Autosomal Recessive Primary Microcephaly and Related Centrosome/Spindle Malformations

name: Primary Microcephaly Spectrum
display_name: Autosomal Recessive Primary Microcephaly and Related Centrosome/Spindle Malformations
creation_date: "2026-06-13T00:00:00Z"
description: >-
  A group of neurodevelopmental malformations in which defects in centrosome,
  mitotic-spindle, and associated microtubule machinery disrupt the proliferative
  divisions of neural progenitors in the developing cortex. Abnormal spindle
  orientation and centrosome function shift progenitors from symmetric
  proliferative to premature neurogenic or apoptotic fates, depleting the
  progenitor pool and reducing neuronal output. The shared consequence is a
  small brain — congenital microcephaly — frequently combined with simplified
  gyration, heterotopia, or lissencephaly depending on the gene.
grouping_basis:
- SHARED_MECHANISM
grouping_rationale: >-
  Grouped on a shared developmental mechanism: each member conforms to the
  neural_progenitor_centrosome_spindle_dysfunction module (centrosome/spindle
  perturbation -> abnormal progenitor division and fate -> progenitor-pool
  distortion -> reduced cortical neuron output). Members are kept as separate
  Disease entries because they affect different nodes of the centrosome/spindle
  apparatus (spindle-pole and centriole proteins, katanin microtubule severing,
  dynein regulators, tubulin) and differ in whether the dominant phenotype is
  pure microcephaly, microlissencephaly, or heterotopia. The criteria are
  NECESSARY: centrosome/spindle-module conformance with congenital microcephaly
  is entailed by membership, but reduced brain size alone has many other causes,
  so the criteria are not stated as sufficient.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0001149
      label: microcephaly
    mapping_predicate: skos:relatedMatch
    mapping_source: MONDO
    mapping_justification: >-
      relatedMatch rather than broad/closeMatch: this grouping is defined by a
      MECHANISM (neural-progenitor centrosome/spindle dysfunction), whereas
      MONDO:0001149 (microcephaly) is the phenotype/feature class. The two
      overlap heavily but neither cleanly is-a-subsumes the other — several
      members (e.g., Lissencephaly Spectrum) are not classified under
      "microcephaly," and many microcephaly descendants are acquired or
      syndromic forms outside this mechanistic grouping.
    consistency:
    - reference: MONDO
      consistent: INCONSISTENT
      notes: >-
        Only 1/5 listed members maps under MONDO:0001149; three members declare
        no MONDO id and Lissencephaly Spectrum (MONDO:0018838) sits outside the
        microcephaly subtree. The mapping is conceptual (microcephaly is the
        cardinal shared feature), not an is-a correspondence.
membership_criteria:
- description: >-
    A member conforms to the neural-progenitor centrosome/spindle dysfunction
    module (a centrosome/spindle defect distorting progenitor divisions) AND
    presents with congenital microcephaly.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - criterion_predicate: CONFORMS_TO_MODULE
      module: neural_progenitor_centrosome_spindle_dysfunction#Centrosome and Mitotic Spindle Perturbation
      description: >-
        Conforms to the centrosome/spindle perturbation node of the progenitor
        module.
    - criterion_predicate: HAS_PHENOTYPE
      description: Congenital microcephaly.
      phenotype_term:
        preferred_term: Microcephaly
        term:
          id: HP:0000252
          label: Microcephaly
members:
- member: Autosomal Recessive Primary Microcephaly
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The prototype (MCPH), most commonly ASPM, with a spindle-pole defect that
      depletes the progenitor pool, producing pure congenital microcephaly with
      simplified gyration and relatively preserved architecture.
    gene:
      preferred_term: ASPM
      term:
        id: hgnc:19048
        label: ASPM
- member: NDE1-related Microcephaly-Lissencephaly
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDE1 regulates dynein at the spindle and is required for both proliferation
      and migration; loss produces the severe combination of extreme microcephaly
      with lissencephaly (microlissencephaly).
    gene:
      preferred_term: NDE1
      term:
        id: hgnc:17619
        label: NDE1
- member: KATNB1-related Cortical Malformation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      KATNB1 is the regulatory subunit of the microtubule-severing enzyme
      katanin; loss links centrosome integrity to microtubule dynamics, giving
      microcephaly with complex cortical malformation (lissencephaly /
      polymicrogyria).
    gene:
      preferred_term: KATNB1
      term:
        id: hgnc:6217
        label: KATNB1
- member: TUBB/TUBB5-related Microcephaly
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      TUBB (TUBB5) couples a microtubule/tubulin defect to abnormal progenitor
      division, producing microcephaly with structural cortical malformation;
      also a member of the tubulinopathy gene-family grouping.
    gene:
      preferred_term: TUBB
      term:
        id: hgnc:20778
        label: TUBB
- member: Lissencephaly Spectrum Disorders
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The classic LIS1 (PAFAH1B1) lissencephaly spectrum overlaps this group
      through its dynein-regulatory role at the spindle and microtubule
      apparatus; microcephaly accompanies the smooth-brain malformation.
    gene:
      preferred_term: PAFAH1B1
      term:
        id: hgnc:8574
        label: PAFAH1B1
notes: >-
  Overlaps the microtubule_dependent_neuronal_migration_failure space; several
  members (KATNB1, NDE1, Lissencephaly Spectrum, TUBB/TUBB5) conform to both
  modules. This grouping is organized around the proliferative
  (progenitor-depletion) mechanism that produces small brain size, whereas the
  tubulinopathy grouping is organized around the tubulin gene family. EML1-related
  ribbon heterotopia conforms to the same centrosome/spindle module but is
  deliberately excluded here because it presents with megalencephaly rather than
  microcephaly — the membership audit flags this phenotype mismatch.