Heritable Thoracic Aortic Aneurysm and Dissection (HTAD)

name: Heritable Thoracic Aortic Disease
display_name: Heritable Thoracic Aortic Aneurysm and Dissection (HTAD)
creation_date: "2026-06-12T00:00:00Z"
description: >-
  Heritable thoracic aortic disease (HTAD) is a group of Mendelian disorders
  that predispose to thoracic aortic aneurysm and dissection. Despite diverse
  primary lesions — extracellular-matrix defects, smooth-muscle contractile
  defects, or TGF-beta receptor/signaling defects — they converge on
  paradoxically increased aortic-wall TGF-beta signaling, medial degeneration,
  and progressive aortic dilation. The group spans syndromic forms (with
  skeletal, cutaneous, or craniofacial features) and nonsyndromic familial
  forms.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PATHWAY
grouping_rationale: >-
  Grouped on the shared aortopathy mechanism: each member conforms to the
  aortopathy_tgfbeta_dysregulation module (primary wall lesion -> increased
  TGF-beta signaling -> medial degeneration -> aortic dilation -> dissection).
  Members are kept as separate Disease entries because the primary lesion
  differs (FBN1 microfibril deficiency in Marfan; TGFBR1/2 and SMAD3 in
  Loeys-Dietz; SLC2A10 in arterial tortuosity; ACTA2/MYH11 contractile-apparatus
  defects in nonsyndromic familial TAAD; SKI in Shprintzen-Goldberg), as do the
  extravascular features. The criteria are stated as NECESSARY: aortopathy
  module conformance plus aortic aneurysm/dissection is entailed by membership,
  but those features alone do not establish a heritable etiology.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019625
      label: familial thoracic aortic aneurysm and aortic dissection
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      Downgraded from closeMatch to broadMatch: MONDO:0019625 (familial thoracic
      aortic aneurysm and aortic dissection) is-a-subsumes only the NONSYNDROMIC
      familial forms (the ACTA2/MYH11/etc. "aortic aneurysm, familial thoracic
      N" series), whereas this grouping is broader and also includes the
      syndromic members (Marfan -> MONDO:0007947, Loeys-Dietz, vascular EDS,
      Shprintzen-Goldberg) that MONDO classifies under connective-tissue disease.
      The grouping is therefore broader than this MONDO class.
    consistency:
    - reference: MONDO
      consistent: INCONSISTENT
      notes: >-
        Only 1/5 listed members (Familial Thoracic Aortic Aneurysm and Aortic
        Dissection) is an is-a descendant of MONDO:0019625; the four syndromic
        members fall outside its is-a subtree. The 9 nonsyndromic "familial
        thoracic aortic aneurysm N" leaf classes under MONDO:0019625 are now
        covered by that member as has_subtypes rows (each anchored via
        subtype_term) plus matching skos:narrowMatch mondo_mappings, resolving
        the descendant-coverage gap tracked in issue #4241; the INCONSISTENT
        verdict here reflects only the four syndromic members that fall outside
        the MONDO:0019625 subtree (see research/grouping_mondo_gaps.md).
membership_criteria:
- description: >-
    A member conforms to the aortopathy TGF-beta dysregulation module (primary
    aortic-wall lesion driving increased TGF-beta signaling) AND exhibits
    thoracic aortic aneurysm and/or dissection.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - criterion_predicate: CONFORMS_TO_MODULE
      module: aortopathy_tgfbeta_dysregulation#TGF-beta Signaling Dysregulation
      description: >-
        Conforms to the aortopathy module's TGF-beta signaling dysregulation
        node.
    - operator: OR
      description: Thoracic aortic aneurysm and/or dissection is present.
      operands:
      - criterion_predicate: HAS_PHENOTYPE
        description: Aortic root aneurysm.
        phenotype_term:
          preferred_term: Aortic root aneurysm
          term:
            id: HP:0002616
            label: Aortic root aneurysm
      - criterion_predicate: HAS_PHENOTYPE
        description: Aortic dissection.
        phenotype_term:
          preferred_term: Aortic dissection
          term:
            id: HP:0002647
            label: Aortic dissection
members:
- member: Marfan Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      FBN1 pathogenic variants reduce fibrillin-1 microfibrils, weakening the
      aortic media and releasing sequestered TGF-beta. Distinguished by ectopia
      lentis and disproportionate tall stature/arachnodactyly.
    gene:
      preferred_term: FBN1
      term:
        id: hgnc:3603
        label: FBN1
- member: Loeys-Dietz Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Defects in TGF-beta receptor signaling (e.g., TGFBR1/TGFBR2) cause
      aggressive, more distal arterial aneurysms and tortuosity, hypertelorism,
      bifid uvula/cleft palate — a more diffuse arteriopathy than Marfan.
    gene:
      preferred_term: TGFBR1
      term:
        id: hgnc:11772
        label: TGFBR1
- member: Arterial Tortuosity Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Recessive SLC2A10 (GLUT10) deficiency causes elongation and tortuosity of
      large and medium arteries with stenoses, distinguishing it from the
      predominantly aneurysmal syndromic forms.
    gene:
      preferred_term: SLC2A10
      term:
        id: hgnc:13444
        label: SLC2A10
- member: Familial Thoracic Aortic Aneurysm and Aortic Dissection
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Nonsyndromic, often autosomal-dominant aortopathy from smooth-muscle
      contractile-apparatus genes (e.g., ACTA2, MYH11), typically without the
      systemic features of Marfan or Loeys-Dietz.
    gene:
      preferred_term: ACTA2
      term:
        id: hgnc:130
        label: ACTA2
- member: Shprintzen-Goldberg Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      SKI variants produce a Marfanoid habitus with craniosynostosis and
      intellectual disability; aortic involvement is typically milder than in
      Marfan or Loeys-Dietz.
    gene:
      preferred_term: SKI
      term:
        id: hgnc:10896
        label: SKI
notes: >-
  Worked example with NECESSARY criteria and a nested AND/OR phenotype branch.
  All members declare conforms_to edges to the aortopathy module, so the
  advisory audit reports them as SATISFIED.