical

"These were confirmed to be infantile spasms, with associated electrodecrements, and periods of intermittent hypsarrhythmia noted on continuous video electroencephalogram"

EEG-confirmed infantile spasms in a KIF2A patient.

Global Developmental Delay Severe global developmental delay HP:0011344

Show evidence (2 references)

PMID:27896282 SUPPORT Human Clinical

"The patient's clinical status was also remarkable for profound developmental delay."

Profound developmental delay in a KIF2A patient.

PMID:35315043 SUPPORT Human Clinical

"had presented with motor developmental delay, lissencephaly, severe cognitive impairments, absent speech and congenital laryngomalacia"

Motor delay, severe cognitive impairment and absent speech in a Gly318Arg patient.

Absent Speech HP:0001344

Show evidence (1 reference)

PMID:35315043 SUPPORT Human Clinical

"had presented with motor developmental delay, lissencephaly, severe cognitive impairments, absent speech and congenital laryngomalacia"

Absent speech in a Gly318Arg patient.

Intellectual Disability HP:0001249

Show evidence (1 reference)

PMID:37331001 SUPPORT Human Clinical

"The proband, a 23-month-old boy, was previously diagnosed with GDD, and his brother, aged nine years, had ID"

Intellectual disability and global developmental delay in two brothers carrying a KIF2A variant.

Dysplastic Corpus Callosum HP:0006989

Show evidence (1 reference)

PMID:27896282 SUPPORT Human Clinical

"The corpus callosum is dysplastic."

Dysplastic corpus callosum on MRI.

Frontal Pachygyria 4/9 HP:0001302

Show evidence (1 reference)

PMID:37331001 SUPPORT Human Clinical

"| 6 | CDCBM3 | F | 0.8 y | Profound | – | Absent seizures, spastic tetraplegia, and axial hypotonia | Microcephaly, round face, subtle synophrys, and thin and tented lips | Posterior agyria, frontal pachygyria |"

One of the four Table 1 rows recording frontal pachygyria with posterior agyria (patients 4, 5, 6 and 7).

Respiratory 1

Laryngomalacia HP:0001601

Show evidence (1 reference)

PMID:35315043 SUPPORT Human Clinical

"Furthermore, the congenital laryngomalacia found in our patient was absent in previously reported CDCBM3 cases."

A single-case finding not seen in other CDCBM3 patients.

Growth 1

Growth Delay 5/9 HP:0001510

Show evidence (2 references)

PMID:37331001 SUPPORT Human Clinical

"| 3 | CDCBM3 | F | 4.8 y | Profound | – | Seizures, spastic tetraplegia, and cortical blindness | Growth retardation, microcephaly, small ears, a mildly enlarged nose bridge, thin and tented lips, and scoliosis |"

One of the five Table 1 rows recording growth retardation (patients 1, 3, 4, 7 and 10).

PMID:37331001 SUPPORT Human Clinical

"| 10 | CDCBM3 | M | 7 y | Profound, standing without assistance at age 8 | – | Seizures, hypotonia | Growth retardation, microcephaly, and scoliosis |"

Growth retardation in the Ser433Tyr patient.

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Genetic Associations

1

KIF2A (Causative)

Gene: KIF2A hgnc:6318 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (3 references)

PMID:23603762 SUPPORT Human Clinical

"Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C, in subjects with MCD."

Founding report of pathogenic KIF2A missense variants in malformations of cortical development.

PMID:27747449 SUPPORT Human Clinical

"The identification of mutations only in the residues Ser317 and His321 suggests these are hotspots for de novo mutations."

Establishes the recurrent hotspot residues.

PMID:23603762 SUPPORT BACKGROUND In Vitro

"Rather than a direct involvement in microtubule-based motility, KIF2A functions by driving the ATP-dependent depolymerization of microtubules19."

States the molecular function of the gene product.

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Medical Actions

2

Anti-Seizure Medication

Action: Pharmacotherapy NCIT:C15986

Agent: vigabatrin CHEBI:63638

Platform: Small molecule

Seizure treatment is symptomatic. In the one reported case of infantile spasms, levetiracetam and topiramate were ineffective, valproate with clobazam was partly effective, and vigabatrin nearly stopped the spasms. No disease-specific comparative data exist.

Show evidence (1 reference)

PMID:27896282 SUPPORT Human Clinical

"Vigabatrin produced near-cessation of clinical spasms."

Single-patient response of infantile spasms to vigabatrin.

Genetic Counseling

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

Platform: Behavioral / lifestyle

Most cases are de novo, so sibling recurrence risk is low, but parental germline mosaicism has been suggested in an affected sibling pair.

Show evidence (1 reference)

PMID:37331001 SUPPORT Human Clinical

"Findings in this case also suggest a rare parental germline mosaicism of KIF2A G440R."

Germline mosaicism is the main consideration for recurrence counseling.

🔬

Diagnosis

2

Brain magnetic resonance imaging

MRI shows classic lissencephaly with a posterior-to-anterior gradient, sometimes with band heterotopia and a dysplastic corpus callosum. The pattern is almost indistinguishable from LIS1-related lissencephaly, so imaging alone does not identify the gene.

magnetic resonance imaging NCIT:C16809

Show evidence (1 reference)

PMID:27747449 SUPPORT Human Clinical

"Both mutations lead to a classic form of lissencephaly, with a posterior to anterior gradient, almost indistinguishable from LIS1-related lissencephaly."

Describes the MRI pattern and its overlap with LIS1 lissencephaly.

Molecular genetic testing

Diagnosis is confirmed by a heterozygous pathogenic KIF2A variant found on a brain-malformation multigene panel or by exome sequencing, ideally as a trio to establish de novo origin.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:27896282 SUPPORT Human Clinical

"Genetic testing included a commercial next-generation (NextGen) sequencing panel assessing known causes of brain malformations, which revealed a heterozygous c.959C>T (p.Thr320Ile) missense mutation in KIF2A, a member of the kinesin family."

Diagnosis by a brain-malformation gene panel.

PMID:33506645 SUPPORT Human Clinical

"Whole-exome sequencing identified a heterozygous mutation of NM_001098511.2:c.1298C>A [p.(Ser433Tyr)]."

Diagnosis by whole-exome sequencing.

🌍

Epidemiology

1

Rarity

Very rare. Roughly ten cases had been reported worldwide by 2023, and no population prevalence estimate exists.

Show evidence (1 reference)

PMID:37331001 SUPPORT Human Clinical

"No more than 10, as far as we know, cases of CDCBM3 were previously reported globally"

Gives the approximate global case count.

🐁

Animal Models

2

Kif2a H321D conditional knock-in mouse

Carries a patient variant. Shows neuroanatomical anomalies, microcephaly, behavioral deficits and susceptibility to epilepsy, with increased apoptosis and an abnormal multipolar-to-bipolar transition.

Species

Mouse

Genotype

Kif2a p.His321Asp conditional knock-in (Cre-switched)

Publication

PMID:31919497

Pathograph links

Defective Neuronal Migration and Positioning recapitulates fidelity: high Patient-variant knock-in reproducing the neuronal transition defect.

Limitations: Mouse cortex is lissencephalic, so the human gyral phenotype cannot be reproduced.

Show evidence (1 reference)

PMID:31919497 SUPPORT Model Organism

"These mice present with neuroanatomical anomalies and microcephaly associated with behavioral deficiencies and susceptibility to epilepsy, correlating with the described human phenotype."

The authors report correspondence with the human phenotype.

Increased Neuronal Apoptosis recapitulates fidelity: moderate

Show evidence (1 reference)

PMID:31919497 SUPPORT Model Organism

"We show that the expression of the p.His321Asp pathogenic variant increases apoptosis"

Reports increased apoptosis in the knock-in.

kif2a knockout zebrafish

Null model with microcephaly, seizure susceptibility, reduced neuronal proliferation and increased apoptosis.

Species

Zebrafish

Genotype

kif2a homozygous knockout

Publication

PMID:34404749

Pathograph links

Increased Neuronal Apoptosis partially recapitulates fidelity: low Reproduces apoptosis and microcephaly through loss of function.

Limitations: A null allele, unlike the heterozygous missense variants of the human disease, in a species without a layered six-layer neocortex.

Show evidence (1 reference)

PMID:34404749 SUPPORT Model Organism

"Here, we present a novel kif2a knock-out zebrafish model, showing hypoactivity, habituation deficits, pentylenetetrazole-induced seizure susceptibility and microcephaly, as well as neuronal cell proliferation defects and increased apoptosis."

Describes the model phenotype.

{ }

Source YAML

click to show

name: KIF2A-related Complex Cortical Dysplasia
creation_date: "2026-10-13T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: complex cortical dysplasia with other brain malformations 3
  term:
    id: MONDO:0014170
    label: complex cortical dysplasia with other brain malformations 3
synonyms:
- CDCBM3
- KIF2A-related cortical malformation
- KIF2A complex cortical dysplasia with other brain malformations
- complex cortical dysplasia with other brain malformations type 3
description: >-
  KIF2A-related complex cortical dysplasia (CDCBM3) is a rare autosomal dominant
  malformation of cortical development caused by heterozygous, typically de novo
  missense variants in KIF2A, which encodes a kinesin-13 family member. Unlike
  most kinesins, KIF2A does not transport cargo: it uses ATP to depolymerize
  microtubule ends. Pathogenic variants cluster in and around the
  nucleotide-binding pocket of the motor domain, with recurrent hotspots at
  Ser317 and His321, and are expected to disrupt ATP binding or hydrolysis and
  therefore the microtubule-depolymerizing activity. The typical picture is
  classic posterior-predominant lissencephaly (agyria/pachygyria), closely
  resembling LIS1/PAFAH1B1 lissencephaly, combined with congenital or postnatal
  microcephaly, early-onset epilepsy including infantile spasms, and severe
  motor and cognitive impairment. Milder presentations with intellectual
  disability or developmental delay have been reported for variants just outside
  the core nucleotide-binding residues. In model systems the variants disturb
  several microtubule-dependent steps of corticogenesis: the multipolar-to-bipolar
  transition and positioning of projection neurons, interneuron migration,
  progenitor proliferation coupled to ciliogenesis, and neuronal survival.
parents:
- congenital nervous system disorder
- hereditary neurological disease
- neuronal migration disorder
references:
- reference: PMID:23603762
  title: "Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly."
- reference: PMID:27747449
  title: Recurrent KIF2A mutations are responsible for classic lissencephaly.
- reference: PMID:27896282
  title: "A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A."
- reference: PMID:33506645
  title: "Variants in KIF2A cause broad clinical presentation; the computational structural analysis of a novel variant in a patient with a cortical dysplasia, complex, with other brain malformations 3."
- reference: PMID:35315043
  title: "[Genetic and clinical analysis of KIF2A gene variant in a Chinese patient with complex cortical dysplasia and other brain malformations]."
- reference: PMID:37331001
  title: "Mutations obstructing ATP's emplacement in KIF2A nucleotide-binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability."
- reference: PMID:29077851
  title: Ciliogenesis and cell cycle alterations contribute to KIF2A-related malformations of cortical development.
- reference: PMID:31919497
  title: Conditional switching of KIF2A mutation provides new insights into cortical malformation pathogeny.
- reference: PMID:12887924
  title: Kinesin superfamily protein 2A (KIF2A) functions in suppression of collateral branch extension.
- reference: PMID:36343267
  title: KIF2A deficiency causes early-onset neurodegeneration.
- reference: PMID:36733270
  title: Inhibitory synapse dysfunction and epileptic susceptibility associated with KIF2A deletion in cortical interneurons.
- reference: PMID:34404749
  title: Modeling Neurodevelopmental Disorders and Epilepsy Caused by Loss of Function of kif2a in Zebrafish.
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK350554/pdf/Bookshelf_NBK350554.pdf
  title: "https://www.ncbi.nlm.nih.gov/books/NBK350554/pdf/Bookshelf_NBK350554.pdf"
  tags:
  - GeneReviews
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous missense variants, de novo in nearly all reported probands. One
    sibling pair carrying the same variant absent from both parents suggests
    parental germline mosaicism, which bears on recurrence risk.
  evidence:
  - reference: PMID:33506645
    reference_title: "Variants in KIF2A cause broad clinical presentation; the computational structural analysis of a novel variant in a patient with a cortical dysplasia, complex, with other brain malformations 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cortical dysplasia, complex, with other brain malformations 3 (CDCBM3) is a
      rare autosomal dominant syndrome caused by Kinesin family Member 2A (KIF2A)
      gene mutation.
    explanation: >-
      Directly states the autosomal dominant mode of inheritance for CDCBM3.
  - reference: PMID:27747449
    reference_title: Recurrent KIF2A mutations are responsible for classic lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we detected two de novo p.Ser317Asn and p.His321Pro mutations in
      KIF2A in two patients with lissencephaly and microcephaly.
    explanation: >-
      De novo heterozygous occurrence in independent probands.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK350554/pdf/Bookshelf_NBK350554.pdf
    reference_title: "https://www.ncbi.nlm.nih.gov/books/NBK350554/pdf/Bookshelf_NBK350554.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Microcephaly w/cortical malformations KIF2A Complex cortical dysplasia
      w/other brain malformations 3 (OMIM 615411) AD
    explanation: >-
      The GeneReviews Tubulinopathies Overview lists KIF2A-related CDCBM3 among
      the differential diagnoses with autosomal dominant inheritance.
  - reference: PMID:37331001
    reference_title: "Mutations obstructing ATP's emplacement in KIF2A nucleotide-binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Findings in this case also suggest a rare parental germline mosaicism of
      KIF2A G440R.
    explanation: >-
      An affected sibling pair with a variant absent from both parents points to
      parental germline mosaicism, a qualification of the typically de novo
      pattern.
epidemiology:
- name: Rarity
  description: >-
    Very rare. Roughly ten cases had been reported worldwide by 2023, and no
    population prevalence estimate exists.
  evidence:
  - reference: PMID:37331001
    reference_title: "Mutations obstructing ATP's emplacement in KIF2A nucleotide-binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No more than 10, as far as we know, cases of CDCBM3 were previously
      reported globally
    explanation: >-
      Gives the approximate global case count.
pathophysiology:
- name: KIF2A Motor-Domain Nucleotide-Pocket Disruption
  role: TRIGGER
  biological_scale: MOLECULAR
  conforms_to: microtubule_dependent_neuronal_migration_failure#Microtubule Apparatus Perturbation
  description: >-
    Pathogenic missense variants alter residues in or next to the
    nucleotide-binding pocket of the central KIF2A motor domain (recurrently
    Ser317 and His321, also Gly318, Thr320, Ser433 and Gly440). The altered
    motor domain is expected to bind or hydrolyse ATP poorly. Recombinant mutant
    motor domains are poorly soluble, consistent with misfolding, and mutant
    proteins mislocalize in cells. Because both alleles are expressed and KIF2A
    acts as a dimer, the original report considered the data consistent with a
    dominant-negative effect.
  genetic_context:
    functional_impact_category: DOMINANT_NEGATIVE
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    allele_type: missense
    description: >-
      Only heterozygous missense alleles in the motor domain are associated with
      CDCBM3. The dominant-negative call follows the authors' stated
      interpretation ("consistent with a dominant-negative effect") and has not
      been demonstrated directly, for example by mixing mutant and wild-type
      dimers.
  genes:
  - preferred_term: KIF2A
    term:
      id: hgnc:6318
      label: KIF2A
  molecular_functions:
  - preferred_term: ATP hydrolysis activity
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
    modifier: DECREASED
  - preferred_term: microtubule binding
    term:
      id: GO:0008017
      label: microtubule binding
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:23603762
    reference_title: "Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      both conserved residues p.S317 and p.H321 are located around the
      nucleotide binding pocket, suggesting that the ability of KIF2A mutants to
      bind and/or hydrolyse ATP is likely to be impaired.
    explanation: >-
      Structural mapping places the founding variants at the nucleotide-binding
      pocket and predicts impaired ATP binding or hydrolysis.
  - reference: PMID:23603762
    reference_title: "Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These data imply that the mutations lead to substantially reduced
      solubility as a result of misfolding, and therefore at a minimum result in
      a reduced yield of functional protein.
    explanation: >-
      Recombinant mutant motor domains are poorly soluble, indicating misfolding.
  - reference: PMID:23603762
    reference_title: "Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      In view of the fact that both KIF2A alleles are expressed in patient
      fibroblasts (Supplementary Fig. 4b) and that the KIF2A molecule functions
      as a dimer22, our in vitro and in vivo data are consistent with a
      dominant-negative effect of these mutations.
    explanation: >-
      Basis for the dominant-negative functional-impact call, which the authors
      present as an interpretation rather than a direct measurement.
  - reference: PMID:27747449
    reference_title: Recurrent KIF2A mutations are responsible for classic lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Located in the motor domain of the KIF2A protein, the Ser317 and His321
      alterations are expected to disrupt binding or hydrolysis of ATP and
      consequently the MT depolymerizing activity.
    explanation: >-
      Links the recurrent hotspot residues to loss of ATP handling and of
      depolymerase activity.
  - reference: PMID:27896282
    reference_title: "A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The KIF2A p.Thr320Ile mutant protein exhibited abnormal solubility, and
      KIF2A p.Thr320Ile overexpression in cultured cells led to the formation of
      aberrant microtubule networks.
    explanation: >-
      An independent ATP-domain variant shows the same insolubility and alters
      cellular microtubule organization.
  - reference: PMID:33506645
    reference_title: "Variants in KIF2A cause broad clinical presentation; the computational structural analysis of a novel variant in a patient with a cortical dysplasia, complex, with other brain malformations 3."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The computational structural analysis showed the p.433 forms the pocket
      with NBD.
    explanation: >-
      Extends the nucleotide-pocket mechanism to a variant outside the core
      nucleotide-binding domain sequence.
  downstream:
  - target: Impaired Microtubule Depolymerization
    description: >-
      A motor domain that cannot bind or hydrolyse ATP cannot drive the
      ATP-dependent depolymerization of microtubule ends.
- name: Impaired Microtubule Depolymerization
  biological_scale: CELLULAR
  description: >-
    Loss of KIF2A depolymerase activity leaves microtubule ends less dynamic.
    In knock-in mice carrying the patient His321Asp variant, the cellular
    phenotypes are attributed to deficient microtubule-depolymerizing function,
    and Kif2a-null growth cones show reduced depolymerizing activity with
    abnormally behaving microtubules at the cell edge.
  cell_types:
  - preferred_term: cortical neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  biological_processes:
  - preferred_term: microtubule depolymerization
    term:
      id: GO:0007019
      label: microtubule depolymerization
    modifier: DECREASED
  evidence:
  - reference: PMID:31919497
    reference_title: Conditional switching of KIF2A mutation provides new insights into cortical malformation pathogeny.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We further demonstrate that the observed cellular phenotypes are likely to
      be linked to deficiency in the microtubule depolymerizing function of
      KIF2A.
    explanation: >-
      In a patient-variant knock-in mouse, the cellular defects are attributed
      to loss of depolymerase function.
  - reference: PMID:12887924
    reference_title: Kinesin superfamily protein 2A (KIF2A) functions in suppression of collateral branch extension.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      In kif2a(-/-) growth cones, microtubule-depolymerizing activity decreased.
    explanation: >-
      Null-allele evidence that KIF2A is required for microtubule
      depolymerization in neurons; indirect because the human disease alleles
      are missense rather than null.
  downstream:
  - target: Defective Neuronal Migration and Positioning
    description: >-
      Migrating neurons need dynamic microtubules to polarize and move.
  - target: Progenitor Ciliogenesis and Cell-Cycle Coupling Defect
    description: >-
      Cilium disassembly and spindle function in dividing progenitors depend on
      microtubule depolymerization.
  - target: Increased Neuronal Apoptosis
    description: >-
      Expression of the mutant protein increases apoptosis in the developing
      cortex.
  - target: Interneuron Inhibitory Synapse Formation Defect
    description: >-
      Interneurons need KIF2A-dependent microtubule remodeling to build
      inhibitory synapses.
- name: Defective Neuronal Migration and Positioning
  biological_scale: CELLULAR
  conforms_to: microtubule_dependent_neuronal_migration_failure#Microtubule-Based Neuronal Motility Failure
  description: >-
    Disease variants disrupt the positioning of radially migrating projection
    neurons and the tangential migration of interneurons. In the knock-in mouse,
    newborn neurons fail to make the normal multipolar-to-bipolar transition,
    the step that precedes locomotion through the cortical plate.
  cell_types:
  - preferred_term: migrating cortical neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  - preferred_term: cortical interneuron
    term:
      id: CL:0000099
      label: interneuron
  biological_processes:
  - preferred_term: cerebral cortex radially oriented cell migration
    term:
      id: GO:0021799
      label: cerebral cortex radially oriented cell migration
    modifier: DECREASED
  - preferred_term: cerebral cortex tangential migration
    term:
      id: GO:0021800
      label: cerebral cortex tangential migration
    modifier: DECREASED
  evidence:
  - reference: PMID:29077851
    reference_title: Ciliogenesis and cell cycle alterations contribute to KIF2A-related malformations of cortical development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using cellular and in utero electroporation approaches, we show here that
      KIF2A disease-causing variants disrupts projection neuron positioning and
      interneuron migration, as well as progenitors proliferation.
    explanation: >-
      In utero electroporation of patient variants disrupts both radial
      positioning of projection neurons and interneuron migration.
  - reference: PMID:31919497
    reference_title: Conditional switching of KIF2A mutation provides new insights into cortical malformation pathogeny.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We show that the expression of the p.His321Asp pathogenic variant
      increases apoptosis and causes abnormal multipolar to bipolar transition
      in newborn neurons
    explanation: >-
      Localizes the migration defect to the multipolar-to-bipolar transition in
      a knock-in model of a patient variant.
  - reference: PMID:36733270
    reference_title: Inhibitory synapse dysfunction and epileptic susceptibility associated with KIF2A deletion in cortical interneurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      KIF2A is essential for tangential migration of cortical interneurons,
      their positioning in the cerebral cortex
    explanation: >-
      Interneuron-specific deletion confirms KIF2A is needed for tangential
      migration; indirect because the allele is a null.
  downstream:
  - target: Posterior-Predominant Classic Lissencephaly
    description: >-
      Neurons that fail to complete migration leave a thick, poorly gyrated
      cortex.
- name: Progenitor Ciliogenesis and Cell-Cycle Coupling Defect
  biological_scale: CELLULAR
  description: >-
    In cortical progenitors, disease variants reduce proliferation and alter the
    regulation of primary cilium assembly and disassembly across the cell cycle.
    The authors propose that uncoupling ciliogenesis from cell-cycle progression
    contributes to the brain malformation, and the reduced progenitor output is
    a plausible contributor to microcephaly. This node rests on electroporation
    of patient variants; conditional Kif2a knockout in mouse did not impair
    embryonic neurogenesis, an inconsistency recorded as an open discussion.
  cell_types:
  - preferred_term: cortical neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: cilium disassembly
    term:
      id: GO:0061523
      label: cilium disassembly
    modifier: DYSREGULATED
  - preferred_term: neural precursor cell proliferation
    term:
      id: GO:0061351
      label: neural precursor cell proliferation
    modifier: DECREASED
  evidence:
  - reference: PMID:29077851
    reference_title: Ciliogenesis and cell cycle alterations contribute to KIF2A-related malformations of cortical development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Interestingly, further dissection of this latter process revealed that
      ciliogenesis regulation is also altered during progenitors cell cycle.
    explanation: >-
      Shows altered ciliogenesis regulation during the progenitor cell cycle.
  - reference: PMID:29077851
    reference_title: Ciliogenesis and cell cycle alterations contribute to KIF2A-related malformations of cortical development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Altogether, our data suggest that deregulation of the coupling between
      ciliogenesis and cell cycle might contribute to the pathogenesis of
      KIF2A-related brain malformations.
    explanation: >-
      The authors' proposed link from the progenitor defect to the
      malformation, stated as a suggestion.
  downstream:
  - target: Microcephaly
    description: >-
      Reduced progenitor proliferation lowers neuronal output and brain size.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced neuronal output from cortical progenitors
- name: Increased Neuronal Apoptosis
  biological_scale: CELLULAR
  description: >-
    Expression of the His321Asp variant increases apoptosis in the developing
    cortex, and kif2a-null zebrafish show increased apoptosis with
    microcephaly. Cell loss is one plausible route to the small brain.
  cell_types:
  - preferred_term: cortical neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  biological_processes:
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:31919497
    reference_title: Conditional switching of KIF2A mutation provides new insights into cortical malformation pathogeny.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We show that the expression of the p.His321Asp pathogenic variant
      increases apoptosis
    explanation: >-
      Patient-variant knock-in mice show increased apoptosis.
  - reference: PMID:34404749
    reference_title: Modeling Neurodevelopmental Disorders and Epilepsy Caused by Loss of Function of kif2a in Zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Here, we present a novel kif2a knock-out zebrafish model, showing
      hypoactivity, habituation deficits, pentylenetetrazole-induced seizure
      susceptibility and microcephaly, as well as neuronal cell proliferation
      defects and increased apoptosis.
    explanation: >-
      A null zebrafish model shows increased apoptosis alongside microcephaly;
      indirect because the allele class differs from the human missense
      variants.
  downstream:
  - target: Microcephaly
    description: >-
      Loss of neurons and progenitors reduces brain size.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cortical cell loss
- name: Interneuron Inhibitory Synapse Formation Defect
  biological_scale: CELLULAR
  description: >-
    Beyond migration, KIF2A is needed in cortical GABAergic interneurons for
    the formation of inhibitory synapses. Forebrain interneuron-specific Kif2a
    deletion in mouse impairs inhibitory synapse formation and increases
    epilepsy susceptibility, offering a route to seizures that is separate from
    the gross malformation. The evidence is from a null allele in mouse, not
    from a patient variant.
  cell_types:
  - preferred_term: cortical GABAergic interneuron
    term:
      id: CL:0010011
      label: cerebral cortex GABAergic interneuron
  biological_processes:
  - preferred_term: inhibitory synapse assembly
    term:
      id: GO:1904862
      label: inhibitory synapse assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:36733270
    reference_title: Inhibitory synapse dysfunction and epileptic susceptibility associated with KIF2A deletion in cortical interneurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      KIF2A is essential for tangential migration of cortical interneurons,
      their positioning in the cerebral cortex, and for formation of inhibitory
      synapses in vivo.
    explanation: >-
      Conditional interneuron deletion shows KIF2A is required for inhibitory
      synapse formation; indirect because the allele is a null.
  - reference: PMID:36733270
    reference_title: Inhibitory synapse dysfunction and epileptic susceptibility associated with KIF2A deletion in cortical interneurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      We report that adult mice with specific deletion of KIF2A in GABAergic
      interneurons display abnormal behavior and increased susceptibility to
      epilepsy.
    explanation: >-
      Links the interneuron defect to epilepsy susceptibility.
  downstream:
  - target: Seizures
    description: >-
      Reduced inhibitory synapse formation lowers cortical inhibition and
      favours seizures.
- name: Posterior-Predominant Classic Lissencephaly
  biological_scale: TISSUE
  conforms_to: microtubule_dependent_neuronal_migration_failure#Cortical Dyslamination and Neuronal Ectopia
  description: >-
    The cortical malformation is classic lissencephaly with a
    posterior-to-anterior gradient (posterior agyria or pachygyria), close to
    the LIS1/PAFAH1B1 pattern, sometimes with anterior subcortical band
    heterotopia and a dysplastic corpus callosum. This malformed cortex is the
    substrate for the epilepsy and the neurodevelopmental impairment.
  biological_processes:
  - preferred_term: cerebral cortex radially oriented cell migration
    term:
      id: GO:0021799
      label: cerebral cortex radially oriented cell migration
    modifier: DECREASED
  evidence:
  - reference: PMID:27747449
    reference_title: Recurrent KIF2A mutations are responsible for classic lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both mutations lead to a classic form of lissencephaly, with a posterior to
      anterior gradient, almost indistinguishable from LIS1-related lissencephaly.
    explanation: >-
      Defines the cortical malformation and its gradient in four patients with
      hotspot variants.
  - reference: PMID:33506645
    reference_title: "Variants in KIF2A cause broad clinical presentation; the computational structural analysis of a novel variant in a patient with a cortical dysplasia, complex, with other brain malformations 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with CDCBM3 exhibit posterior dominant agyria/pachygyria with
      severe motor dysfunction.
    explanation: >-
      Summarizes the posterior-dominant agyria/pachygyria of CDCBM3.
  downstream:
  - target: Lissencephaly
    description: The malformation itself, as seen on MRI.
  - target: Anterior Subcortical Band Heterotopia
    description: >-
      Arrested migration can leave a band of neurons beneath the cortex.
  - target: Seizures
    description: The malformed cortex is epileptogenic.
  - target: Infantile Spasms
    description: The malformed cortex is epileptogenic.
  - target: Global Developmental Delay
    description: >-
      Disorganized cortex underlies the motor and cognitive impairment.
  - target: Intellectual Disability
    description: >-
      Disorganized cortex underlies the cognitive impairment in milder cases.
  - target: Absent Speech
    description: >-
      Disorganized cortex underlies the severe language impairment.
  - target: Spastic Tetraplegia
    description: >-
      Malformed motor cortex and its descending projections produce the
      spastic tetraplegia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - abnormal corticospinal output from malformed cortex
  - target: Hypotonia
    description: >-
      Central (axial) hypotonia accompanies the cortical malformation.
  - target: Cortical Blindness
    description: >-
      The posterior-predominant malformation involves visual cortex.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - malformed occipital cortex
  - target: Frontal Pachygyria
    description: >-
      The anterior end of the posterior-to-anterior migration gradient.
phenotypes:
- name: Lissencephaly
  category: Nervous System
  frequency: 4/4
  description: >-
    Classic lissencephaly with posterior-to-anterior gradient (agyria to
    pachygyria) in all four patients with the Ser317 and His321 hotspot
    variants.
  phenotype_term:
    preferred_term: Posterior-predominant lissencephaly
    term:
      id: HP:0001339
      label: Lissencephaly
  evidence:
  - reference: PMID:27747449
    reference_title: Recurrent KIF2A mutations are responsible for classic lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both mutations lead to a classic form of lissencephaly, with a posterior to
      anterior gradient, almost indistinguishable from LIS1-related lissencephaly.
    explanation: >-
      Lissencephaly in the four patients carrying the two hotspot variants.
  - reference: PMID:27896282
    reference_title: "A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI of the brain revealed lissencephaly, perhaps with a slight posterior
      predominance, with a dysplastic corpus callosum, and slightly diminutive
      brainstem
    explanation: >-
      Lissencephaly in an independent patient with a Thr320Ile variant.
- name: Anterior Subcortical Band Heterotopia
  category: Nervous System
  description: >-
    Frontal band heterotopia together with posterior-predominant pachygyria was
    reported in the first His321Asp patient.
  phenotype_term:
    preferred_term: Frontal band heterotopia
    term:
      id: HP:0032412
      label: Anterior predominant subcortical band heterotopia
  evidence:
  - reference: PMID:23603762
    reference_title: "Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we found a single de novo missense change in KIF2A (c.961C>G, p.H321D) in
      a female patient (P462, Table 1) with frontal band heterotopia and
      posterior predominant pachygyria, severe congenital microcephaly and
      neonatal onset seizures
    explanation: >-
      Documents frontal band heterotopia in a KIF2A patient.
- name: Microcephaly
  category: Nervous System
  frequency: 3/4
  description: >-
    Congenital or postnatal microcephaly, down to -5 SD, in three of four
    patients with hotspot variants; severe congenital microcephaly in both
    original patients.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:27747449
    reference_title: Recurrent KIF2A mutations are responsible for classic lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, three fourths of patients also showed variable congenital and
      postnatal microcephaly, up to -5 SD.
    explanation: >-
      Gives the frequency (three of four) and severity of microcephaly.
  - reference: PMID:23603762
    reference_title: "Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified a second de novo KIF2A missense variation, c.950G>A, p.S317N
      (P147: Table 1 and Fig. 2a and 2b) in a girl affected by congenital
      microcephaly and posterior predominant agyria
    explanation: >-
      Congenital microcephaly with posterior agyria in the second original
      patient.
- name: Seizures
  category: Nervous System
  description: >-
    Early-onset epilepsy, from the neonatal period in the first described
    patient.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:23603762
    reference_title: "Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with frontal band heterotopia and posterior predominant pachygyria, severe
      congenital microcephaly and neonatal onset seizures
    explanation: >-
      Neonatal-onset seizures in a KIF2A patient.
- name: Infantile Spasms
  category: Nervous System
  description: >-
    Infantile spasms with hypsarrhythmia from 8 months in the Thr320Ile patient,
    largely controlled by vigabatrin after several other drugs failed.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:27896282
    reference_title: "A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These were confirmed to be infantile spasms, with associated
      electrodecrements, and periods of intermittent hypsarrhythmia noted on
      continuous video electroencephalogram
    explanation: >-
      EEG-confirmed infantile spasms in a KIF2A patient.
- name: Global Developmental Delay
  category: Nervous System
  description: >-
    Severe to profound global delay with absent speech in the classic
    lissencephaly presentation.
  phenotype_term:
    preferred_term: Severe global developmental delay
    term:
      id: HP:0011344
      label: Severe global developmental delay
  evidence:
  - reference: PMID:27896282
    reference_title: "A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient's clinical status was also remarkable for profound
      developmental delay.
    explanation: >-
      Profound developmental delay in a KIF2A patient.
  - reference: PMID:35315043
    reference_title: "[Genetic and clinical analysis of KIF2A gene variant in a Chinese patient with complex cortical dysplasia and other brain malformations]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      had presented with motor developmental delay, lissencephaly, severe
      cognitive impairments, absent speech and congenital laryngomalacia
    explanation: >-
      Motor delay, severe cognitive impairment and absent speech in a
      Gly318Arg patient.
- name: Absent Speech
  category: Nervous System
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:35315043
    reference_title: "[Genetic and clinical analysis of KIF2A gene variant in a Chinese patient with complex cortical dysplasia and other brain malformations]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      had presented with motor developmental delay, lissencephaly, severe
      cognitive impairments, absent speech and congenital laryngomalacia
    explanation: >-
      Absent speech in a Gly318Arg patient.
- name: Intellectual Disability
  category: Nervous System
  description: >-
    Intellectual disability is reported in milder presentations, including two
    brothers with a Gly440Arg variant.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:37331001
    reference_title: "Mutations obstructing ATP's emplacement in KIF2A nucleotide-binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband, a 23-month-old boy, was previously diagnosed with GDD, and his
      brother, aged nine years, had ID
    explanation: >-
      Intellectual disability and global developmental delay in two brothers
      carrying a KIF2A variant.
- name: Hypotonia
  category: Nervous System
  phenotype_term:
    preferred_term: Central hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:27896282
    reference_title: "A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was significant central hypotonia with poor head control
    explanation: >-
      Central hypotonia in a KIF2A patient.
- name: Dysplastic Corpus Callosum
  category: Nervous System
  phenotype_term:
    preferred_term: Dysplastic corpus callosum
    term:
      id: HP:0006989
      label: Dysplastic corpus callosum
  evidence:
  - reference: PMID:27896282
    reference_title: "A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The corpus callosum is dysplastic.
    explanation: >-
      Dysplastic corpus callosum on MRI.
- name: Nystagmus
  category: Eye
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:27896282
    reference_title: "A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient presented with microcephaly, profound global developmental
      delay, nystagmus, and hypotonia, similar to a previous report
    explanation: >-
      Nystagmus in a KIF2A patient.
- name: Microphthalmia
  category: Eye
  description: >-
    Unilateral microphthalmia in a single patient; not described in other KIF2A
    cases, so its link to the disease is uncertain.
  phenotype_term:
    preferred_term: Unilateral microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: PMID:27896282
    reference_title: "A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patient additionally had microphthalmia and PHPV, which were not
      previously described, and may represent a slight expansion of the
      phenotypic spectrum of this disorder.
    explanation: >-
      Reports microphthalmia in one patient as a possible expansion of the
      phenotype.
- name: Persistent Hyperplastic Primary Vitreous
  category: Eye
  description: >-
    Bilateral persistent hyperplastic primary vitreous in the same single
    patient; its link to the disease is uncertain.
  phenotype_term:
    preferred_term: Persistent hyperplastic primary vitreous
    term:
      id: HP:0007968
      label: Remnants of the hyaloid vascular system
  evidence:
  - reference: PMID:27896282
    reference_title: "A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI of the orbits (not shown) demonstrated bilateral PHPV with decreased
      size of the left globe and thin optic nerves bilaterally.
    explanation: >-
      Bilateral PHPV on orbital MRI.
- name: Laryngomalacia
  category: Respiratory
  description: >-
    Congenital laryngomalacia in a single Gly318Arg patient.
  phenotype_term:
    preferred_term: Congenital laryngomalacia
    term:
      id: HP:0001601
      label: Laryngomalacia
  evidence:
  - reference: PMID:35315043
    reference_title: "[Genetic and clinical analysis of KIF2A gene variant in a Chinese patient with complex cortical dysplasia and other brain malformations]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, the congenital laryngomalacia found in our patient was absent
      in previously reported CDCBM3 cases.
    explanation: >-
      A single-case finding not seen in other CDCBM3 patients.
- name: Spastic Tetraplegia
  category: Nervous System
  frequency: 4/9
  description: >-
    Spastic tetraplegia in four of nine CDCBM3 patients, all with the classic
    posterior agyria presentation. Count is from the nine CDCBM3 patients in Table 1 of PMID:37331001, a literature summary that includes the two new patients and seven earlier published cases.
  phenotype_term:
    preferred_term: Spastic tetraplegia
    term:
      id: HP:0002510
      label: Spastic tetraplegia
  evidence:
  - reference: PMID:37331001
    reference_title: "Mutations obstructing ATP's emplacement in KIF2A nucleotide-binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | 4 | CDCBM3 | F | 8 y | Profound | – | Seizures, spastic tetraplegia, and cortical blindness |
    explanation: >-
      One of the four Table 1 rows recording spastic tetraplegia (patients 3, 4, 6 and 7).
  - reference: PMID:37331001
    reference_title: "Mutations obstructing ATP's emplacement in KIF2A nucleotide-binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | 7 | CDCBM3 | M | 13 y | Profound | – | Seizures, spastic tetraplegia, axial hypotonia, and nystagmus |
    explanation: >-
      A second row recording spastic tetraplegia, here with axial hypotonia and nystagmus.
  - reference: PMID:37331001
    reference_title: "Mutations obstructing ATP's emplacement in KIF2A nucleotide-binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including corpus callosum hypoplasia, spastic tetraplegia, cortical dysplasia, anencephaly, and subcortical banding heterotopia
    explanation: >-
      The authors list spastic tetraplegia among the features of CDCBM3.
- name: Growth Delay
  category: Growth
  frequency: 5/9
  description: >-
    Growth retardation, often mild, in five of nine CDCBM3 patients;
    intrauterine growth retardation is also listed among CDCBM3 features.
    Count is from the nine CDCBM3 patients in Table 1 of PMID:37331001, a literature summary that includes the two new patients and seven earlier published cases.
  phenotype_term:
    preferred_term: Growth retardation
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:37331001
    reference_title: "Mutations obstructing ATP's emplacement in KIF2A nucleotide-binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | 3 | CDCBM3 | F | 4.8 y | Profound | – | Seizures, spastic tetraplegia, and cortical blindness | Growth retardation, microcephaly, small ears, a mildly enlarged nose bridge, thin and tented lips, and scoliosis |
    explanation: >-
      One of the five Table 1 rows recording growth retardation (patients 1, 3, 4, 7 and 10).
  - reference: PMID:37331001
    reference_title: "Mutations obstructing ATP's emplacement in KIF2A nucleotide-binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | 10 | CDCBM3 | M | 7 y | Profound, standing without assistance at age 8 | – | Seizures, hypotonia | Growth retardation, microcephaly, and scoliosis |
    explanation: >-
      Growth retardation in the Ser433Tyr patient.
- name: Scoliosis
  category: Musculoskeletal
  frequency: 3/9
  description: >-
    Scoliosis in three of nine CDCBM3 patients. Count is from the nine CDCBM3 patients in Table 1 of PMID:37331001, a literature summary that includes the two new patients and seven earlier published cases.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:37331001
    reference_title: "Mutations obstructing ATP's emplacement in KIF2A nucleotide-binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | 7 | CDCBM3 | M | 13 y | Profound | – | Seizures, spastic tetraplegia, axial hypotonia, and nystagmus | Mild growth retardation and scoliosis |
    explanation: >-
      One of the three Table 1 rows recording scoliosis (patients 3, 7 and 10).
  - reference: PMID:37331001
    reference_title: "Mutations obstructing ATP's emplacement in KIF2A nucleotide-binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | 10 | CDCBM3 | M | 7 y | Profound, standing without assistance at age 8 | – | Seizures, hypotonia | Growth retardation, microcephaly, and scoliosis |
    explanation: >-
      Scoliosis in the Ser433Tyr patient.
- name: Cortical Blindness
  category: Eye
  frequency: 2/9
  description: >-
    Cortical blindness in two of nine CDCBM3 patients. Count is from the nine CDCBM3 patients in Table 1 of PMID:37331001, a literature summary that includes the two new patients and seven earlier published cases.
  phenotype_term:
    preferred_term: Cortical blindness
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  evidence:
  - reference: PMID:37331001
    reference_title: "Mutations obstructing ATP's emplacement in KIF2A nucleotide-binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | 4 | CDCBM3 | F | 8 y | Profound | – | Seizures, spastic tetraplegia, and cortical blindness |
    explanation: >-
      Cortical blindness recorded for patient 4 (also patient 3).
- name: Thin Lips
  category: Craniofacial
  frequency: 2/9
  description: >-
    Thin lips, described as thin and tented, in two of nine CDCBM3 patients.
    Other facial findings (small ears, a mildly enlarged nasal bridge, a long
    nose, a short philtrum, a round face, subtle synophrys) were each reported
    in a single patient and are not curated separately. The tented shape is not
    bound because the source does not say which lip is affected. Count is from the nine CDCBM3 patients in Table 1 of PMID:37331001, a literature summary that includes the two new patients and seven earlier published cases.
  phenotype_term:
    preferred_term: Thin lips
    term:
      id: HP:0000233
      label: Thin vermilion border
  evidence:
  - reference: PMID:37331001
    reference_title: "Mutations obstructing ATP's emplacement in KIF2A nucleotide-binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | 6 | CDCBM3 | F | 0.8 y | Profound | – | Absent seizures, spastic tetraplegia, and axial hypotonia | Microcephaly, round face, subtle synophrys, and thin and tented lips |
    explanation: >-
      Thin and tented lips in patient 6 (also patient 3).
  - reference: PMID:33506645
    reference_title: "Variants in KIF2A cause broad clinical presentation; the computational structural analysis of a novel variant in a patient with a cortical dysplasia, complex, with other brain malformations 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical findings of patients with KIF2A variants appear restricted to
      the central nervous system and facial anomalies.
    explanation: >-
      States that facial anomalies are part of the KIF2A phenotype.
- name: Frontal Pachygyria
  category: Nervous System
  frequency: 4/9
  description: >-
    Frontal pachygyria anterior to posterior agyria, the anterior end of the
    posterior-to-anterior gradient, in four of nine CDCBM3 patients. Bound to
    Pachygyria rather than to an anterior-predominant term, because the
    malformation as a whole is posterior-predominant. Count is from the nine CDCBM3 patients in Table 1 of PMID:37331001, a literature summary that includes the two new patients and seven earlier published cases.
  phenotype_term:
    preferred_term: Frontal pachygyria
    term:
      id: HP:0001302
      label: Pachygyria
  evidence:
  - reference: PMID:37331001
    reference_title: "Mutations obstructing ATP's emplacement in KIF2A nucleotide-binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | 6 | CDCBM3 | F | 0.8 y | Profound | – | Absent seizures, spastic tetraplegia, and axial hypotonia | Microcephaly, round face, subtle synophrys, and thin and tented lips | Posterior agyria, frontal pachygyria |
    explanation: >-
      One of the four Table 1 rows recording frontal pachygyria with posterior agyria (patients 4, 5, 6 and 7).
genetic:
- name: KIF2A
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  gene_term:
    preferred_term: KIF2A
    term:
      id: hgnc:6318
      label: KIF2A
  notes: >-
    KIF2A encodes a kinesin-13 microtubule depolymerase. Disease variants are
    heterozygous missense changes in the motor domain, with hotspots at Ser317
    and His321. Heterozygous KIF2A variants reported in epilepsy or autism
    without cortical malformation are outside this entry.
  evidence:
  - reference: PMID:23603762
    reference_title: "Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report the discovery of multiple pathogenic missense mutations in
      TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in
      KIF5C, in subjects with MCD.
    explanation: >-
      Founding report of pathogenic KIF2A missense variants in malformations of
      cortical development.
  - reference: PMID:27747449
    reference_title: Recurrent KIF2A mutations are responsible for classic lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identification of mutations only in the residues Ser317 and His321
      suggests these are hotspots for de novo mutations.
    explanation: >-
      Establishes the recurrent hotspot residues.
  - reference: PMID:23603762
    reference_title: "Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: >-
      Rather than a direct involvement in microtubule-based motility, KIF2A
      functions by driving the ATP-dependent depolymerization of microtubules19.
    explanation: >-
      States the molecular function of the gene product.
diagnosis:
- name: Brain magnetic resonance imaging
  description: >-
    MRI shows classic lissencephaly with a posterior-to-anterior gradient,
    sometimes with band heterotopia and a dysplastic corpus callosum. The
    pattern is almost indistinguishable from LIS1-related lissencephaly, so
    imaging alone does not identify the gene.
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:27747449
    reference_title: Recurrent KIF2A mutations are responsible for classic lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both mutations lead to a classic form of lissencephaly, with a posterior to
      anterior gradient, almost indistinguishable from LIS1-related lissencephaly.
    explanation: >-
      Describes the MRI pattern and its overlap with LIS1 lissencephaly.
- name: Molecular genetic testing
  description: >-
    Diagnosis is confirmed by a heterozygous pathogenic KIF2A variant found on a
    brain-malformation multigene panel or by exome sequencing, ideally as a trio
    to establish de novo origin.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:27896282
    reference_title: "A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic testing included a commercial next-generation (NextGen) sequencing
      panel assessing known causes of brain malformations, which revealed a
      heterozygous c.959C>T (p.Thr320Ile) missense mutation in KIF2A, a member of
      the kinesin family.
    explanation: >-
      Diagnosis by a brain-malformation gene panel.
  - reference: PMID:33506645
    reference_title: "Variants in KIF2A cause broad clinical presentation; the computational structural analysis of a novel variant in a patient with a cortical dysplasia, complex, with other brain malformations 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing identified a heterozygous mutation of
      NM_001098511.2:c.1298C>A [p.(Ser433Tyr)].
    explanation: >-
      Diagnosis by whole-exome sequencing.
treatments:
- name: Anti-Seizure Medication
  description: >-
    Seizure treatment is symptomatic. In the one reported case of infantile
    spasms, levetiracetam and topiramate were ineffective, valproate with
    clobazam was partly effective, and vigabatrin nearly stopped the spasms.
    No disease-specific comparative data exist.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: vigabatrin
      term:
        id: CHEBI:63638
        label: vigabatrin
  evidence:
  - reference: PMID:27896282
    reference_title: "A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vigabatrin produced near-cessation of clinical spasms.
    explanation: >-
      Single-patient response of infantile spasms to vigabatrin.
- name: Genetic Counseling
  description: >-
    Most cases are de novo, so sibling recurrence risk is low, but parental
    germline mosaicism has been suggested in an affected sibling pair.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37331001
    reference_title: "Mutations obstructing ATP's emplacement in KIF2A nucleotide-binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Findings in this case also suggest a rare parental germline mosaicism of
      KIF2A G440R.
    explanation: >-
      Germline mosaicism is the main consideration for recurrence counseling.
animal_models:
- name: Kif2a H321D conditional knock-in mouse
  species: Mouse
  genotype: Kif2a p.His321Asp conditional knock-in (Cre-switched)
  publication: PMID:31919497
  description: >-
    Carries a patient variant. Shows neuroanatomical anomalies, microcephaly,
    behavioral deficits and susceptibility to epilepsy, with increased
    apoptosis and an abnormal multipolar-to-bipolar transition.
  modeled_mechanisms:
  - target: Defective Neuronal Migration and Positioning
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Patient-variant knock-in reproducing the neuronal transition defect.
    limitations: >-
      Mouse cortex is lissencephalic, so the human gyral phenotype cannot be
      reproduced.
    evidence:
    - reference: PMID:31919497
      reference_title: Conditional switching of KIF2A mutation provides new insights into cortical malformation pathogeny.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These mice present with neuroanatomical anomalies and microcephaly
        associated with behavioral deficiencies and susceptibility to epilepsy,
        correlating with the described human phenotype.
      explanation: >-
        The authors report correspondence with the human phenotype.
  - target: Increased Neuronal Apoptosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    evidence:
    - reference: PMID:31919497
      reference_title: Conditional switching of KIF2A mutation provides new insights into cortical malformation pathogeny.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We show that the expression of the p.His321Asp pathogenic variant
        increases apoptosis
      explanation: Reports increased apoptosis in the knock-in.
- name: kif2a knockout zebrafish
  species: Zebrafish
  genotype: kif2a homozygous knockout
  publication: PMID:34404749
  description: >-
    Null model with microcephaly, seizure susceptibility, reduced neuronal
    proliferation and increased apoptosis.
  modeled_mechanisms:
  - target: Increased Neuronal Apoptosis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Reproduces apoptosis and microcephaly through loss of function.
    limitations: >-
      A null allele, unlike the heterozygous missense variants of the human
      disease, in a species without a layered six-layer neocortex.
    evidence:
    - reference: PMID:34404749
      reference_title: Modeling Neurodevelopmental Disorders and Epilepsy Caused by Loss of Function of kif2a in Zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we present a novel kif2a knock-out zebrafish model, showing
        hypoactivity, habituation deficits, pentylenetetrazole-induced seizure
        susceptibility and microcephaly, as well as neuronal cell proliferation
        defects and increased apoptosis.
      explanation: Describes the model phenotype.
discussions:
- discussion_id: gap_kif2a_progenitor_versus_null
  prompt: >-
    Do KIF2A disease variants impair cortical progenitor proliferation, given
    that conditional loss of Kif2a in mouse does not?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Progenitor Ciliogenesis and Cell-Cycle Coupling Defect
  rationale: >-
    In utero electroporation of patient variants reduces progenitor
    proliferation and alters ciliogenesis, but conditional inactivation of Kif2a
    in cortical progenitors leaves embryonic neurogenesis intact and instead
    causes postnatal neuronal maturation failure and degeneration. If the
    missense variants act dominant-negatively, they could impair progenitors in a
    way that removing the protein does not; alternatively the electroporation
    result may reflect overexpression. The answer decides whether microcephaly
    in this disease comes mainly from reduced progenitor output or from neuronal
    loss.
  evidence:
  - reference: PMID:29077851
    reference_title: Ciliogenesis and cell cycle alterations contribute to KIF2A-related malformations of cortical development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using cellular and in utero electroporation approaches, we show here that
      KIF2A disease-causing variants disrupts projection neuron positioning and
      interneuron migration, as well as progenitors proliferation.
    explanation: Variant electroporation reduces progenitor proliferation.
  - reference: PMID:36343267
    reference_title: KIF2A deficiency causes early-onset neurodegeneration.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we report that KIF2A is dispensable for embryogenic neurogenesis but
      critical in postnatal stages for maturation, connectivity, and maintenance
      of neurons.
    explanation: >-
      Conditional loss of Kif2a does not impair embryonic neurogenesis, which
      argues against a simple loss-of-function route to reduced progenitor
      output.

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References & Deep Research

References

13

PMID:23603762

Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.