Centrosomopathies (Centrosome-Spindle Disorders of Neural Progenitors)

name: Centrosomopathies
display_name: Centrosomopathies (Centrosome-Spindle Disorders of Neural Progenitors)
creation_date: "2026-08-02T01:01:07Z"
description: >-
  The centrosomopathies are hereditary disorders caused by dysfunction of the
  centrosome, centriole, or mitotic spindle apparatus. Because the centrosome
  governs the orientation, symmetry, and timing of progenitor cell division, the
  lesion is felt most acutely in cortical neurogenesis, where it distorts the
  balance between proliferative and differentiative divisions and depletes or
  mis-specifies the neural progenitor pool. The shared clinical output is reduced
  cortical neuron production — primary microcephaly, microlissencephaly, and
  simplified gyration — and in members whose affected protein also acts outside
  the brain, a systemic growth defect (microcephalic primordial dwarfism).
grouping_basis:
- SHARED_MECHANISM
- SHARED_PATHWAY
grouping_rationale: >-
  Grouped on a shared subcellular machine rather than a shared phenotype. This is
  the deliberate complement of two groupings dismech already has:
  Primary_Microcephaly_Spectrum and Lissencephaly_and_Neuronal_Migration_Disorders
  are organized by the resulting brain malformation, so each mixes
  centrosome/spindle lesions with mechanistically unrelated causes (migration
  arrest, cell-adhesion failure, metabolic and infectious insults). This grouping
  cuts the other way: it collects the disorders that share the centrosome-spindle
  mechanism regardless of whether the malformation is scored as microcephaly,
  lissencephaly, or heterotopia. It is also the structural sibling of the MONDO
  ciliopathy class (the centriole in its non-mitotic, basal-body role) and of the
  tubulinopathy class (the microtubule polymer rather than its organizing centre).
  Members are kept as separate Disease entries because they differ in which step
  is hit — centriole duplication, spindle pole integrity, spindle orientation,
  microtubule severing, or the apoptotic arm of progenitor number control.

  Criteria are NECESSARY rather than NECESSARY_AND_SUFFICIENT: they characterize
  every listed member and should be used to audit the list, but dismech has not
  curated the full MCPH/MOPD gene set (ASPM, WDR62, CENPJ, CEP152, CEP63, CENPE
  and others remain uncurated or lack their own entries), so the criteria must not
  be used to close the class.
membership_criteria:
- description: >-
    Every member's pathophysiology conforms to the neural progenitor
    centrosome-spindle dysfunction module — a centrosome, centriole, spindle, or
    progenitor-number-control perturbation that distorts the neural progenitor
    pool and alters cortical neuron output.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: CONFORMS_TO_MODULE
    module: neural_progenitor_centrosome_spindle_dysfunction
    description: >-
      Conforms to the neural_progenitor_centrosome_spindle_dysfunction module at
      one or more nodes. Deliberately scoped to the module rather than to its
      "Centrosome and Mitotic Spindle Perturbation" node, because the
      programmed-cell-death arm (CRADD) is a legitimate progenitor-number-control
      member that enters the module at a different node.
members:
- member: Autosomal Recessive Primary Microcephaly
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The prototype and the broadest member — an umbrella of MCPH loci
      (MCPH1, WDR62, CDK5RAP2, KNL1 and others) converging on centrosome
      duplication, spindle pole integrity, and spindle-orientation control, with
      a phenotype essentially restricted to reduced brain size and a
      near-normal gyral pattern.
    gene:
      preferred_term: MCPH1
      term:
        id: hgnc:6954
        label: MCPH1
    module: neural_progenitor_centrosome_spindle_dysfunction#Centrosome and Mitotic Spindle Perturbation
- member: Microcephalic Osteodysplastic Primordial Dwarfism Type II
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Pericentrin anchors the pericentriolar material, and because it is required
      for centrosome function in every proliferating tissue rather than only in
      neural progenitors, loss produces the systemic member of the class —
      profound pre- and postnatal growth restriction and skeletal dysplasia
      alongside the microcephaly, plus a distinctive cerebrovascular
      (moyamoya/aneurysm) risk.
    gene:
      preferred_term: PCNT
      term:
        id: hgnc:16068
        label: PCNT
- member: NDE1-related Microcephaly-Lissencephaly
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDE1 couples the centrosome to dynein-driven nuclear and spindle movement,
      so loss produces the most severe end of the spectrum — extreme
      microlissencephaly in which the cortex is both tiny and agyric, rather than
      the size-only reduction of classic MCPH.
    gene:
      preferred_term: NDE1
      term:
        id: hgnc:17619
        label: NDE1
- member: KATNB1-related Cortical Malformation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The microtubule-severing member: the katanin regulatory subunit controls
      spindle microtubule length and number, so the lesion perturbs spindle
      architecture by a mechanism distinct from the centriole-duplication and
      pericentriolar-material members, producing microlissencephaly with
      polymicrogyria-like cortical dysplasia.
    gene:
      preferred_term: KATNB1
      term:
        id: hgnc:6217
        label: KATNB1
- member: EML1-related Ribbon-like Subcortical Heterotopia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      EML1 loss mislocalizes radial glial progenitors away from the ventricular
      surface, so the defect manifests as ectopic progenitor division rather than
      progenitor depletion — the phenotype is a ribbon-like subcortical
      heterotopia rather than microcephaly, making this the member that
      demonstrates the mechanism is not synonymous with reduced brain size.
    gene:
      preferred_term: EML1
      term:
        id: hgnc:3330
        label: EML1
- member: TUBB/TUBB5-related Microcephaly
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The tubulin-subunit member, and the bridge to the MONDO tubulinopathy class:
      the lesion is in the spindle's polymer rather than its organizing centre,
      producing microcephaly with corpus callosum and basal ganglia dysmorphism.
      Legitimately dual-classified as both a centrosomopathy and a tubulinopathy.
    gene:
      preferred_term: TUBB
      term:
        id: hgnc:20778
        label: TUBB
- member: Lissencephaly Spectrum Disorders
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      An umbrella entry whose members are mechanistically heterogeneous; it enters
      this grouping through the centrosome-spindle arm (PAFAH1B1/LIS1 and
      DYNC1H1 acting on the dynein-centrosome axis), while its DCX-driven
      migration arm belongs to the neuronal-migration grouping instead. Listed
      here for the centrosomal arm only.
    gene:
      preferred_term: PAFAH1B1
      term:
        id: hgnc:8574
        label: PAFAH1B1
  notes: >-
    Partial-overlap member: only the LIS1/dynein-centrosome arm of this umbrella
    entry conforms to the module. If the umbrella is later split by mechanism,
    this membership should follow the centrosomal subtype rather than the whole
    entry.
- member: CRADD-Related Thin Lissencephaly
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The apoptotic member: CRADD acts in the PIDDosome-caspase-2 pathway of
      programmed cell death rather than on the centrosome itself, and conforms to
      the module at its Programmed Cell Death Imbalance branch. Progenitor number
      is therefore distorted by failed elimination rather than failed division,
      producing a thin, megalencephalic-to-normocephalic lissencephaly rather
      than microcephaly — the reverse size direction from every other member.
    gene:
      preferred_term: CRADD
      term:
        id: hgnc:2340
        label: CRADD
    module: neural_progenitor_centrosome_spindle_dysfunction#Programmed Cell Death Imbalance Branch
  notes: >-
    Boundary case, listed deliberately. If the class is later narrowed to strict
    centrosome/spindle structural lesions, this member is the first that should be
    reconsidered — it is retained because the module treats progenitor-number
    control as one mechanism with two arms.
notes: >-
  Curated as the dismech-side counterpart of proposed MONDO node #5 in
  docs/reports/mondo-mechanism-classification-proposal-2026-08-01.md. No
  `mappings:` block is given because MONDO has no term for this class at any
  granularity — searches of MONDO labels, synonyms, and definition text for
  "centrosomopathy", "centriole", "pericentriolar", and "spindle assembly"
  return zero hits, and the only candidate broader terms (hereditary disease,
  nervous system disorder) are too broad to carry information. A mapping should
  be added if and when the proposed term is minted.

  Three members — NDE1-related Microcephaly-Lissencephaly, KATNB1-related
  Cortical Malformation, and TUBB/TUBB5-related Microcephaly — currently lack a
  `disease_term` in their disease entries, so they cannot yet be aligned to
  MONDO. That gap is tracked in §5 of the report above.