Lissencephaly and Neuronal Migration/Cortical Positioning Disorders

name: Lissencephaly and Neuronal Migration Disorders
display_name: Lissencephaly and Neuronal Migration/Cortical Positioning Disorders
creation_date: "2026-06-13T00:00:00Z"
description: >-
  A group of malformations of cortical development in which defective neuronal
  positioning, cortical lamination, radial or tangential migration, terminal
  translocation, pial-boundary integrity, apical neuroependyma integrity, or
  progenitor output disrupts normal cortical gyration and layering. The shared
  clinical-anatomic space includes lissencephaly, pachygyria, subcortical band
  heterotopia, polymicrogyria, periventricular nodular heterotopia, and related
  cortical dyslamination phenotypes.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped as an auditable union of cortical malformation entries where the
  primary disease model disrupts cortical neuron placement, cortical lamination,
  or cortical gyration. The members are deliberately kept as separate Disease
  entries because the proximal mechanisms are not interchangeable: PAFAH1B1/DCX
  and tubulin disorders perturb microtubule-dependent migration, RELN/VLDLR
  disorders perturb terminal somal translocation and lamination, ARX disorders
  perturb interneuron specification and tangential migration, ADGRG1/GPR56
  disease perturbs pial basement membrane/radial-glial endfoot integrity, FLNA
  and related periventricular heterotopia genes perturb apical neuroependyma
  integrity, and CRADD/EML1/KATNB1/NDE1 connect cortical malformation to
  progenitor, apoptosis, centrosome, or microtubule branches. The criteria are
  NECESSARY: membership entails a cortical positioning/lamination/gyration
  mechanism and a cortical malformation phenotype, but those features alone are
  not sufficient to infer membership because broad developmental brain
  malformations, tumor-associated dyslamination, and acquired cortical injury
  can converge on similar imaging terms.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018838
      label: lissencephaly spectrum disorders
    mapping_predicate: skos:relatedMatch
    mapping_source: MONDO
    mapping_justification: >-
      relatedMatch rather than closeMatch: the grouping includes the MONDO
      lissencephaly spectrum core but is intentionally broader, spanning related
      cortical positioning phenotypes such as polymicrogyria, heterotopia, and
      selected tubulinopathy/cortical malformation entries.
    consistency:
    - reference: MONDO
      consistent: INCONSISTENT
      notes: >-
        Several members are not is-a descendants of MONDO:0018838 because this
        grouping is mechanism and phenotype oriented rather than a direct
        recapitulation of the MONDO lissencephaly subtree.
membership_criteria:
- description: >-
    A member has a primary developmental cortical-positioning mechanism
    represented by one of the dismech cortical malformation modules, and has a
    cortical malformation phenotype such as lissencephaly, thin lissencephaly,
    pachygyria, polymicrogyria, bilateral perisylvian polymicrogyria, gray
    matter heterotopia, subcortical band heterotopia, periventricular nodular
    heterotopia, or abnormal neuronal migration.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - operator: OR
      operands:
      - criterion_predicate: CONFORMS_TO_MODULE
        module: "microtubule_dependent_neuronal_migration_failure#Microtubule-Based Neuronal Motility Failure"
        description: >-
          Microtubule-dependent neuronal motility, nucleokinesis, migration, or
          cortical dyslamination failure.
      - criterion_predicate: CONFORMS_TO_MODULE
        module: "reelin_terminal_translocation_lamination_failure#Terminal Somal Translocation Failure"
        description: >-
          Reelin-pathway terminal somal translocation and cortical lamination
          failure.
      - criterion_predicate: CONFORMS_TO_MODULE
        module: "interneuron_specification_tangential_migration_failure#Tangential Migration Failure from Ganglionic Eminences"
        description: >-
          Interneuron specification, differentiation, or tangential migration
          failure from subpallial progenitor domains.
      - criterion_predicate: CONFORMS_TO_MODULE
        module: "pial_basement_membrane_radial_glial_endfoot_failure#Neuronal Overmigration Across the Pial Boundary"
        description: >-
          Pial basement membrane or radial-glial basal endfoot failure with
          neuronal overmigration.
      - criterion_predicate: CONFORMS_TO_MODULE
        module: "apical_neuroependyma_integrity_failure#Secondary Neuronal Positioning and Migration Defects"
        description: >-
          Apical neuroependyma or ventricular-surface integrity failure causing
          secondary neuronal positioning defects.
      - criterion_predicate: CONFORMS_TO_MODULE
        module: "neural_progenitor_centrosome_spindle_dysfunction#Abnormal Cortical Neuron Output and Gyration"
        description: >-
          Progenitor centrosome, spindle, apoptosis, or cell-output defects that
          produce abnormal cortical size, gyration, or lamination.
    - operator: OR
      operands:
      - criterion_predicate: HAS_PHENOTYPE
        description: Lissencephaly.
        phenotype_term:
          preferred_term: Lissencephaly
          term:
            id: HP:0001339
            label: Lissencephaly
      - criterion_predicate: HAS_PHENOTYPE
        description: Thin lissencephaly.
        phenotype_term:
          preferred_term: Thin lissencephaly
          term:
            id: HP:0020188
            label: Anterior predominant pachygyria with 5-10 mm cortical thickness
      - criterion_predicate: HAS_PHENOTYPE
        description: Pachygyria.
        phenotype_term:
          preferred_term: Pachygyria
          term:
            id: HP:0001302
            label: Pachygyria
      - criterion_predicate: HAS_PHENOTYPE
        description: Polymicrogyria.
        phenotype_term:
          preferred_term: Polymicrogyria
          term:
            id: HP:0002126
            label: Polymicrogyria
      - criterion_predicate: HAS_PHENOTYPE
        description: Bilateral perisylvian polymicrogyria.
        phenotype_term:
          preferred_term: Bilateral perisylvian polymicrogyria
          term:
            id: HP:0032407
            label: Bilateral perisylvian polymicrogyria
      - criterion_predicate: HAS_PHENOTYPE
        description: Gray matter heterotopia.
        phenotype_term:
          preferred_term: Gray matter heterotopia
          term:
            id: HP:0002282
            label: Gray matter heterotopia
      - criterion_predicate: HAS_PHENOTYPE
        description: Subcortical band heterotopia.
        phenotype_term:
          preferred_term: Subcortical band heterotopia
          term:
            id: HP:0032409
            label: Subcortical band heterotopia
      - criterion_predicate: HAS_PHENOTYPE
        description: Periventricular nodular heterotopia.
        phenotype_term:
          preferred_term: Periventricular nodular heterotopia
          term:
            id: HP:0032388
            label: Periventricular nodular heterotopia
      - criterion_predicate: HAS_PHENOTYPE
        description: Abnormality of neuronal migration.
        phenotype_term:
          preferred_term: Abnormality of neuronal migration
          term:
            id: HP:0002269
            label: Abnormality of neuronal migration
members:
- member: Lissencephaly Spectrum Disorders
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The classic lissencephaly/subcortical-band-heterotopia core, especially
      PAFAH1B1/LIS1 dosage-sensitive dynein regulation and DCX-dependent
      microtubule stabilization, anchors the microtubule migration branch.
    gene:
      preferred_term: PAFAH1B1
      term:
        id: hgnc:8574
        label: PAFAH1B1
    module: "microtubule_dependent_neuronal_migration_failure#Microtubule Apparatus Perturbation"
  - description: >-
      DCX variants distinguish the X-linked lissencephaly/subcortical band
      heterotopia branch through microtubule binding and stabilization defects
      in migrating neurons.
    gene:
      preferred_term: DCX
      term:
        id: hgnc:2714
        label: DCX
    module: "microtubule_dependent_neuronal_migration_failure#Microtubule-Based Neuronal Motility Failure"
- member: Miller-Dieker Lissencephaly Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A 17p13.3 contiguous-gene deletion removes PAFAH1B1/LIS1 and produces a
      severe classic lissencephaly phenotype with additional deletion-syndrome
      features.
    gene:
      preferred_term: PAFAH1B1
      term:
        id: hgnc:8574
        label: PAFAH1B1
    module: "microtubule_dependent_neuronal_migration_failure#Microtubule Apparatus Perturbation"
  - description: >-
      YWHAE co-deletion helps distinguish Miller-Dieker syndrome from isolated
      PAFAH1B1-related lissencephaly sequence.
    gene:
      preferred_term: YWHAE
      term:
        id: hgnc:12851
        label: YWHAE
- member: Reelin Pathway Lissencephaly
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      RELN/VLDLR/LRP8/DAB1 signaling failure disrupts terminal somal
      translocation and inside-out lamination rather than the LIS1/DCX
      microtubule migration skeleton.
    gene:
      preferred_term: RELN
      term:
        id: hgnc:9957
        label: RELN
    module: "reelin_terminal_translocation_lamination_failure#Terminal Somal Translocation Failure"
- member: X-Linked Lissencephaly With Abnormal Genitalia (ARX-Related)
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ARX perturbs subpallial interneuron lineage programs and tangential
      migration, linking cortical malformation to interneuron deficit, genital
      anomalies, and severe developmental epilepsy.
    gene:
      preferred_term: ARX
      term:
        id: hgnc:18060
        label: ARX
    module: "interneuron_specification_tangential_migration_failure#Tangential Migration Failure from Ganglionic Eminences"
- member: NDE1-related Microcephaly-Lissencephaly
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDE1 links dynein/centrosome function to both neural progenitor division
      and postmitotic migration, producing the severe microlissencephaly branch.
    gene:
      preferred_term: NDE1
      term:
        id: hgnc:17619
        label: NDE1
    module: "neural_progenitor_centrosome_spindle_dysfunction#Centrosome and Mitotic Spindle Perturbation"
- member: CRADD-Related Thin Lissencephaly
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      CRADD/RAIDD loss reduces PIDDosome-caspase-2 developmental neuronal
      apoptosis, producing megalencephaly with thin lissencephaly rather than a
      canonical migration-arrest lissencephaly.
    gene:
      preferred_term: CRADD
      term:
        id: hgnc:2340
        label: CRADD
    module: "neural_progenitor_centrosome_spindle_dysfunction#Abnormal Cortical Neuron Output and Gyration"
- member: TUBA1A-related Tubulinopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      TUBA1A is the major neuronal alpha-tubulin branch, with alpha-tubulin
      heterodimer and MAP-binding defects causing lissencephaly, basal ganglia
      dysmorphism, corpus callosum anomalies, and cerebellar hypoplasia.
    gene:
      preferred_term: TUBA1A
      term:
        id: hgnc:20766
        label: TUBA1A
    module: "microtubule_dependent_neuronal_migration_failure#Microtubule Apparatus Perturbation"
- member: TUBB2A/TUBB2B-related Cortical Malformation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      TUBB2A/TUBB2B beta-tubulin defects preferentially produce polymicrogyria
      or dysgyria-like cortical malformations, distinguishing this branch from
      classic LIS1/DCX lissencephaly.
    gene:
      preferred_term: TUBB2A
      term:
        id: hgnc:12412
        label: TUBB2A
    module: "microtubule_dependent_neuronal_migration_failure#Cortical Dyslamination and Neuronal Ectopia"
  - description: >-
      TUBB2B contributes the second beta-tubulin locus in this paired
      tubulinopathy entry.
    gene:
      preferred_term: TUBB2B
      term:
        id: hgnc:30829
        label: TUBB2B
- member: TUBB3-related Tubulinopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      TUBB3 is distinguished by a strong axon guidance and projection-wiring
      branch, with variable cortical dyslamination and extraocular motor-neuron
      phenotypes.
    gene:
      preferred_term: TUBB3
      term:
        id: hgnc:20772
        label: TUBB3
    module: "microtubule_dependent_neuronal_migration_failure#Axon Guidance and Projection Wiring Defects"
- member: TUBB/TUBB5-related Microcephaly
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      TUBB/TUBB5 couples beta-tubulin dysfunction to both microtubule-dependent
      migration failure and progenitor-output defects, producing microcephaly
      with cortical malformation.
    gene:
      preferred_term: TUBB
      term:
        id: hgnc:20778
        label: TUBB
    module: "microtubule_dependent_neuronal_migration_failure#Microtubule Apparatus Perturbation"
- member: TUBG1-related Tubulinopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The gamma-tubulin branch: TUBG1 perturbs microtubule NUCLEATION rather than
      the lattice, and the resulting migration failure has a distinctive imaging
      signature - posterior-predominant pachygyria with posteriorly accentuated
      ventriculomegaly, but with basal ganglia, corpus callosum, brainstem and
      cerebellum often normal. On MRI it therefore resembles LIS1/PAFAH1B1
      lissencephaly more closely than it resembles the alpha- and beta-tubulin
      members of this grouping.
    gene:
      preferred_term: TUBG1
      term:
        id: hgnc:12417
        label: TUBG1
    module: "microtubule_dependent_neuronal_migration_failure#Microtubule Apparatus Perturbation"
- member: TUBGCP2-related Lissencephaly Spectrum Disorder
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The gamma-tubulin RING COMPLEX branch, one step further from the
      microtubule than TUBG1: GCP2 does not polymerize or nucleate itself but
      forms, with GCP3, the repeating unit that scaffolds gamma-tubulin into the
      nucleating ring. It is also the only recessive member of the tubulin-family
      contingent here - biallelic missense, splice, frameshift and multi-exon
      deletion alleles - and the only one with a recognizable facial gestalt
      (narrow forehead, thick eyebrows, bulbous nose, widely spaced teeth)
      accompanying the pachygyria and subcortical band heterotopia. It is
      excluded from the Tubulinopathies grouping on gene identity (GCP2 is a
      complex protein, not a tubulin) despite conforming to the same module.
    gene:
      preferred_term: TUBGCP2
      term:
        id: hgnc:18599
        label: TUBGCP2
    module: "microtubule_dependent_neuronal_migration_failure#Microtubule Apparatus Perturbation"
- member: ADGRG1-related Bilateral Frontoparietal Polymicrogyria
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ADGRG1/GPR56 disrupts collagen III-associated pial ECM signaling,
      radial-glial endfoot anchoring, and pial boundary integrity, causing
      regional overmigration and frontoparietal polymicrogyria.
    gene:
      preferred_term: ADGRG1
      term:
        id: hgnc:4512
        label: ADGRG1
    module: "pial_basement_membrane_radial_glial_endfoot_failure#Neuronal Overmigration Across the Pial Boundary"
- member: SRPX2-related Speech-Epilepsy-Polymicrogyria
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      SRPX2 links speech-language epilepsy phenotypes to polymicrogyria through
      a microtubule/migration-associated cortical dyslamination branch.
    gene:
      preferred_term: SRPX2
      term:
        id: hgnc:30668
        label: SRPX2
    module: "microtubule_dependent_neuronal_migration_failure#Cortical Dyslamination and Neuronal Ectopia"
- member: Periventricular Nodular Heterotopia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      FLNA and related apical-neuroependyma genes disrupt ventricular-surface
      integrity and progenitor/neuron positioning, producing periventricular
      heterotopic nodules rather than surface gyral simplification.
    gene:
      preferred_term: FLNA
      term:
        id: hgnc:3754
        label: FLNA
    module: "apical_neuroependyma_integrity_failure#Periventricular Heterotopic Nodules"
- member: EML1-related Ribbon-like Subcortical Heterotopia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      EML1/EMAP-1 perturbs centrosome and microtubule organization in neural
      progenitors, producing megalencephaly with ribbon-like subcortical
      heterotopia rather than the classic lissencephaly pattern.
    gene:
      preferred_term: EML1
      term:
        id: hgnc:3330
        label: EML1
    module: "neural_progenitor_centrosome_spindle_dysfunction#Abnormal Cortical Neuron Output and Gyration"
- member: KATNB1-related Cortical Malformation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      KATNB1, the regulatory subunit of katanin, links centrosome integrity and
      microtubule severing to both neural progenitor defects and neuronal
      migration/cortical dyslamination.
    gene:
      preferred_term: KATNB1
      term:
        id: hgnc:6217
        label: KATNB1
    module: "microtubule_dependent_neuronal_migration_failure#Cortical Dyslamination and Neuronal Ectopia"
notes: >-
  This grouping intentionally overlaps Tubulinopathies and Primary Microcephaly
  Spectrum: those groupings organize different axes (gene family and
  progenitor-pool depletion), whereas this grouping organizes the shared
  malformation-of-cortical-development space around cortical positioning,
  lamination, and gyration. Congenital Zika Syndrome is excluded for now because
  it is primarily an acquired infectious fetal progenitor-cytopathy entry rather
  than a member of the inherited lissencephaly/neuronal-positioning nosology,
  although it remains a useful mechanistic comparator for disrupted cortical
  neurogenesis and congenital cortical malformation.