Holoprosencephaly caused by Sonic hedgehog pathway lesions

name: Hedgehog Pathway Holoprosencephaly
display_name: Holoprosencephaly caused by Sonic hedgehog pathway lesions
creation_date: "2026-08-01T00:00:00Z"
description: >-
  Holoprosencephaly — failure of the embryonic prosencephalon to cleave into paired
  cerebral hemispheres, with a graded midline craniofacial deficiency — arising from
  germline lesions at successive levels of Sonic hedgehog (SHH) signal transduction.
  Members share the same developmental readout (insufficient ventralizing Hedgehog
  output across the rostral midline at the time of forebrain cleavage) but perturb the
  pathway at different levels: the ligand itself, the terminal transcriptional
  activator, and the post-transcriptional machinery that sets where SHH is expressed.
  The severity gradient (alobar → semilobar → lobar → microform, down to isolated
  single central incisor) is characteristic of dose-sensitive Hedgehog signalling and
  is seen within, not only between, members.
grouping_basis:
- SHARED_PATHWAY
- SHARED_PHENOTYPE
grouping_rationale: >-
  This grouping is deliberately minted over the *genetic Hedgehog-pathway subset* of
  holoprosencephaly rather than over the clinical entity. Holoprosencephaly as a
  clinical diagnosis also arises non-genetically (maternal pregestational diabetes,
  prenatal alcohol and other teratogen exposure), chromosomally (trisomy 13, 18p
  deletion), and through non-Hedgehog developmental genes (e.g. TGIF1, ZIC2, FGF8
  pathway), so a grouping anchored on the clinical parent would assert a shared
  pathway its members do not share. The members are kept as separate Disease entries
  because the lesion level differs — SHH ligand haploinsufficiency, GLI2 activator
  dose, CNOT1-dependent SHH repression — and because the non-CNS features track the
  lesion level rather than the shared forebrain phenotype (pituitary and limb defects
  with GLI2; pancreatic agenesis with CNOT1). Criteria are stated as NECESSARY, not
  sufficient: holoprosencephaly with Hedgehog involvement is entailed by membership,
  but Hedgehog-pathway disruption alone produces many other phenotypes (Gorlin
  syndrome, Pallister-Hall, medulloblastoma) that are not holoprosencephaly.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0016296
      label: holoprosencephaly
    mapping_predicate: skos:relatedMatch
    mapping_source: MONDO
    mapping_justification: >-
      Direction, stated explicitly to avoid broad/narrow ambiguity: this grouping is
      NARROWER than MONDO:0016296. It covers only the Hedgehog-pathway genetic members
      and deliberately excludes the non-genetic (maternal diabetes, teratogenic),
      chromosomal, and non-Hedgehog genetic forms of holoprosencephaly that the MONDO
      class subsumes. relatedMatch (rather than close/exact) also avoids implying that
      every MONDO descendant is a curation gap for this grouping — most are numbered
      HPE loci whose gene is unidentified, which by design cannot be members.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        All three members are is-a descendants of MONDO:0016296 (MONDO:0007733 HPE3,
        MONDO:0012563 HPE9, MONDO:0032787 HPE12). The reverse does not hold and is not
        claimed. Note that MONDO:0016296 currently carries has_characteristic
        MONDO:0021152 (inherited) sourced only to OMIMPS:236100, which is why the
        genetic subset needs an explicit grouping rather than being read off the
        clinical class — see docs/reports/omim-phenotypic-series-groupings-2026-08-01.md.
membership_criteria:
- description: >-
    A member presents with holoprosencephaly AND its pathophysiology runs through
    Hedgehog (smoothened) signal transduction.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - criterion_predicate: HAS_PHENOTYPE
      description: Holoprosencephaly (any grade, alobar through microform).
      phenotype_term:
        preferred_term: Holoprosencephaly
        term:
          id: HP:0001360
          label: Holoprosencephaly
    - criterion_predicate: HAS_BIOLOGICAL_PROCESS
      description: >-
        The causal chain passes through Hedgehog signal transduction, whether by
        reducing ligand, reducing transcriptional output, or mislocating SHH
        expression.
      biological_processes:
      - preferred_term: smoothened signaling pathway
        term:
          id: GO:0007224
          label: smoothened signaling pathway
members:
- member: SHH Holoprosencephaly Spectrum
  member_type: DISEASE
  display_name: SHH-related holoprosencephaly spectrum (HPE3)
  differentiating_mechanisms:
  - description: >-
      Lesion at the LIGAND. Heterozygous SHH loss-of-function reduces the ventralizing
      morphogen itself, so the entire downstream pathway is under-driven in the rostral
      midline. This is the prototype of the grouping and shows the widest intrafamilial
      severity range, from alobar holoprosencephaly to a solitary median maxillary
      central incisor in a clinically unaffected transmitting parent — the clearest
      demonstration that the phenotype is set by residual Hedgehog dose plus modifiers.
    gene:
      preferred_term: SHH
      term:
        id: hgnc:10848
        label: SHH
    biological_processes:
    - preferred_term: smoothened signaling pathway
      term:
        id: GO:0007224
        label: smoothened signaling pathway
    modifier: DECREASED
- member: Holoprosencephaly 9
  member_type: DISEASE
  display_name: GLI2-related holoprosencephaly 9
  differentiating_mechanisms:
  - description: >-
      Lesion at the TERMINAL TRANSCRIPTIONAL ACTIVATOR. GLI2 haploinsufficiency
      attenuates Hedgehog transcriptional output downstream of ligand and receptor, so
      the forebrain midline defect is typically milder and less penetrant than with SHH
      loss, while the GLI2-dependent tissues dominate the clinical picture:
      hypopituitarism from defective Rathke pouch and anterior pituitary organogenesis,
      postaxial polydactyly, and midface hypoplasia. Frank holoprosencephaly is the
      minority presentation despite the disease name.
    gene:
      preferred_term: GLI2
      term:
        id: hgnc:4318
        label: GLI2
    biological_processes:
    - preferred_term: smoothened signaling pathway
      term:
        id: GO:0007224
        label: smoothened signaling pathway
    modifier: DECREASED
- member: Holoprosencephaly 12 With or Without Pancreatic Agenesis
  member_type: DISEASE
  display_name: CNOT1-related holoprosencephaly 12
  differentiating_mechanisms:
  - description: >-
      Lesion in the POST-TRANSCRIPTIONAL REGULATOR that sets the SHH expression
      boundary. The recurrent de novo CNOT1 p.Arg535Cys variant perturbs the CCR4-NOT
      deadenylase scaffold, and the resulting failure to repress SHH in the dorsal
      foregut endoderm blocks pancreatic progenitor specification — so this member
      couples midline prosencephalic patterning failure to pancreatic agenesis with
      neonatal diabetes, a combination no other member shows. It is also the member
      whose SHH perturbation is directionally opposite in the second affected tissue:
      too LITTLE Hedgehog output in the forebrain, too MUCH SHH expression in the
      foregut.
    gene:
      preferred_term: CNOT1
      term:
        id: hgnc:7877
        label: CNOT1
    biological_processes:
    - preferred_term: smoothened signaling pathway
      term:
        id: GO:0007224
        label: smoothened signaling pathway
notes: >-
  Created as a worked example from the OMIM phenotypic series audit
  (docs/reports/omim-phenotypic-series-groupings-2026-08-01.md), which recommends
  minting groupings over the genetic subset of a broad clinical class rather than over
  the class itself. Membership is small by design and by curation state: MONDO's
  holoprosencephaly subtree holds ~20 descendants, but most are numbered HPE loci with
  no identified gene, and dismech curates only these three. Obvious future members as
  they are curated: ZIC2 (HPE5) and TGIF1 (HPE4) — both genuinely holoprosencephaly but
  NOT Hedgehog-pathway lesions, so they would need either a broader grouping
  ("holoprosencephaly, genetic forms") or their own sibling grouping rather than
  admission here. SIX3 (HPE2) does act on the Hedgehog axis (SHH transcriptional
  activation in the ventral forebrain) and would be a direct fit. GLI2 also appears in
  the hypogonadotropic-hypogonadism space through its pituitary role — the two
  groupings intersect at Holoprosencephaly 9, which is expected, not an error.