NDE1-related Microcephaly-Lissencephaly

Mendelian Pathograph 6 Show in embeddings browser Microcephaly Lissencephaly neuronal migration disorder

NDE1-related microcephaly-lissencephaly is a severe autosomal recessive malformation of cortical development caused by biallelic NDE1 loss of function. The coherent disease skeleton is not generic primary microcephaly: loss of the centrosomal and dynein-regulatory NDE1 protein disrupts radial-glial progenitor cell-cycle progression, apical interkinetic nuclear migration, G2-to-M transition, and cilia-linked G1-to-S control, reducing prenatal neuron production. A connected dynein/LIS1 microtubule branch also impairs postmitotic neuronal migration and cortical lamination. The clinical result is extreme congenital microcephaly with grossly simplified gyration (microlissencephaly/lissencephaly), severe developmental impairment, frequent callosal agenesis, and epilepsy in many reported patients. The entry is split from broad MCPH and generic lissencephaly entries because the same upstream NDE1-dynein-centrosome lesion explains both the progenitor-depletion and lamination branches.

Ask OpenScientist

Ask a research question about NDE1-related Microcephaly-Lissencephaly. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

5
Pathophys.
8
Phenotypes
2
Gaps
6
Pathograph
1
Genes
3
Medical Actions
7
References
1
Deep Research
?

Discussions and Knowledge Gaps

2
Which NDE1-dependent radial-glial progenitor, outer-radial-glial, and neuronal-migration defects seen in rodent and biochemical systems are conserved in human iPSC-derived cortical organoids or fetal cortical tissue?
HUMAN MODEL MISMATCH OPEN gap_nde1_human_organoid_translatability
Attached to
pathophysiology#Biallelic NDE1 Loss and Centrosome-Dynein Perturbation pathophysiology#Progenitor Cell-Cycle Arrest and Failed Neurogenesis pathophysiology#Dynein-Dependent Neuronal Migration Failure
NDE1 disease has direct human genetic evidence, rat in utero perturbation evidence, and in vitro dynein reconstitution, but the Falcon review did not identify an NDE1-specific patient iPSC or organoid model. This matters because human cortical expansion depends on OSVZ and outer radial glia, which are not fully represented in lissencephalic rodent cortex. A direct NDE1 organoid experiment is needed to determine whether the disease has an oRG-specific branch beyond the apical radial-glial defects observed in rat.
Proposed experiments
NDE1 isogenic cortical-organoid cell-cycle and migration experiment
isogenic cortical organoid perturbation experiment
exp_nde1_isogenic_cortical_organoid_cell_cycle_migration
Generate patient-derived or CRISPR-engineered human cortical organoids carrying biallelic NDE1 loss-of-function variants, with isogenic corrected and knock-in controls, and compare apical radial-glial INM, ciliary dynamics, G2-to-M transition, oRG mitosis, neuronal migration, and dynein/LIS1 rescue against the rodent and biochemical expectations.
Model systems
NDE1 human iPSC-derived cortical organoid
Three-dimensional human cortical organoid with radial-glial progenitors, oRG-like cells, and migrating cortical neurons, derived from patient-specific or engineered iPSCs.
ORGANOID namo:Organoid link
human NCBITaxon:9606
cerebral cortex UBERON:0000956
radial glial cell CL:0000681 neural progenitor cell CL:0011020 migrating cortical neuron CL:0000540
Perturbations
NDE1 variant correction or biallelic knockout/knock-in
pathophysiology#Biallelic NDE1 Loss and Centrosome-Dynein Perturbation
Correct patient variants or introduce representative truncating variants in an isogenic human iPSC background.
NDE1 hgnc:17619
Readouts
Radial-glial INM and cell-cycle transitions
pathophysiology#Progenitor Cell-Cycle Arrest and Failed Neurogenesis
nuclear migration GO:0007097 ↓ DECREASED mitotic cell cycle GO:0000278 ↕ DYSREGULATED cilium organization GO:0044782 ↕ DYSREGULATED
live-cell imaging assay immunostaining
Direction: NEGATIVE
Neuronal migration and cortical lamination
pathophysiology#Dynein-Dependent Neuronal Migration Failure
neuron migration GO:0001764 ↓ DECREASED
live-cell imaging assay single-cell transcriptomic profiling
Direction: NEGATIVE
Controls
Isogenic corrected organoids
Variant-corrected patient-derived organoids differentiated in parallel.
Isogenic biallelic knock-in organoids
Wild-type-background organoids carrying engineered NDE1 loss-of-function alleles.
Decision criterion
The NDE1 disease skeleton is strengthened if mutant organoids reproduce apical INM, G2-to-M, ciliary, neuronal-output, and migration defects that are rescued by isogenic correction and reproduced by knock-in. A human-specific branch is supported if oRG mitosis or OSVZ-like output is abnormal in organoids beyond what rodent IUE predicts.
Would support
pathophysiology#Biallelic NDE1 Loss and Centrosome-Dynein Perturbation pathophysiology#Progenitor Cell-Cycle Arrest and Failed Neurogenesis pathophysiology#Dynein-Dependent Neuronal Migration Failure
Show evidence (3 references)
PMID:27553190 SUPPORT Model Organism
"Relative to rodents, development of the human neocortex relies on an expanded outer subventricular zone containing many additional RGPs"
The NDE1 mechanism paper itself flags the rodent-to-human progenitor translation issue.
PMID:28111201 SUPPORT Other
"However, the mouse brain is naturally lissencephalic, suggesting that certain aspects of cortical development may not be adequately assessed in mice."
Supports a human/model mismatch gap for lissencephaly mechanisms.
PMID:28111201 SUPPORT In Vitro
"Here, we find that cerebral organoids generate oRG-like cells with matching properties defined in vivo, including position, morphology, mitotic behavior, and molecular identity."
Supports cortical organoids as an appropriate new-approach model for testing human oRG vulnerability.
How should NDE1/NDEL1 paralog compensation and 16p13.11 CNV-plus-sequence variant unmasking be incorporated into diagnosis and mechanism-specific curation?
KNOWLEDGE GAP OPEN gap_nde1_paralog_and_cnv_diagnostics
Attached to
pathophysiology#Progenitor Cell-Cycle Arrest and Failed Neurogenesis genetic#NDE1
The mechanism literature shows overlapping but non-identical NDE1 and NDEL1 functions, including an NDE1-specific G2-to-M transition role. Separately, case literature shows that a 16p13.11 deletion can unmask a truncating NDE1 variant on the other chromosome. These observations create two curation questions: which cell-cycle functions are truly NDE1-specific in human cortex, and when should CMA plus sequencing be treated as required to resolve biallelic NDE1 disease?
Proposed experiments
NDE1/NDEL1 rescue and CNV-plus-sequence diagnostic resolution
combined organoid rescue and genomic diagnostic study
exp_nde1_ndel1_rescue_and_diagnostic_resolution
In NDE1 mutant human cortical organoids, compare NDE1, NDEL1, dynein/LIS1, and cilia-pathway rescue at INM, G1-to-S, and G2-to-M checkpoints; in parallel, assemble a clinical series of severe congenital microcephaly cases with 16p13.11 deletions and sequence NDE1 on the retained allele.
Would support
pathophysiology#Progenitor Cell-Cycle Arrest and Failed Neurogenesis genetic#NDE1
Show evidence (2 references)
PMID:27553190 SUPPORT Model Organism
"Further work will be required to define the nature of this very interesting function."
The authors explicitly leave the NDE1-specific G2-to-M function unresolved.
PMID:29191162 SUPPORT Human Clinical
"Sequencing NDE1 and CMA in patients with severe congenital microcephaly may be warranted."
Supports the diagnostic gap around combined CNV and sequence analysis.
⚙

Pathophysiology

5
Biallelic NDE1 Loss and Centrosome-Dynein Perturbation
Homozygous or compound biallelic NDE1 loss-of-function variants remove or destabilize the C-terminal dynein-binding and centrosome-targeting functions of NDE1. NDE1 normally localizes to centrosomes and mitotic spindle poles in proliferating neural progenitors and cooperates with LIS1 to activate cytoplasmic dynein. Loss of this molecular platform perturbs the centrosome-spindle apparatus and dynein-dependent microtubule transport at the top of the pathograph.
radial glial cell CL:0000681 neural progenitor cell CL:0011020
NDE1 hgnc:17619
centrosome cycle GO:0007098 ↕ DYSREGULATED mitotic spindle organization GO:0007052 ↕ DYSREGULATED microtubule-based process GO:0007017 ↕ DYSREGULATED
Downstream
Progenitor Cell-Cycle Arrest and Failed Neurogenesis Loss of NDE1-dependent centrosome/dynein regulation blocks multiple radial-glial progenitor cell-cycle steps.
Dynein-Dependent Neuronal Migration Failure The same dynein-regulatory apparatus also contributes to postmitotic neuronal migration and cortical lamination.
Show evidence (3 references)
PMID:21529751 SUPPORT Human Clinical
"they carry homozygous frameshift mutations in NDE1, which encodes a multidomain protein that localizes to the centrosome and mitotic spindle poles."
Identifies biallelic NDE1 frameshift variants and localizes NDE1 to the centrosome and mitotic spindle poles, supporting the proximal trigger.
PMID:21529751 SUPPORT In Vitro
"We show that the patient NDE1 proteins are unstable, cannot bind cytoplasmic dynein, and do not localize properly to the centrosome."
Patient-mutant protein assays support loss of NDE1 stability, dynein binding, and centrosome localization as the molecular lesion.
PMID:37940657 SUPPORT In Vitro
"Nde1 recruits Lis1 to autoinhibited dynein and promotes Lis1-mediated assembly of dynein-dynactin adaptor complexes."
Biochemical reconstitution supports the dynein/LIS1-activation function disrupted by NDE1 loss.
Progenitor Cell-Cycle Arrest and Failed Neurogenesis
In radial-glial progenitors, NDE1 deficiency produces a multi-stage cell-cycle failure rather than a single mitotic-spindle defect. Model data support arrest during apical interkinetic nuclear migration, arrest at the G2-to-M transition, and a cilia-linked G1-to-S transition defect. These defects prevent progenitors from reaching or completing productive mitosis and thereby reduce cortical neuron production.
radial glial cell CL:0000681 neural progenitor cell CL:0011020
nuclear migration GO:0007097 ↓ DECREASED mitotic cell cycle GO:0000278 ↕ DYSREGULATED cilium organization GO:0044782 ↕ DYSREGULATED neurogenesis GO:0022008 ↓ DECREASED
Downstream
Progenitor Pool Depletion and Microlissencephaly
Show evidence (2 references)
PMID:27553190 SUPPORT Model Organism
"Here using in utero electroporation of NDE1 short hairpin RNA (shRNA) in embryonic rat brains, we observe cell cycle arrest of proliferating neural progenitors at three distinct stages: during apical interkinetic nuclear migration, at the G2-to-M transition and in regulation of primary cilia at..."
Rat in utero perturbation directly supports multi-stage radial-glial progenitor arrest downstream of NDE1 loss.
PMID:21529752 SUPPORT Human Clinical
"NDE1 deficiency causes both a severe failure of neurogenesis and a deficiency in cortical lamination."
Human genetics and patient-cell evidence connect NDE1 deficiency to severe neurogenesis failure.
Progenitor Pool Depletion and Microlissencephaly
Failed progenitor proliferation depletes the prenatal cortical neuron output. The resulting cerebral cortex is extremely small and grossly simplified, producing microlissencephaly rather than isolated small-brain primary microcephaly. This node captures the shared downstream state of the progenitor module before the separate migration/lamination branch is added.
neural progenitor cell CL:0011020 cortical neuron CL:0000540
maintenance of cell number GO:0098727 ↓ DECREASED neurogenesis GO:0022008 ↓ DECREASED
Downstream
Cortical Dyslamination and Lissencephaly
Show evidence (2 references)
PMID:21529752 SUPPORT Human Clinical
"affected individuals had brains less than 10% of expected size"
Documents profound brain-size reduction in NDE1-deficient patients.
PMID:21529751 SUPPORT Human Clinical
"we report two families with extreme microcephaly and grossly simplified cortical gyral structure, a condition referred to as microlissencephaly"
Supports the cortical-size and simplified-gyration endpoint of biallelic NDE1 disease.
Dynein-Dependent Neuronal Migration Failure
In addition to the dominant radial-glial progenitor branch, NDE1 and its paralog NDEL1 regulate postmitotic neuronal migration through the dynein/LIS1 microtubule apparatus. NDE1 loss therefore has a migration branch that helps explain cortical lamination abnormalities and lissencephaly features beyond reduced neuron output alone.
migrating cortical neuron CL:0000540 radial glial cell CL:0000681
neuron migration GO:0001764 ↓ DECREASED microtubule-based movement GO:0007018 ↕ DYSREGULATED
Downstream
Cortical Dyslamination and Lissencephaly
Show evidence (2 references)
PMID:27553190 SUPPORT Model Organism
"In contrast, NDE1 and NDEL1 RNAi have comparable effects on postmitotic neuronal migration."
Supports a postmitotic migration branch in addition to the progenitor cell-cycle branch.
PMID:27553190 SUPPORT Model Organism
"these changes in postmitotic migration likely explain the subsidiary cortical laminar dysplasia seen in many of the patients with NDE1 microcephaly"
Links the animal migration defect to the lamination abnormalities observed in human NDE1 disease.
Cortical Dyslamination and Lissencephaly
Reduced neuron output and impaired dynein-dependent migration converge on a malformed cerebral cortex with deficient lamination, severe simplified gyration, and lissencephaly/microlissencephaly. The endpoint is accompanied in many patients by corpus callosum agenesis and severe neurodevelopmental impairment.
cortical neuron CL:0000540
cerebral cortex development GO:0021987 ↕ DYSREGULATED neuron migration GO:0001764 ↓ DECREASED
cerebral cortex UBERON:0000956
Show evidence (2 references)
PMID:21529752 SUPPORT Human Clinical
"in addition to a massive reduction in neuron production they displayed partially deficient cortical lamination (microlissencephaly)."
Supports cortical lamination deficiency as part of the NDE1 endpoint.
PMID:29191162 SUPPORT Human Clinical
"all patients had mental retardation, severe microcephaly, and corpus callosum agenesis."
Review of reported NDE1 cases supports the severe neurodevelopmental and callosal endpoint.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for NDE1-related Microcephaly-Lissencephaly Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Head and Neck 1
Extreme Congenital Microcephaly Microcephaly HP:0000252
Severity: SEVERE Onset: CONGENITAL
Show evidence (1 reference)
PMID:21529752 SUPPORT Human Clinical
"We investigated three families whose offspring had extreme microcephaly at birth and profound mental retardation."
Establishes congenital extreme microcephaly as a core human phenotype.
Musculoskeletal 1
Hypertonia Hypertonia HP:0001276
Show evidence (1 reference)
PMID:21529751 SUPPORT Human Clinical
Full-text clinical description in this paper reports marked hypertonia in an affected child; the generated PMID cache is abstract-only, so no validator-checkable snippet is included here.
Nervous System 5
Agenesis of Corpus Callosum Agenesis of corpus callosum HP:0001274
Show evidence (2 references)
PMID:29191162 SUPPORT Human Clinical
"all patients had mental retardation, severe microcephaly, and corpus callosum agenesis."
Literature review statement supports callosal agenesis as a recurrent phenotype.
PMID:30637988 SUPPORT Human Clinical
"Further, they had agenesis of corpus callosum, cerebellar, and brainstem hypoplasia."
Provides additional NDE1-family evidence linking callosal agenesis with posterior fossa hypoplasia.
Cerebellar Hypoplasia Cerebellar hypoplasia HP:0001321
Show evidence (1 reference)
PMID:30637988 SUPPORT Human Clinical
"Further, they had agenesis of corpus callosum, cerebellar, and brainstem hypoplasia."
Directly reports cerebellar hypoplasia in affected NDE1 siblings.
Ventriculomegaly Ventriculomegaly HP:0002119
Show evidence (1 reference)
PMID:30637988 SUPPORT Human Clinical
"We report on three sibs in which the brain MRI and CT scans demonstrated variable degree of reduced volume of cerebral hemispheres and ventriculomegaly."
Directly supports ventriculomegaly as a reported neuroimaging feature in NDE1-related disease.
Global Developmental Delay / Intellectual Disability Global developmental delay HP:0001263
Severity: SEVERE
Show evidence (1 reference)
PMID:21529752 SUPPORT Human Clinical
"We investigated three families whose offspring had extreme microcephaly at birth and profound mental retardation."
Supports profound neurodevelopmental impairment in affected children.
Seizures / Epilepsy Seizure HP:0001250
Show evidence (1 reference)
PMID:21529752 SUPPORT Human Clinical
Full-text clinical description in this paper reports early epileptic seizures in affected children; the generated PMID cache is abstract-only, so no validator-checkable snippet is included here.
Other 1
Lissencephaly / Microlissencephaly Lissencephaly HP:0001339
Severity: SEVERE
Show evidence (1 reference)
PMID:21529751 SUPPORT Human Clinical
"extreme microcephaly and grossly simplified cortical gyral structure, a condition referred to as microlissencephaly"
Documents the lissencephaly-like simplified gyral phenotype in NDE1 disease.
🧬

Genetic Associations

1
NDE1 (Causative)
Gene: NDE1 hgnc:17619
Autosomal recessive inheritance
Show evidence (2 references)
PMID:21529751 SUPPORT Human Clinical
"show that they carry homozygous frameshift mutations in NDE1"
Establishes homozygous NDE1 frameshift variants in affected families.
PMID:29191162 SUPPORT Human Clinical
"Genetic studies found a 16p13.11 deletion containing NDE1 gene, and a novel NDE1 mutation"
Supports a compound CNV plus sequence-variant mechanism that produces biallelic NDE1 loss.
💊

Medical Actions

3
Supportive and Rehabilitative Care
Action: supportive care MAXO:0000950
No disease-modifying therapy is established. Management is supportive and directed at severe developmental impairment, feeding or respiratory complications when present, mobility, and family support.
Anti-Seizure Medication
Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986
Symptomatic pharmacotherapy for seizures or epilepsy when present.
Genetic Counseling
Action: Genetic Counseling NCIT:C15240
Autosomal recessive recurrence-risk counseling, carrier testing, and reproductive counseling are appropriate after molecular diagnosis.
{ }

Source YAML

click to show 
name: NDE1-related Microcephaly-Lissencephaly
creation_date: "2026-06-12T03:31:46Z"
category: Mendelian
description: >-
  NDE1-related microcephaly-lissencephaly is a severe autosomal recessive
  malformation of cortical development caused by biallelic NDE1 loss of
  function. The coherent disease skeleton is not generic primary microcephaly:
  loss of the centrosomal and dynein-regulatory NDE1 protein disrupts
  radial-glial progenitor cell-cycle progression, apical interkinetic nuclear
  migration, G2-to-M transition, and cilia-linked G1-to-S control, reducing
  prenatal neuron production. A connected dynein/LIS1 microtubule branch also
  impairs postmitotic neuronal migration and cortical lamination. The clinical
  result is extreme congenital microcephaly with grossly simplified gyration
  (microlissencephaly/lissencephaly), severe developmental impairment, frequent
  callosal agenesis, and epilepsy in many reported patients. The entry is split
  from broad MCPH and generic lissencephaly entries because the same upstream
  NDE1-dynein-centrosome lesion explains both the progenitor-depletion and
  lamination branches.
parents:
- Microcephaly
- Lissencephaly
- neuronal migration disorder
references:
- reference: PMID:21529751
  title: "Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected]."
- reference: PMID:21529752
  title: The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis.
- reference: PMID:27553190
  title: Severe NDE1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages.
- reference: PMID:29191162
  title: "Severe congenital microcephaly with 16p13.11 microdeletion combined with NDE1 mutation, a case report and literature review."
- reference: PMID:30637988
  title: "Phenotypic spectrum of NDE1-related disorders: from microlissencephaly to microhydranencephaly."
- reference: PMID:37940657
  title: Nde1 promotes Lis1-mediated activation of dynein.
- reference: PMID:28111201
  title: Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia.
pathophysiology:
- name: Biallelic NDE1 Loss and Centrosome-Dynein Perturbation
  description: >-
    Homozygous or compound biallelic NDE1 loss-of-function variants remove or
    destabilize the C-terminal dynein-binding and centrosome-targeting functions
    of NDE1. NDE1 normally localizes to centrosomes and mitotic spindle poles in
    proliferating neural progenitors and cooperates with LIS1 to activate
    cytoplasmic dynein. Loss of this molecular platform perturbs the
    centrosome-spindle apparatus and dynein-dependent microtubule transport at
    the top of the pathograph.
  conforms_to: neural_progenitor_centrosome_spindle_dysfunction#Centrosome and Mitotic Spindle Perturbation
  role: trigger
  genes:
  - preferred_term: NDE1
    term:
      id: hgnc:17619
      label: NDE1
  cell_types:
  - preferred_term: radial glial cell
    term:
      id: CL:0000681
      label: radial glial cell
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: centrosome cycle
    term:
      id: GO:0007098
      label: centrosome cycle
    modifier: DYSREGULATED
  - preferred_term: mitotic spindle organization
    term:
      id: GO:0007052
      label: mitotic spindle organization
    modifier: DYSREGULATED
  - preferred_term: microtubule-based process
    term:
      id: GO:0007017
      label: microtubule-based process
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:21529751
    reference_title: "Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      they carry homozygous frameshift mutations in NDE1, which encodes a
      multidomain protein that localizes to the centrosome and mitotic spindle
      poles.
    explanation: >-
      Identifies biallelic NDE1 frameshift variants and localizes NDE1 to the
      centrosome and mitotic spindle poles, supporting the proximal trigger.
  - reference: PMID:21529751
    reference_title: "Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected]."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that the patient NDE1 proteins are unstable, cannot bind
      cytoplasmic dynein, and do not localize properly to the centrosome.
    explanation: >-
      Patient-mutant protein assays support loss of NDE1 stability, dynein
      binding, and centrosome localization as the molecular lesion.
  - reference: PMID:37940657
    reference_title: Nde1 promotes Lis1-mediated activation of dynein.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Nde1 recruits Lis1 to autoinhibited dynein and promotes Lis1-mediated
      assembly of dynein-dynactin adaptor complexes.
    explanation: >-
      Biochemical reconstitution supports the dynein/LIS1-activation function
      disrupted by NDE1 loss.
  downstream:
  - target: Progenitor Cell-Cycle Arrest and Failed Neurogenesis
    description: >-
      Loss of NDE1-dependent centrosome/dynein regulation blocks multiple
      radial-glial progenitor cell-cycle steps.
  - target: Dynein-Dependent Neuronal Migration Failure
    description: >-
      The same dynein-regulatory apparatus also contributes to postmitotic
      neuronal migration and cortical lamination.

- name: Progenitor Cell-Cycle Arrest and Failed Neurogenesis
  description: >-
    In radial-glial progenitors, NDE1 deficiency produces a multi-stage
    cell-cycle failure rather than a single mitotic-spindle defect. Model data
    support arrest during apical interkinetic nuclear migration, arrest at the
    G2-to-M transition, and a cilia-linked G1-to-S transition defect. These
    defects prevent progenitors from reaching or completing productive mitosis
    and thereby reduce cortical neuron production.
  conforms_to: neural_progenitor_centrosome_spindle_dysfunction#Abnormal Progenitor Division and Fate Choice
  role: central_effector
  cell_types:
  - preferred_term: radial glial cell
    term:
      id: CL:0000681
      label: radial glial cell
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: nuclear migration
    term:
      id: GO:0007097
      label: nuclear migration
    modifier: DECREASED
  - preferred_term: mitotic cell cycle
    term:
      id: GO:0000278
      label: mitotic cell cycle
    modifier: DYSREGULATED
  - preferred_term: cilium organization
    term:
      id: GO:0044782
      label: cilium organization
    modifier: DYSREGULATED
  - preferred_term: neurogenesis
    term:
      id: GO:0022008
      label: neurogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:27553190
    reference_title: Severe NDE1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here using in utero electroporation of NDE1 short hairpin RNA (shRNA) in
      embryonic rat brains, we observe cell cycle arrest of proliferating neural
      progenitors at three distinct stages: during apical interkinetic nuclear
      migration, at the G2-to-M transition and in regulation of primary cilia at
      the G1-to-S transition.
    explanation: >-
      Rat in utero perturbation directly supports multi-stage radial-glial
      progenitor arrest downstream of NDE1 loss.
  - reference: PMID:21529752
    reference_title: The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NDE1 deficiency causes both a severe failure of neurogenesis and a
      deficiency in cortical lamination.
    explanation: >-
      Human genetics and patient-cell evidence connect NDE1 deficiency to severe
      neurogenesis failure.
  downstream:
  - target: Progenitor Pool Depletion and Microlissencephaly

- name: Progenitor Pool Depletion and Microlissencephaly
  description: >-
    Failed progenitor proliferation depletes the prenatal cortical neuron
    output. The resulting cerebral cortex is extremely small and grossly
    simplified, producing microlissencephaly rather than isolated small-brain
    primary microcephaly. This node captures the shared downstream state of the
    progenitor module before the separate migration/lamination branch is added.
  conforms_to: neural_progenitor_centrosome_spindle_dysfunction#Progenitor Pool Distortion
  role: effector
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: cortical neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: maintenance of cell number
    term:
      id: GO:0098727
      label: maintenance of cell number
    modifier: DECREASED
  - preferred_term: neurogenesis
    term:
      id: GO:0022008
      label: neurogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:21529752
    reference_title: The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      affected individuals had brains less than 10% of expected size
    explanation: >-
      Documents profound brain-size reduction in NDE1-deficient patients.
  - reference: PMID:21529751
    reference_title: "Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report two families with extreme microcephaly and grossly simplified
      cortical gyral structure, a condition referred to as microlissencephaly
    explanation: >-
      Supports the cortical-size and simplified-gyration endpoint of biallelic
      NDE1 disease.
  downstream:
  - target: Cortical Dyslamination and Lissencephaly

- name: Dynein-Dependent Neuronal Migration Failure
  description: >-
    In addition to the dominant radial-glial progenitor branch, NDE1 and its
    paralog NDEL1 regulate postmitotic neuronal migration through the
    dynein/LIS1 microtubule apparatus. NDE1 loss therefore has a migration
    branch that helps explain cortical lamination abnormalities and
    lissencephaly features beyond reduced neuron output alone.
  conforms_to: microtubule_dependent_neuronal_migration_failure#Microtubule-Based Neuronal Motility Failure
  role: central_effector
  cell_types:
  - preferred_term: migrating cortical neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: radial glial cell
    term:
      id: CL:0000681
      label: radial glial cell
  biological_processes:
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: DECREASED
  - preferred_term: microtubule-based movement
    term:
      id: GO:0007018
      label: microtubule-based movement
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:27553190
    reference_title: Severe NDE1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In contrast, NDE1 and NDEL1 RNAi have comparable effects on postmitotic
      neuronal migration.
    explanation: >-
      Supports a postmitotic migration branch in addition to the progenitor
      cell-cycle branch.
  - reference: PMID:27553190
    reference_title: Severe NDE1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      these changes in postmitotic migration likely explain the subsidiary
      cortical laminar dysplasia seen in many of the patients with NDE1
      microcephaly
    explanation: >-
      Links the animal migration defect to the lamination abnormalities observed
      in human NDE1 disease.
  downstream:
  - target: Cortical Dyslamination and Lissencephaly

- name: Cortical Dyslamination and Lissencephaly
  description: >-
    Reduced neuron output and impaired dynein-dependent migration converge on a
    malformed cerebral cortex with deficient lamination, severe simplified
    gyration, and lissencephaly/microlissencephaly. The endpoint is accompanied
    in many patients by corpus callosum agenesis and severe neurodevelopmental
    impairment.
  conforms_to: microtubule_dependent_neuronal_migration_failure#Cortical Dyslamination and Neuronal Ectopia
  role: outcome
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  cell_types:
  - preferred_term: cortical neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: cerebral cortex development
    term:
      id: GO:0021987
      label: cerebral cortex development
    modifier: DYSREGULATED
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: DECREASED
  evidence:
  - reference: PMID:21529752
    reference_title: The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in addition to a massive reduction in neuron production they displayed
      partially deficient cortical lamination (microlissencephaly).
    explanation: >-
      Supports cortical lamination deficiency as part of the NDE1 endpoint.
  - reference: PMID:29191162
    reference_title: "Severe congenital microcephaly with 16p13.11 microdeletion combined with NDE1 mutation, a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all patients had mental retardation, severe microcephaly, and corpus
      callosum agenesis.
    explanation: >-
      Review of reported NDE1 cases supports the severe neurodevelopmental and
      callosal endpoint.
phenotypes:
- name: Extreme Congenital Microcephaly
  description: >-
    Profoundly reduced brain and head size is present from birth or prenatal
    development and is much more severe than typical primary microcephaly.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
    severity: SEVERE
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:21529752
    reference_title: The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We investigated three families whose offspring had extreme microcephaly at
      birth and profound mental retardation.
    explanation: >-
      Establishes congenital extreme microcephaly as a core human phenotype.
- name: Lissencephaly / Microlissencephaly
  description: >-
    The cortical malformation combines severe microcephaly with grossly
    simplified gyration and deficient lamination.
  phenotype_term:
    preferred_term: Lissencephaly
    term:
      id: HP:0001339
      label: Lissencephaly
    severity: SEVERE
  evidence:
  - reference: PMID:21529751
    reference_title: "Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      extreme microcephaly and grossly simplified cortical gyral structure, a
      condition referred to as microlissencephaly
    explanation: >-
      Documents the lissencephaly-like simplified gyral phenotype in NDE1
      disease.
- name: Agenesis of Corpus Callosum
  description: >-
    Corpus callosum agenesis is repeatedly reported with the severe
    microcephaly-lissencephaly phenotype.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: PMID:29191162
    reference_title: "Severe congenital microcephaly with 16p13.11 microdeletion combined with NDE1 mutation, a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all patients had mental retardation, severe microcephaly, and corpus
      callosum agenesis.
    explanation: >-
      Literature review statement supports callosal agenesis as a recurrent
      phenotype.
  - reference: PMID:30637988
    reference_title: "Phenotypic spectrum of NDE1-related disorders: from microlissencephaly to microhydranencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further, they had agenesis of corpus callosum, cerebellar, and brainstem
      hypoplasia.
    explanation: >-
      Provides additional NDE1-family evidence linking callosal agenesis with
      posterior fossa hypoplasia.
- name: Cerebellar Hypoplasia
  description: >-
    Cerebellar hypoplasia or proportionate cerebellar size reduction is part of
    the reported NDE1-related brain malformation spectrum.
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  evidence:
  - reference: PMID:30637988
    reference_title: "Phenotypic spectrum of NDE1-related disorders: from microlissencephaly to microhydranencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further, they had agenesis of corpus callosum, cerebellar, and brainstem
      hypoplasia.
    explanation: >-
      Directly reports cerebellar hypoplasia in affected NDE1 siblings.
- name: Ventriculomegaly
  description: >-
    Ventriculomegaly, including posterior lateral ventricular enlargement or
    hydranencephaly-like CSF expansion in the severe end of the spectrum, is
    reported in NDE1-related disorders.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:30637988
    reference_title: "Phenotypic spectrum of NDE1-related disorders: from microlissencephaly to microhydranencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on three sibs in which the brain MRI and CT scans demonstrated
      variable degree of reduced volume of cerebral hemispheres and
      ventriculomegaly.
    explanation: >-
      Directly supports ventriculomegaly as a reported neuroimaging feature in
      NDE1-related disease.
- name: Global Developmental Delay / Intellectual Disability
  description: >-
    Affected individuals have profound developmental and cognitive impairment.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
    severity: SEVERE
  evidence:
  - reference: PMID:21529752
    reference_title: The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We investigated three families whose offspring had extreme microcephaly at
      birth and profound mental retardation.
    explanation: >-
      Supports profound neurodevelopmental impairment in affected children.
- name: Hypertonia
  description: >-
    Marked hypertonia is reported in affected children with NDE1
    microlissencephaly.
  phenotype_term:
    preferred_term: Hypertonia
    term:
      id: HP:0001276
      label: Hypertonia
  evidence:
  - reference: PMID:21529751
    reference_title: "Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    explanation: >-
      Full-text clinical description in this paper reports marked hypertonia in
      an affected child; the generated PMID cache is abstract-only, so no
      validator-checkable snippet is included here.
- name: Seizures / Epilepsy
  description: >-
    Epilepsy is common in the reported NDE1 case literature, though robust
    cohort-level frequency estimates are not available.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:21529752
    reference_title: The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    explanation: >-
      Full-text clinical description in this paper reports early epileptic
      seizures in affected children; the generated PMID cache is abstract-only,
      so no validator-checkable snippet is included here.
genetic:
- name: NDE1
  association: Causative
  gene_term:
    preferred_term: NDE1
    term:
      id: hgnc:17619
      label: NDE1
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:21529751
      reference_title: "Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        show that they carry homozygous frameshift mutations in NDE1
      explanation: >-
        Homozygous NDE1 loss-of-function variants in affected children support
        autosomal recessive inheritance.
  evidence:
  - reference: PMID:21529751
    reference_title: "Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      show that they carry homozygous frameshift mutations in NDE1
    explanation: >-
      Establishes homozygous NDE1 frameshift variants in affected families.
  - reference: PMID:29191162
    reference_title: "Severe congenital microcephaly with 16p13.11 microdeletion combined with NDE1 mutation, a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic studies found a 16p13.11 deletion containing NDE1 gene, and a
      novel NDE1 mutation
    explanation: >-
      Supports a compound CNV plus sequence-variant mechanism that produces
      biallelic NDE1 loss.
treatments:
- name: Supportive and Rehabilitative Care
  description: >-
    No disease-modifying therapy is established. Management is supportive and
    directed at severe developmental impairment, feeding or respiratory
    complications when present, mobility, and family support.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
- name: Anti-Seizure Medication
  description: >-
    Symptomatic pharmacotherapy for seizures or epilepsy when present.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Genetic Counseling
  description: >-
    Autosomal recessive recurrence-risk counseling, carrier testing, and
    reproductive counseling are appropriate after molecular diagnosis.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
discussions:
- discussion_id: gap_nde1_human_organoid_translatability
  prompt: >-
    Which NDE1-dependent radial-glial progenitor, outer-radial-glial, and
    neuronal-migration defects seen in rodent and biochemical systems are
    conserved in human iPSC-derived cortical organoids or fetal cortical tissue?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Biallelic NDE1 Loss and Centrosome-Dynein Perturbation
  - pathophysiology#Progenitor Cell-Cycle Arrest and Failed Neurogenesis
  - pathophysiology#Dynein-Dependent Neuronal Migration Failure
  rationale: >-
    NDE1 disease has direct human genetic evidence, rat in utero perturbation
    evidence, and in vitro dynein reconstitution, but the Falcon review did not
    identify an NDE1-specific patient iPSC or organoid model. This matters
    because human cortical expansion depends on OSVZ and outer radial glia,
    which are not fully represented in lissencephalic rodent cortex. A direct
    NDE1 organoid experiment is needed to determine whether the disease has an
    oRG-specific branch beyond the apical radial-glial defects observed in rat.
  evidence:
  - reference: PMID:27553190
    reference_title: Severe NDE1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Relative to rodents, development of the human neocortex relies on an
      expanded outer subventricular zone containing many additional RGPs
    explanation: >-
      The NDE1 mechanism paper itself flags the rodent-to-human progenitor
      translation issue.
  - reference: PMID:28111201
    reference_title: Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, the mouse brain is naturally lissencephalic, suggesting that
      certain aspects of cortical development may not be adequately assessed in
      mice.
    explanation: >-
      Supports a human/model mismatch gap for lissencephaly mechanisms.
  - reference: PMID:28111201
    reference_title: Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we find that cerebral organoids generate oRG-like cells with matching
      properties defined in vivo, including position, morphology, mitotic
      behavior, and molecular identity.
    explanation: >-
      Supports cortical organoids as an appropriate new-approach model for
      testing human oRG vulnerability.
  proposed_experiments:
  - experiment_id: exp_nde1_isogenic_cortical_organoid_cell_cycle_migration
    name: NDE1 isogenic cortical-organoid cell-cycle and migration experiment
    description: >-
      Generate patient-derived or CRISPR-engineered human cortical organoids
      carrying biallelic NDE1 loss-of-function variants, with isogenic corrected
      and knock-in controls, and compare apical radial-glial INM, ciliary
      dynamics, G2-to-M transition, oRG mitosis, neuronal migration, and
      dynein/LIS1 rescue against the rodent and biochemical expectations.
    experiment_type:
      preferred_term: isogenic cortical organoid perturbation experiment
    model_systems:
    - name: NDE1 human iPSC-derived cortical organoid
      description: >-
        Three-dimensional human cortical organoid with radial-glial progenitors,
        oRG-like cells, and migrating cortical neurons, derived from
        patient-specific or engineered iPSCs.
      experimental_model_type: ORGANOID
      namo_type: namo:Organoid
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
      tissue_term:
        preferred_term: cerebral cortex
        term:
          id: UBERON:0000956
          label: cerebral cortex
      cell_types:
      - preferred_term: radial glial cell
        term:
          id: CL:0000681
          label: radial glial cell
      - preferred_term: neural progenitor cell
        term:
          id: CL:0011020
          label: neural progenitor cell
      - preferred_term: migrating cortical neuron
        term:
          id: CL:0000540
          label: neuron
      conditions:
      - NDE1-related microcephaly-lissencephaly
      - microlissencephaly
      - progenitor cell-cycle arrest
      cell_source: Patient-derived or CRISPR-engineered human induced pluripotent stem cells
      culture_system: Three-dimensional cortical organoid with live-imaging and single-cell readouts
    perturbations:
    - name: NDE1 variant correction or biallelic knockout/knock-in
      target: pathophysiology#Biallelic NDE1 Loss and Centrosome-Dynein Perturbation
      genes:
      - preferred_term: NDE1
        term:
          id: hgnc:17619
          label: NDE1
      description: >-
        Correct patient variants or introduce representative truncating variants
        in an isogenic human iPSC background.
    readouts:
    - name: Radial-glial INM and cell-cycle transitions
      target: pathophysiology#Progenitor Cell-Cycle Arrest and Failed Neurogenesis
      biological_processes:
      - preferred_term: nuclear migration
        term:
          id: GO:0007097
          label: nuclear migration
        modifier: DECREASED
      - preferred_term: mitotic cell cycle
        term:
          id: GO:0000278
          label: mitotic cell cycle
        modifier: DYSREGULATED
      - preferred_term: cilium organization
        term:
          id: GO:0044782
          label: cilium organization
        modifier: DYSREGULATED
      assays:
      - preferred_term: live-cell imaging assay
      - preferred_term: immunostaining
      direction: NEGATIVE
    - name: Neuronal migration and cortical lamination
      target: pathophysiology#Dynein-Dependent Neuronal Migration Failure
      biological_processes:
      - preferred_term: neuron migration
        term:
          id: GO:0001764
          label: neuron migration
        modifier: DECREASED
      assays:
      - preferred_term: live-cell imaging assay
      - preferred_term: single-cell transcriptomic profiling
      direction: NEGATIVE
    controls:
    - name: Isogenic corrected organoids
      description: Variant-corrected patient-derived organoids differentiated in parallel.
    - name: Isogenic biallelic knock-in organoids
      description: Wild-type-background organoids carrying engineered NDE1 loss-of-function alleles.
    decision_criterion: >-
      The NDE1 disease skeleton is strengthened if mutant organoids reproduce
      apical INM, G2-to-M, ciliary, neuronal-output, and migration defects that
      are rescued by isogenic correction and reproduced by knock-in. A
      human-specific branch is supported if oRG mitosis or OSVZ-like output is
      abnormal in organoids beyond what rodent IUE predicts.
    would_support:
    - pathophysiology#Biallelic NDE1 Loss and Centrosome-Dynein Perturbation
    - pathophysiology#Progenitor Cell-Cycle Arrest and Failed Neurogenesis
    - pathophysiology#Dynein-Dependent Neuronal Migration Failure

- discussion_id: gap_nde1_paralog_and_cnv_diagnostics
  prompt: >-
    How should NDE1/NDEL1 paralog compensation and 16p13.11 CNV-plus-sequence
    variant unmasking be incorporated into diagnosis and mechanism-specific
    curation?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Progenitor Cell-Cycle Arrest and Failed Neurogenesis
  - genetic#NDE1
  rationale: >-
    The mechanism literature shows overlapping but non-identical NDE1 and NDEL1
    functions, including an NDE1-specific G2-to-M transition role. Separately,
    case literature shows that a 16p13.11 deletion can unmask a truncating NDE1
    variant on the other chromosome. These observations create two curation
    questions: which cell-cycle functions are truly NDE1-specific in human
    cortex, and when should CMA plus sequencing be treated as required to
    resolve biallelic NDE1 disease?
  evidence:
  - reference: PMID:27553190
    reference_title: Severe NDE1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Further work will be required to define the nature of this very
      interesting function.
    explanation: >-
      The authors explicitly leave the NDE1-specific G2-to-M function unresolved.
  - reference: PMID:29191162
    reference_title: "Severe congenital microcephaly with 16p13.11 microdeletion combined with NDE1 mutation, a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing NDE1 and CMA in patients with severe congenital microcephaly may
      be warranted.
    explanation: >-
      Supports the diagnostic gap around combined CNV and sequence analysis.
  proposed_experiments:
  - experiment_id: exp_nde1_ndel1_rescue_and_diagnostic_resolution
    name: NDE1/NDEL1 rescue and CNV-plus-sequence diagnostic resolution
    description: >-
      In NDE1 mutant human cortical organoids, compare NDE1, NDEL1, dynein/LIS1,
      and cilia-pathway rescue at INM, G1-to-S, and G2-to-M checkpoints; in
      parallel, assemble a clinical series of severe congenital microcephaly
      cases with 16p13.11 deletions and sequence NDE1 on the retained allele.
    experiment_type:
      preferred_term: combined organoid rescue and genomic diagnostic study
    would_support:
    - pathophysiology#Progenitor Cell-Cycle Arrest and Failed Neurogenesis
    - genetic#NDE1
notes: >-
  Entry created from cortical-malformation epic 4098 / issue 4093, using the
  Falcon deep-research report in
  research/NDE1-related_Microcephaly_Lissencephaly-deep-research-falcon.md as
  leads and independently verified cached PMID snippets. A disease_term is
  deliberately not forced: MONDO has microlissencephaly and a generic
  microcephaly-with-lissencephaly/hydranencephaly term, but the entry boundary
  here is the coherent NDE1 centrosome-dynein/progenitor-cell-cycle plus
  migration mechanism rather than the presence of a stable ontology identifier.
datasets: []
📚

References & Deep Research

References

7
PMID:21529751
Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected].
No top-level findings curated for this source.
PMID:21529752
The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis.
No top-level findings curated for this source.
PMID:27553190
Severe NDE1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages.
No top-level findings curated for this source.
PMID:29191162
Severe congenital microcephaly with 16p13.11 microdeletion combined with NDE1 mutation, a case report and literature review.
No top-level findings curated for this source.
PMID:30637988
Phenotypic spectrum of NDE1-related disorders: from microlissencephaly to microhydranencephaly.
No top-level findings curated for this source.
PMID:37940657
Nde1 promotes Lis1-mediated activation of dynein.
No top-level findings curated for this source.
PMID:28111201
Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 27 citations 2026-06-11T20:46:47.318719

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: NDE1-related Microcephaly-Lissencephaly
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on NDE1-related Microcephaly-Lissencephaly covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Disease Characteristics Report: NDE1-related Microcephaly–Lissencephaly

Target disease

Disease name: NDE1-related Microcephaly–Lissencephaly (often described as microlissencephaly; Norman–Roberts–type lissencephaly spectrum) (alkuraya2011humanmutationsin pages 1-2, OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1)

High-level overview (current understanding): NDE1-related microcephaly–lissencephaly is a severe, typically congenital-onset neurodevelopmental malformation characterized by extreme primary microcephaly with markedly simplified cortical gyration (microlissencephaly), frequently accompanied by agenesis of the corpus callosum and cerebellar hypoplasia, and leading to profound global developmental delay/intellectual disability with common epilepsy (tan2017severecongenitalmicrocephaly pages 3-4, alkuraya2011humanmutationsin pages 2-3, bakircioglu2011theessentialrole pages 1-3).

Evidence type note: The core disorder description and many phenotype statements are derived from small numbers of affected individuals/families reported in primary case series/case reports (human clinical genetics and neuroimaging), complemented by mechanistic work in rodent neurodevelopment models and in vitro dynein reconstitution (bakircioglu2011theessentialrole pages 1-3, doobin2016severende1mediatedmicrocephaly pages 1-2, zhao2023nde1promoteslis1mediated pages 1-2).

1. Disease information

Key concepts and definitions

Microlissencephaly refers to the combination of (i) severe microcephaly (markedly reduced brain/head size) and (ii) extremely simplified cortical gyration/absent sulcation (lissencephaly-like), and is used in the NDE1 literature to describe a syndrome resembling historic Norman–Roberts cases (alkuraya2011humanmutationsin pages 1-2, alkuraya2011humanmutationsin pages 2-3).

Key identifiers (from available evidence)

  • MONDO: microlissencephaly MONDO_0015204 (OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1)
  • Orphanet disease entity: Lissencephaly syndrome, Norman-Roberts type Orphanet_89844 (OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1)
  • HPO term noted in evidence linkage: Lissencephaly HP:0001339 (OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1)
  • Gene: NDE1 (Ensembl ENSG00000072864; approved name “nudE neurodevelopment protein 1”) (OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1)
  • Primary supporting PubMed IDs surfaced in Open Targets evidence: PMID: 21529751, 21529752 (these correspond to the 2011 AJHG NDE1 papers) (OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1)

Common synonyms / alternative names

  • NDE1-associated microlissencephaly
  • Extreme microcephaly with lissencephaly
  • Norman–Roberts syndrome / Norman–Roberts–type lissencephaly (as a syndrome resemblance) (alkuraya2011humanmutationsin pages 1-2, OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1)

2. Etiology

Disease causal factors

Primary cause: biallelic (autosomal recessive) loss-of-function in NDE1, a centrosomal/dynein regulatory protein essential for neurogenesis and cortical lamination (bakircioglu2011theessentialrole pages 1-3, OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1).

Risk factors

  • Genetic: parental carrier status for pathogenic NDE1 variants; increased likelihood in consanguineous families is implied by early reports identifying homozygous variants within shared homozygous regions (alkuraya2011humanmutationsin pages 4-6, bakircioglu2011theessentialrole pages 1-3).
  • Structural variant “unmasking” mechanism: a 16p13.11 deletion including NDE1 can unmask a pathogenic variant on the non-deleted homolog, yielding biallelic loss (compound CNV + SNV/indel) (tan2017severecongenitalmicrocephaly pages 1-3, tan2017severecongenitalmicrocephaly pages 3-4).

Protective factors / gene–environment interactions

No disease-specific protective factors or gene–environment interactions were identified in the retrieved evidence (tan2017severecongenitalmicrocephaly pages 1-3).

3. Phenotypes (clinical spectrum)

Core phenotypes and characteristics (human)

  • Extreme congenital microcephaly (prenatal/congenital onset). Example quantitative severity: head circumference reported 8.9 SD to 13.4 SD below mean across ages in affected individuals (alkuraya2011humanmutationsin pages 2-3).
  • Global developmental delay / profound intellectual disability (severe). Affected brains were described as “less than 10% of expected size” in the 2011 AJHG series (bakircioglu2011theessentialrole pages 1-3).
  • Tone abnormalities including hypertonia are reported (alkuraya2011humanmutationsin pages 2-3).
  • Seizures/epilepsy: epilepsy occurred in most reported patients in the 2017 case review (tan2017severecongenitalmicrocephaly pages 3-4).

Neuroimaging phenotypes

  • Simplified gyral pattern / microlissencephaly: “The gyral folding of the cerebral cortex was extremely simplified; there were almost no detectable sulci other than the Sylvian fissure” (alkuraya2011humanmutationsin pages 2-3).
  • Agenesis of the corpus callosum (common) (tan2017severecongenitalmicrocephaly pages 3-4, bakircioglu2011theessentialrole pages 1-3).
  • Ventriculomegaly/posterior ventricular enlargement (tan2017severecongenitalmicrocephaly pages 3-4).
  • Cerebellar hypoplasia / small cerebellum (common, but not universal) (tan2017severecongenitalmicrocephaly pages 3-4, alkuraya2011humanmutationsin pages 4-6).

Phenotype frequencies

The evidence base is dominated by small case series; robust percentages across large cohorts were not available in retrieved materials. However, the 2017 review states “All patients had mental retardation, severe microcephaly, and corpus callosum agenesis,” and notes epilepsy occurred in most patients (tan2017severecongenitalmicrocephaly pages 3-4).

Quality-of-life impact

Given profound neurodevelopmental impairment and frequent epilepsy, the disease is expected to have severe, lifelong functional impact; formal QoL instrument data (e.g., EQ-5D/SF-36) were not found in the retrieved evidence (tan2017severecongenitalmicrocephaly pages 3-4).

Suggested HPO terms (non-exhaustive; derived from phenotypes explicitly described)

  • Microcephaly HP:0000252
  • Lissencephaly HP:0001339 (present in evidence) (OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1)
  • Agenesis of corpus callosum HP:0001274 (tan2017severecongenitalmicrocephaly pages 3-4, bakircioglu2011theessentialrole pages 1-3)
  • Cerebellar hypoplasia HP:0001321 (alkuraya2011humanmutationsin pages 4-6, bakircioglu2011theessentialrole pages 1-3)
  • Ventriculomegaly HP:0002119 (tan2017severecongenitalmicrocephaly pages 3-4, alkuraya2011humanmutationsin pages 4-6)
  • Global developmental delay HP:0001263 (alkuraya2011humanmutationsin pages 2-3)
  • Seizures HP:0001250 / Epilepsy HP:0001250 (reported qualitatively) (tan2017severecongenitalmicrocephaly pages 3-4)
  • Hypertonia HP:0001276 (alkuraya2011humanmutationsin pages 2-3)

4. Genetic / molecular information

Causal gene

  • NDE1 (nudE neurodevelopment protein 1) (OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1)

Pathogenic variant classes (from retrieved primary/clinical literature)

  • Homozygous frameshift and splice-site loss-of-function variants: e.g., c.83+1G>T (splice) and c.684_685del (frameshift) (bakircioglu2011theessentialrole pages 7-9).
  • Additional frameshift noted in review: c.733dupC (tan2017severecongenitalmicrocephaly pages 3-4).
  • Compound CNV + sequence variant: 16p13.11 deletion including NDE1 plus a point change c.555_556GC>CT yielding p.K185N and p.Q186X on the non-deleted allele in a reported case (tan2017severecongenitalmicrocephaly pages 1-3).

Functional consequences

  • Patient NDE1 proteins were reported to be unstable, unable to bind dynein, and mislocalized from the centrosome (alkuraya2011humanmutationsin pages 1-2).
  • Mutant NDE1 proteins (in patient cells) failed to localize to the centrosome, consistent with loss of centrosomal function in proliferating neuroepithelial/radial glial cells (bakircioglu2011theessentialrole pages 7-9).

Population frequency (limited, but explicit in retrieved evidence)

  • The 2017 report notes one NDE1 allele was seen in only a single East Asian individual among >120,000 in gnomAD, supporting rarity of some pathogenic alleles (tan2017severecongenitalmicrocephaly pages 3-4).

Modifier genes / epigenetics

No NDE1-specific modifier genes or epigenetic signatures for this disorder were identified in the retrieved evidence (granata2022wholeexomesequencing pages 1-2).

5. Environmental information

No convincing non-genetic environmental contributors were identified for the monogenic NDE1 microlissencephaly syndrome in the retrieved evidence (tan2017severecongenitalmicrocephaly pages 1-3).

6. Mechanism / pathophysiology

Causal chain (integrated model)

  1. Upstream trigger: biallelic NDE1 loss → absent/unstable NDE1 protein at the centrosome/dynein regulatory complexes (alkuraya2011humanmutationsin pages 1-2, bakircioglu2011theessentialrole pages 7-9).
  2. Cellular-level defects: neural progenitors exhibit cell-cycle arrests at multiple stages, including apical interkinetic nuclear migration (INM), G2-to-M transition, and primary cilia-linked G1-to-S transition (doobin2016severende1mediatedmicrocephaly pages 1-2).
  3. Tissue-level outcome: profound reduction of prenatal neuron production plus deficient cortical lamination → extreme microcephaly and simplified gyral pattern/microlissencephaly (bakircioglu2011theessentialrole pages 9-11, bakircioglu2011theessentialrole pages 1-3).

Molecular pathways / processes implicated

  • Dynein–LIS1–NDE1 regulation: 2023 mechanistic reconstitution showed Nde1 promotes Lis1-mediated assembly/activation of dynein–dynactin–adaptor complexes (zhao2023nde1promoteslis1mediated pages 1-2).
  • Quantitative statistic: Lis1 increased run frequency up to 2.6-fold, and adding low-nanomolar Nde1 with Lis1 produced up to a 16-fold run-frequency increase in single-molecule assays; excess Nde1 inhibited motility (zhao2023nde1promoteslis1mediated pages 1-2).
  • Neural progenitor cell-cycle and nuclear migration: NDE1 depletion causes arrest during apical nuclear migration and reduces mitotic index; NDEL1 can compensate for some but not all NDE1 functions (notably not the G2-to-M transition) (doobin2016severende1mediatedmicrocephaly pages 1-2, doobin2016severende1mediatedmicrocephaly pages 4-5).

Suggested GO biological process terms (based on described mechanisms)

  • Mitotic cell cycle GO:0000278 (doobin2016severende1mediatedmicrocephaly pages 1-2)
  • Nuclear migration GO:0006913 / Interkinetic nuclear migration (conceptual; INM explicitly referenced) (doobin2016severende1mediatedmicrocephaly pages 1-2)
  • Microtubule-based process GO:0007017 (dynein-based motility) (zhao2023nde1promoteslis1mediated pages 1-2)
  • Cilium organization GO:0044782 (primary cilia regulation at G1-to-S) (doobin2016severende1mediatedmicrocephaly pages 1-2)

Suggested Cell Ontology (CL) terms (primary implicated cell types)

  • Radial glial cell CL:0000679 (apical neural precursors/RGCs implicated) (bakircioglu2011theessentialrole pages 1-3, doobin2016severende1mediatedmicrocephaly pages 1-2)
  • Neural progenitor cell CL:0011020 (doobin2016severende1mediatedmicrocephaly pages 1-2)
  • Neuron CL:0000540 (downstream cortical lamination/migration consequences) (bakircioglu2011theessentialrole pages 9-11)

7. Anatomical structures affected

Organ/system level (dominant)

  • Central nervous system, especially cerebral cortex, corpus callosum, cerebellum, and ventricular system (tan2017severecongenitalmicrocephaly pages 3-4, bakircioglu2011theessentialrole pages 1-3).

Suggested UBERON terms

  • Cerebral cortex UBERON:0000956 (alkuraya2011humanmutationsin pages 2-3)
  • Corpus callosum UBERON:0002796 (tan2017severecongenitalmicrocephaly pages 3-4)
  • Cerebellum UBERON:0002037 (alkuraya2011humanmutationsin pages 4-6)
  • Lateral ventricle UBERON:0002081 (tan2017severecongenitalmicrocephaly pages 3-4)

Subcellular localization (from mechanism papers)

  • Centrosome (GO CC: centrosome GO:0005813) and mitotic spindle-associated localization in apical neural precursors (bakircioglu2011theessentialrole pages 1-3).

8. Temporal development

Onset

  • Congenital/prenatal onset: extreme microcephaly is present at birth; the 2011 AJHG reports emphasize severe prenatal neuron production deficit (bakircioglu2011theessentialrole pages 1-3, bakircioglu2011theessentialrole pages 7-9).

Progression/course

  • The disease is characterized by severe neurodevelopmental disability; longitudinal stage-based natural history, remission patterns, or survival curves were not found in retrieved evidence (tan2017severecongenitalmicrocephaly pages 1-3).

9. Inheritance and population

Inheritance

  • Autosomal recessive, biallelic loss-of-function (“biallelic_autosomal”, “absent_gene_product” in Gene2Phenotype/Open Targets evidence) (OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1).

Epidemiology

  • Disease prevalence/incidence for NDE1 microlissencephaly specifically is not established in the retrieved evidence. The 2017 report emphasizes rarity and summarizes reported case counts: “To date, 14 patients from 8 families” (as of publication) (tan2017severecongenitalmicrocephaly pages 1-3).

Related population statistic (relevant implementation context: 16p13.11 microdeletion)

  • 16p13.11 microdeletion prevalence in general population reported as ~0.04% in a 2022 WES follow-up study; enrichment cited as ~0.13% in schizophrenia and ~0.5–0.6% in epilepsy cohorts (these CNV statistics are not specific to NDE1 biallelic disease but are relevant to diagnostic workflows where 16p13.11 deletions can unmask NDE1) (granata2022wholeexomesequencing pages 1-2).

10. Diagnostics

Clinical/neuroimaging

MRI/brain imaging typically shows severe microcephaly with markedly simplified gyration and frequent callosal agenesis and cerebellar hypoplasia (alkuraya2011humanmutationsin pages 2-3, bakircioglu2011theessentialrole pages 1-3).

Visual evidence: A figure from Alkuraya et al. shows MRI panels comparing an NDE1 patient to a normal control, demonstrating microlissencephaly and agenesis of the corpus callosum (alkuraya2011humanmutationsin media d70b9989).

Genetic testing (recommended approach from retrieved evidence)

  • Chromosomal microarray (CMA/SNP array) to detect deletions at 16p13.11 (tan2017severecongenitalmicrocephaly pages 1-3, tropeano2014clinicalutilitygene pages 1-2).
  • Sequence analysis of NDE1 (targeted sequencing, panel, WES/WGS) to identify biallelic LoF variants (tan2017severecongenitalmicrocephaly pages 1-3, tan2017severecongenitalmicrocephaly pages 3-4).
  • The 2017 case report concludes: “Sequencing NDE1 and CMA in patients with severe congenital microcephaly may be warranted” (tan2017severecongenitalmicrocephaly pages 1-3).
  • WES as an add-on in CNV carriers (2022): because of incomplete penetrance of 16p13.11 microdeletion, WES can be necessary to identify additional variants contributing to phenotype; the study concludes WES is “a fundamental tool” when a predisposing CNV is present (granata2022wholeexomesequencing pages 1-2).

Differential diagnosis

Formal differential lists were not present in retrieved evidence; however, microlissencephaly is genetically heterogeneous (e.g., other genes can cause similar imaging), and NDE1 should be considered in the broader malformations-of-cortical-development workup (sotoperez2020roleofnde1 pages 6-8).

11. Outcome / prognosis

No formal survival or mortality statistics were identified in retrieved evidence. The available literature emphasizes extreme severity, profound neurodevelopmental impairment, and frequent epilepsy, implying a poor neurodevelopmental prognosis (bakircioglu2011theessentialrole pages 1-3, tan2017severecongenitalmicrocephaly pages 3-4).

12. Treatment

Current applications / real-world implementation

  • No disease-modifying therapy specific to NDE1 microlissencephaly was identified in the retrieved evidence.
  • Supportive/symptom-based management is implied by the clinical phenotype and commonly includes epilepsy management, feeding/nutrition support, and multidisciplinary developmental/rehabilitative care (evidence for epilepsy being common is in the 2017 review) (tan2017severecongenitalmicrocephaly pages 3-4).

Clinical trials

A ClinicalTrials.gov search within this session did not yield relevant interventional trials for NDE1 microlissencephaly (tool result: 1 trial retrieved but none relevant/curated as relevant in evidence state) (tan2017severecongenitalmicrocephaly pages 1-3).

Suggested MAXO terms (supportive care; not directly evidenced as standardized protocols in retrieved texts)

  • Antiseizure therapy MAXO:0000602 (conceptual mapping given epilepsy) (tan2017severecongenitalmicrocephaly pages 3-4)
  • Genetic counseling MAXO:0000079 (see Prevention) (OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1)

13. Prevention

Primary prevention

No environmental primary prevention strategies are applicable for this monogenic disorder.

Secondary/tertiary prevention

  • Genetic counseling and reproductive options following molecular diagnosis (carrier testing, cascade testing) are the main prevention-like interventions given autosomal recessive inheritance and recurrence risk (OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1, tan2017severecongenitalmicrocephaly pages 1-3).

14. Other species / natural disease

No naturally occurring non-human species disease analogs were identified in retrieved evidence.

15. Model organisms / experimental systems

  • Rodent developmental cortex models (in utero electroporation/RNAi): NDE1 knockdown in embryonic rat brain produces neural progenitor cell-cycle arrests at multiple stages and markedly reduces migration of neurons to cortical plate, linking NDE1 to neurogenesis and cortical layering (doobin2016severende1mediatedmicrocephaly pages 1-2).
  • In vitro single-molecule reconstitution (2023): mechanistic dissection of Nde1–Lis1 dynein activation demonstrates a quantitative, dose-dependent effect on dynein complex assembly and motility (up to 16-fold run-frequency increase) (zhao2023nde1promoteslis1mediated pages 1-2).

Recent developments and “latest research” emphasis (2023–2024)

  1. Mechanistic refinement of NDE1’s role in dynein activation (2023): single-molecule imaging and in vitro reconstitution clarify that Nde1 promotes Lis1-mediated assembly of active dynein complexes and can both activate (low nM) and inhibit (high concentration) dynein motility, providing a mechanistic explanation for dynein-pathway phenotypes relevant to cortical development disorders (Zhao et al., Nat Commun, May 2023; URL: https://doi.org/10.1038/s41467-023-42907-x) (zhao2023nde1promoteslis1mediated pages 1-2).
  2. Systems-medicine WES follow-up in 16p13.11 microdeletion (2022; near-term context): highlights incomplete penetrance of the CNV and supports routine integration of WES with CMA when interpreting NDE1-containing CNVs—relevant to unmasking recessive NDE1 disease and/or identifying additional contributors (Granata et al., Front Genet, Mar 2022; URL: https://doi.org/10.3389/fgene.2022.798607) (granata2022wholeexomesequencing pages 1-2).
  3. Dynein regulator paralog landscape and cortical malformations (2024): while focused on NDEL1, a 2024 Acta Neuropathologica paper explicitly frames NDE1 loss-of-function as causing microcephaly-related malformations of cortical development and uses single-cell/spatial transcriptomics to distinguish NDE1 vs NDEL1 roles in progenitors vs post-mitotic neurons (Tsai et al., Jan 2024; URL: https://doi.org/10.1007/s00401-023-02665-y) (tsai2024novellissencephalyassociatedndel1 pages 1-2).

Summary table artifact

The following table condenses identifiers, phenotype spectrum, genetics, mechanisms, diagnostics, and management into a knowledge-base–ready format.

Category Key points Key sources
Identifiers/Synonyms • Microlissencephaly is linked to NDE1 with definitive genetic evidence. • Related names in evidence: microlissencephaly, NDE1-related extreme microcephaly with lissencephaly, Norman–Roberts syndrome / Lissencephaly syndrome, Norman-Roberts type. • Database identifiers present in evidence: MONDO_0015204 (microlissencephaly), Orphanet_89844, HP:0001339 (lissencephaly), NDE1 ENSG00000072864. (alkuraya2011humanmutationsin pages 1-2, OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1) Open Targets 2025, NDE1–microlissencephaly association, https://platform.opentargets.org (OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1); Alkuraya 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.04.003 (alkuraya2011humanmutationsin pages 1-2)
Inheritance • Autosomal recessive / biallelic autosomal disease mechanism. • Reported families were consanguineous in seminal reports, with homozygous loss-of-function alleles segregating with disease. • Open Targets/Gene2Phenotype evidence labels allelic requirement as biallelic_autosomal and consequence as absent_gene_product. (alkuraya2011humanmutationsin pages 1-2, OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1, bakircioglu2011theessentialrole pages 7-9) Alkuraya 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.04.003 (alkuraya2011humanmutationsin pages 1-2); Bakircioglu 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.03.019 (bakircioglu2011theessentialrole pages 7-9); Open Targets 2025, https://platform.opentargets.org (OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1)
Core clinical • Congenital or birth-presenting extreme microcephaly, profound/global developmental delay, and profound intellectual disability are core findings. • Hypertonia/abnormal tone, abnormal reflexes, and in some reports early-onset seizures/epilepsy occur. • Overall somatic growth may be relatively preserved despite severe brain growth failure. (tan2017severecongenitalmicrocephaly pages 1-3, alkuraya2011humanmutationsin pages 4-6, alkuraya2011humanmutationsin pages 2-3, bakircioglu2011theessentialrole pages 1-3) Tan 2017, BMC Med Genet, https://doi.org/10.1186/s12881-017-0501-9 (tan2017severecongenitalmicrocephaly pages 1-3); Alkuraya 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.04.003 (alkuraya2011humanmutationsin pages 4-6, alkuraya2011humanmutationsin pages 2-3); Bakircioglu 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.03.019 (bakircioglu2011theessentialrole pages 1-3)
Neuroimaging • Severe microcephaly with extremely simplified gyral pattern / microlissencephaly; in one description, almost no detectable sulci other than the Sylvian fissure. • Frequent agenesis of the corpus callosum and ventricular enlargement. • Cerebellar hypoplasia/small cerebellum is common; additional findings reported include reduced brainstem size and unfused thalami. (tan2017severecongenitalmicrocephaly pages 3-4, alkuraya2011humanmutationsin pages 4-6, alkuraya2011humanmutationsin pages 2-3, bakircioglu2011theessentialrole pages 1-3, alkuraya2011humanmutationsin media d70b9989) Alkuraya 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.04.003 (alkuraya2011humanmutationsin pages 4-6, alkuraya2011humanmutationsin pages 2-3, alkuraya2011humanmutationsin media d70b9989); Bakircioglu 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.03.019 (bakircioglu2011theessentialrole pages 1-3); Tan 2017, BMC Med Genet, https://doi.org/10.1186/s12881-017-0501-9 (tan2017severecongenitalmicrocephaly pages 3-4)
Case counts/rarity • Severe congenital microcephaly due to NDE1 is described as very rare. • Tan et al. reported that “To date, 14 patients from 8 families” had been described at that time. • Early seminal papers documented multiple families (2 families in Alkuraya; 3 families in Bakircioglu). (tan2017severecongenitalmicrocephaly pages 1-3, alkuraya2011humanmutationsin pages 2-3, bakircioglu2011theessentialrole pages 1-3) Tan 2017, BMC Med Genet, https://doi.org/10.1186/s12881-017-0501-9 (tan2017severecongenitalmicrocephaly pages 1-3); Alkuraya 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.04.003 (alkuraya2011humanmutationsin pages 2-3); Bakircioglu 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.03.019 (bakircioglu2011theessentialrole pages 1-3)
Genetics/variant types • Pathogenic alleles in evidence are predominantly biallelic loss-of-function variants: homozygous frameshift and splice-site mutations. • Representative variants reported: c.83+1G>T, c.684_685del, c.733dupC; a compound state combining a 16p13.11 deletion with a truncating sequence variant was also reported. • Mutant proteins are unstable and/or fail to localize to the centrosome. (alkuraya2011humanmutationsin pages 1-2, bakircioglu2011theessentialrole pages 7-9, tan2017severecongenitalmicrocephaly pages 3-4) Alkuraya 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.04.003 (alkuraya2011humanmutationsin pages 1-2); Bakircioglu 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.03.019 (bakircioglu2011theessentialrole pages 7-9); Tan 2017, BMC Med Genet, https://doi.org/10.1186/s12881-017-0501-9 (tan2017severecongenitalmicrocephaly pages 3-4)
Mechanism highlights • NDE1 is a centrosomal/dynein-pathway protein required for neuroepithelial/radial glial progenitor function. • Human and model-system data support failure of prenatal neuron production plus defective cortical lamination as central mechanisms. • Mechanistic studies show arrests during apical interkinetic nuclear migration, G2-to-M transition, and primary-cilia/G1-S regulation; 2023 work showed Nde1 promotes Lis1-mediated dynein activation. (bakircioglu2011theessentialrole pages 9-11, zhao2023nde1promoteslis1mediated pages 1-2, doobin2016severende1mediatedmicrocephaly pages 1-2) Bakircioglu 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.03.019 (bakircioglu2011theessentialrole pages 9-11); Doobin 2016, Nat Commun, https://doi.org/10.1038/ncomms12551 (doobin2016severende1mediatedmicrocephaly pages 1-2); Zhao 2023, Nat Commun, https://doi.org/10.1038/s41467-023-42907-x (zhao2023nde1promoteslis1mediated pages 1-2)
Diagnostics • Diagnosis relies on neuroimaging plus molecular testing. • Evidence-based recommendation from case literature: sequence NDE1 and perform chromosomal microarray in severe congenital microcephaly, especially because 16p13.11 deletions can unmask recessive NDE1 disease. • In CNV-positive patients, 2022 evidence supports adding WES because a predisposing CNV may not fully explain the phenotype. (tan2017severecongenitalmicrocephaly pages 1-3, granata2022wholeexomesequencing pages 1-2, tropeano2014clinicalutilitygene pages 1-2) Tan 2017, BMC Med Genet, https://doi.org/10.1186/s12881-017-0501-9 (tan2017severecongenitalmicrocephaly pages 1-3); Granata 2022, Front Genet, https://doi.org/10.3389/fgene.2022.798607 (granata2022wholeexomesequencing pages 1-2); Tropeano 2014, clinical utility card (tropeano2014clinicalutilitygene pages 1-2)
Treatment/supportive • No disease-modifying therapy or disease-specific interventional trial was identified in the evidence snippets. • Management in available evidence is therefore supportive and symptom-directed, guided by severe neurodevelopmental impairment and seizure risk/epilepsy where present. • Clinical-trial search in this session found no relevant interventional trials. (tan2017severecongenitalmicrocephaly pages 1-3, tan2017severecongenitalmicrocephaly pages 3-4) Tan 2017, BMC Med Genet, https://doi.org/10.1186/s12881-017-0501-9 (tan2017severecongenitalmicrocephaly pages 1-3, tan2017severecongenitalmicrocephaly pages 3-4)
Prevention/counseling • Because the disorder is autosomal recessive, recurrence-risk counseling for families is important. • Molecular confirmation enables carrier testing and family-based reproductive counseling; CNV + sequence analysis may both be needed in some families. • No primary environmental prevention factors were identified in the evidence snippets. (OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1, tan2017severecongenitalmicrocephaly pages 1-3, granata2022wholeexomesequencing pages 1-2) Open Targets 2025, https://platform.opentargets.org (OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1); Tan 2017, BMC Med Genet, https://doi.org/10.1186/s12881-017-0501-9 (tan2017severecongenitalmicrocephaly pages 1-3); Granata 2022, Front Genet, https://doi.org/10.3389/fgene.2022.798607 (granata2022wholeexomesequencing pages 1-2)

Table: This table compiles the key disease-definition, clinical, genetic, mechanistic, diagnostic, and counseling points for NDE1-related microcephaly-lissencephaly using only the evidence snippets available in the conversation. It is designed as a compact reference for downstream knowledge-base curation.

Key primary sources (publication dates and URLs)

  • Bakircioglu et al. May 2011, Am J Hum Genet (PMID in OpenTargets evidence set: 21529752). https://doi.org/10.1016/j.ajhg.2011.03.019 (bakircioglu2011theessentialrole pages 1-3)
  • Alkuraya et al. May 2011, Am J Hum Genet (PMID in OpenTargets evidence set: 21529751). https://doi.org/10.1016/j.ajhg.2011.04.003 (alkuraya2011humanmutationsin pages 1-2)
  • Doobin et al. Aug 2016, Nat Commun. https://doi.org/10.1038/ncomms12551 (doobin2016severende1mediatedmicrocephaly pages 1-2)
  • Tan et al. Dec 2017, BMC Medical Genetics. https://doi.org/10.1186/s12881-017-0501-9 (tan2017severecongenitalmicrocephaly pages 1-3)
  • Granata et al. Mar 2022, Frontiers in Genetics. https://doi.org/10.3389/fgene.2022.798607 (granata2022wholeexomesequencing pages 1-2)
  • Zhao et al. May 2023, Nat Commun. https://doi.org/10.1038/s41467-023-42907-x (zhao2023nde1promoteslis1mediated pages 1-2)
  • Tsai et al. Jan 2024, Acta Neuropathologica. https://doi.org/10.1007/s00401-023-02665-y (tsai2024novellissencephalyassociatedndel1 pages 1-2)

References

  1. (alkuraya2011humanmutationsin pages 1-2): Fowzan S. Alkuraya, Xuyu Cai, Carina Emery, Ganeshwaran H. Mochida, Mohammed S. Al-Dosari, Jillian M. Felie, R. Sean Hill, Brenda J. Barry, Jennifer N. Partlow, Generoso G. Gascon, Amal Kentab, Mohammad Jan, Ranad Shaheen, Yuanyi Feng, and Christopher A. Walsh. Human mutations in nde1 cause extreme microcephaly with lissencephaly [corrected]. American journal of human genetics, 88 5:536-47, May 2011. URL: https://doi.org/10.1016/j.ajhg.2011.04.003, doi:10.1016/j.ajhg.2011.04.003. This article has 269 citations and is from a highest quality peer-reviewed journal.

  2. (OpenTargets Search: microlissencephaly,lissencephaly,microcephaly-NDE1): Open Targets Query (microlissencephaly,lissencephaly,microcephaly-NDE1, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  3. (tan2017severecongenitalmicrocephaly pages 3-4): Li Tan, Bo Bi, Peiwei Zhao, Xiaonan Cai, Chunhui Wan, Jianbo Shao, and Xuelian He. Severe congenital microcephaly with 16p13.11 microdeletion combined with nde1 mutation, a case report and literature review. BMC Medical Genetics, Dec 2017. URL: https://doi.org/10.1186/s12881-017-0501-9, doi:10.1186/s12881-017-0501-9. This article has 30 citations and is from a peer-reviewed journal.

  4. (alkuraya2011humanmutationsin pages 2-3): Fowzan S. Alkuraya, Xuyu Cai, Carina Emery, Ganeshwaran H. Mochida, Mohammed S. Al-Dosari, Jillian M. Felie, R. Sean Hill, Brenda J. Barry, Jennifer N. Partlow, Generoso G. Gascon, Amal Kentab, Mohammad Jan, Ranad Shaheen, Yuanyi Feng, and Christopher A. Walsh. Human mutations in nde1 cause extreme microcephaly with lissencephaly [corrected]. American journal of human genetics, 88 5:536-47, May 2011. URL: https://doi.org/10.1016/j.ajhg.2011.04.003, doi:10.1016/j.ajhg.2011.04.003. This article has 269 citations and is from a highest quality peer-reviewed journal.

  5. (bakircioglu2011theessentialrole pages 1-3): Mehmet Bakircioglu, Ofélia P. Carvalho, Maryam Khurshid, James J. Cox, Beyhan Tuysuz, Tanyeri Barak, Saliha Yilmaz, Okay Caglayan, Alp Dincer, Adeline K. Nicholas, Oliver Quarrell, Kelly Springell, Gulshan Karbani, Saghira Malik, Caroline Gannon, Eamonn Sheridan, Moira Crosier, Steve N. Lisgo, Susan Lindsay, Kaya Bilguvar, Fanni Gergely, Murat Gunel, and C. Geoffrey Woods. The essential role of centrosomal nde1 in human cerebral cortex neurogenesis. American journal of human genetics, 88 5:523-35, May 2011. URL: https://doi.org/10.1016/j.ajhg.2011.03.019, doi:10.1016/j.ajhg.2011.03.019. This article has 206 citations and is from a highest quality peer-reviewed journal.

  6. (doobin2016severende1mediatedmicrocephaly pages 1-2): David J. Doobin, Shahrnaz Kemal, Tiago J. Dantas, and Richard B. Vallee. Severe nde1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages. Nature Communications, Aug 2016. URL: https://doi.org/10.1038/ncomms12551, doi:10.1038/ncomms12551. This article has 81 citations and is from a highest quality peer-reviewed journal.

  7. (zhao2023nde1promoteslis1mediated pages 1-2): Yuanchang Zhao, Sena Oten, and Ahmet Yildiz. Nde1 promotes lis1-mediated activation of dynein. Nature Communications, May 2023. URL: https://doi.org/10.1038/s41467-023-42907-x, doi:10.1038/s41467-023-42907-x. This article has 27 citations and is from a highest quality peer-reviewed journal.

  8. (alkuraya2011humanmutationsin pages 4-6): Fowzan S. Alkuraya, Xuyu Cai, Carina Emery, Ganeshwaran H. Mochida, Mohammed S. Al-Dosari, Jillian M. Felie, R. Sean Hill, Brenda J. Barry, Jennifer N. Partlow, Generoso G. Gascon, Amal Kentab, Mohammad Jan, Ranad Shaheen, Yuanyi Feng, and Christopher A. Walsh. Human mutations in nde1 cause extreme microcephaly with lissencephaly [corrected]. American journal of human genetics, 88 5:536-47, May 2011. URL: https://doi.org/10.1016/j.ajhg.2011.04.003, doi:10.1016/j.ajhg.2011.04.003. This article has 269 citations and is from a highest quality peer-reviewed journal.

  9. (tan2017severecongenitalmicrocephaly pages 1-3): Li Tan, Bo Bi, Peiwei Zhao, Xiaonan Cai, Chunhui Wan, Jianbo Shao, and Xuelian He. Severe congenital microcephaly with 16p13.11 microdeletion combined with nde1 mutation, a case report and literature review. BMC Medical Genetics, Dec 2017. URL: https://doi.org/10.1186/s12881-017-0501-9, doi:10.1186/s12881-017-0501-9. This article has 30 citations and is from a peer-reviewed journal.

  10. (bakircioglu2011theessentialrole pages 7-9): Mehmet Bakircioglu, Ofélia P. Carvalho, Maryam Khurshid, James J. Cox, Beyhan Tuysuz, Tanyeri Barak, Saliha Yilmaz, Okay Caglayan, Alp Dincer, Adeline K. Nicholas, Oliver Quarrell, Kelly Springell, Gulshan Karbani, Saghira Malik, Caroline Gannon, Eamonn Sheridan, Moira Crosier, Steve N. Lisgo, Susan Lindsay, Kaya Bilguvar, Fanni Gergely, Murat Gunel, and C. Geoffrey Woods. The essential role of centrosomal nde1 in human cerebral cortex neurogenesis. American journal of human genetics, 88 5:523-35, May 2011. URL: https://doi.org/10.1016/j.ajhg.2011.03.019, doi:10.1016/j.ajhg.2011.03.019. This article has 206 citations and is from a highest quality peer-reviewed journal.

  11. (granata2022wholeexomesequencing pages 1-2): Paola Granata, Dario Cocciadiferro, Alessandra Zito, Chiara Pessina, Alessandro Bassani, Fabio Zambonin, Antonio Novelli, Mauro Fasano, and Rosario Casalone. Whole exome sequencing in 16p13.11 microdeletion patients reveals new variants through deductive and systems medicine approaches. Frontiers in Genetics, Mar 2022. URL: https://doi.org/10.3389/fgene.2022.798607, doi:10.3389/fgene.2022.798607. This article has 14 citations and is from a peer-reviewed journal.

  12. (bakircioglu2011theessentialrole pages 9-11): Mehmet Bakircioglu, Ofélia P. Carvalho, Maryam Khurshid, James J. Cox, Beyhan Tuysuz, Tanyeri Barak, Saliha Yilmaz, Okay Caglayan, Alp Dincer, Adeline K. Nicholas, Oliver Quarrell, Kelly Springell, Gulshan Karbani, Saghira Malik, Caroline Gannon, Eamonn Sheridan, Moira Crosier, Steve N. Lisgo, Susan Lindsay, Kaya Bilguvar, Fanni Gergely, Murat Gunel, and C. Geoffrey Woods. The essential role of centrosomal nde1 in human cerebral cortex neurogenesis. American journal of human genetics, 88 5:523-35, May 2011. URL: https://doi.org/10.1016/j.ajhg.2011.03.019, doi:10.1016/j.ajhg.2011.03.019. This article has 206 citations and is from a highest quality peer-reviewed journal.

  13. (doobin2016severende1mediatedmicrocephaly pages 4-5): David J. Doobin, Shahrnaz Kemal, Tiago J. Dantas, and Richard B. Vallee. Severe nde1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages. Nature Communications, Aug 2016. URL: https://doi.org/10.1038/ncomms12551, doi:10.1038/ncomms12551. This article has 81 citations and is from a highest quality peer-reviewed journal.

  14. (alkuraya2011humanmutationsin media d70b9989): Fowzan S. Alkuraya, Xuyu Cai, Carina Emery, Ganeshwaran H. Mochida, Mohammed S. Al-Dosari, Jillian M. Felie, R. Sean Hill, Brenda J. Barry, Jennifer N. Partlow, Generoso G. Gascon, Amal Kentab, Mohammad Jan, Ranad Shaheen, Yuanyi Feng, and Christopher A. Walsh. Human mutations in nde1 cause extreme microcephaly with lissencephaly [corrected]. American journal of human genetics, 88 5:536-47, May 2011. URL: https://doi.org/10.1016/j.ajhg.2011.04.003, doi:10.1016/j.ajhg.2011.04.003. This article has 269 citations and is from a highest quality peer-reviewed journal.

  15. (tropeano2014clinicalutilitygene pages 1-2): M Tropeano, J Andrieux, and DA Collier. Clinical utility gene card for: 16p13. 11 microdeletion syndrome. Unknown journal, 2014.

  16. (sotoperez2020roleofnde1 pages 6-8): Jaseph Soto-Perez, Marybeth Baumgartner, and Rahul N. Kanadia. Role of nde1 in the development and evolution of the gyrified cortex. Frontiers in Neuroscience, Dec 2020. URL: https://doi.org/10.3389/fnins.2020.617513, doi:10.3389/fnins.2020.617513. This article has 19 citations and is from a peer-reviewed journal.

  17. (tsai2024novellissencephalyassociatedndel1 pages 1-2): Meng-Han Tsai, Hao-Chen Ke, Wan-Cian Lin, Fang-Shin Nian, Chia-Wei Huang, Haw-Yuan Cheng, Chi-Sin Hsu, Tiziana Granata, Chien-Hui Chang, Barbara Castellotti, Shin-Yi Lin, Fabio M. Doniselli, Cheng-Ju Lu, Silvana Franceschetti, Francesca Ragona, Pei-Shan Hou, Laura Canafoglia, Chien-Yi Tung, Mei-Hsuan Lee, Won-Jing Wang, and Jin-Wu Tsai. Novel lissencephaly-associated ndel1 variant reveals distinct roles of nde1 and ndel1 in nucleokinesis and human cortical malformations. Acta Neuropathologica, Jan 2024. URL: https://doi.org/10.1007/s00401-023-02665-y, doi:10.1007/s00401-023-02665-y. This article has 11 citations and is from a highest quality peer-reviewed journal.

Artifacts