Ehlers-Danlos Syndromes (EDS)

name: Ehlers-Danlos Syndromes
display_name: Ehlers-Danlos Syndromes (EDS)
creation_date: "2026-06-13T00:00:00Z"
description: >-
  A group of heritable connective-tissue disorders whose shared clinical space
  includes joint hypermobility or instability, skin hyperextensibility or
  fragility, atrophic scarring, easy bruising, and variable generalized tissue,
  vascular, ocular, skeletal, periodontal, or hollow-organ fragility. Members
  are explicit Ehlers-Danlos syndrome disease entries, spanning collagen
  fibrillogenesis and processing defects, collagen III vascular-wall fragility,
  glycosaminoglycan/proteoglycan biosynthesis defects, and clinically defined
  hypermobility-spectrum EDS with unresolved molecular etiology.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped as an explicit curated union of EDS disease entries rather than as a
  broad connective-tissue hierarchy clone. The existing knowledge base contains
  an umbrella EDS entry, COL5A1-related classical EDS, and spondylodysplastic
  EDS; this batch adds standalone vascular and hypermobile EDS entries because
  they are high-priority, clinically distinctive subtypes already modeled as
  umbrella subtypes. Members are kept separate because their causal branches
  differ: type V collagen fibrillogenesis in classical EDS, type III collagen
  vascular and hollow-organ fragility in vascular EDS, GAG/proteoglycan defects
  in spondylodysplastic EDS, and clinically defined hypermobile EDS with no
  validated causal gene. The criteria are NECESSARY: EDS members should have
  explicit EDS nosology plus connective-tissue fragility phenotypes, but those
  phenotypes alone are not sufficient because Marfan syndrome, Loeys-Dietz
  syndrome, osteogenesis imperfecta, cutis laxa, and nonsyndromic hypermobility
  can overlap clinically.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0020066
      label: Ehlers-Danlos syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      exactMatch: this grouping is intended to represent the same Ehlers-Danlos
      syndrome class as MONDO:0020066. Current DisMech member coverage is a
      curation-completeness signal, not a reason to weaken the conceptual
      mapping predicate.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        The listed members are EDS entities or explicit EDS subtype entries.
        Uncurated MONDO descendants such as TNXB/AEBP1 classical-like,
        PLOD1/FKBP14 kyphoscoliotic, ADAMTS2 dermatosparaxis,
        COL1A1/COL1A2 arthrochalasia, C1R/C1S periodontal, and COL12A1
        myopathic EDS should be treated as curation gaps surfaced from the
        exact mapping.
membership_criteria:
- description: >-
    A member is an explicit Ehlers-Danlos syndrome disease entry and has at
    least one characteristic connective-tissue fragility phenotype, such as
    joint hypermobility or dislocation, hyperextensible or thin skin, atrophic
    scars, bruising susceptibility, arterial rupture, or intestinal perforation.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    operands:
    - criterion_predicate: HAS_PHENOTYPE
      description: Joint hypermobility.
      phenotype_term:
        preferred_term: Joint hypermobility
        term:
          id: HP:0001382
          label: Joint hypermobility
    - criterion_predicate: HAS_PHENOTYPE
      description: Joint dislocation.
      phenotype_term:
        preferred_term: Joint dislocation
        term:
          id: HP:0001373
          label: Joint dislocation
    - criterion_predicate: HAS_PHENOTYPE
      description: Hyperextensible skin.
      phenotype_term:
        preferred_term: Hyperextensible skin
        term:
          id: HP:0000974
          label: Hyperextensible skin
    - criterion_predicate: HAS_PHENOTYPE
      description: Thin skin.
      phenotype_term:
        preferred_term: Thin skin
        term:
          id: HP:0000963
          label: Thin skin
    - criterion_predicate: HAS_PHENOTYPE
      description: Atrophic scars.
      phenotype_term:
        preferred_term: Atrophic scars
        term:
          id: HP:0001075
          label: Atrophic scars
    - criterion_predicate: HAS_PHENOTYPE
      description: Easy bruising.
      phenotype_term:
        preferred_term: Easy bruising
        term:
          id: HP:0000978
          label: Bruising susceptibility
    - criterion_predicate: HAS_PHENOTYPE
      description: Arterial rupture.
      phenotype_term:
        preferred_term: Arterial rupture
        term:
          id: HP:0025019
          label: Arterial rupture
    - criterion_predicate: HAS_PHENOTYPE
      description: Intestinal perforation.
      phenotype_term:
        preferred_term: Intestinal perforation
        term:
          id: HP:0031368
          label: Intestinal perforation
members:
- member: Ehlers-Danlos Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Umbrella EDS entry representing the heterogeneous subtype family, including
      classical, hypermobile, vascular, kyphoscoliotic, dermatosparaxis,
      classical-like, and periodontal subtype concepts already modeled as
      subtypes or phenotype branches.
- member: Ehlers-Danlos Syndrome, COL5A1-related
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      COL5A1 haploinsufficiency or structural variants reduce type V collagen
      dosage or assembly, disturbing collagen fibrillogenesis and producing
      classical EDS with skin hyperextensibility, atrophic scarring, easy
      bruising, and generalized joint hypermobility.
    gene:
      preferred_term: COL5A1
      term:
        id: hgnc:2209
        label: COL5A1
- member: Vascular Ehlers-Danlos Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      COL3A1/type III collagen variants weaken blood-vessel and hollow-organ
      extracellular matrix, distinguishing vascular EDS by arterial dissection
      or rupture, intestinal or uterine rupture, thin translucent skin, and easy
      bruising.
    gene:
      preferred_term: COL3A1
      term:
        id: hgnc:2201
        label: COL3A1
- member: Hypermobile Ehlers-Danlos Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Hypermobile EDS is clinically defined because no validated monogenic cause
      has been identified; it is differentiated by generalized joint
      hypermobility, joint instability or dislocation, chronic pain, fatigue,
      mild skin features, and multisystem symptoms.
- member: Spondylodysplastic Ehlers-Danlos Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      B4GALT7/B3GALT6 linker-region defects and SLC39A13 metal-transporter
      defects impair proteoglycan/GAG biology or collagen homeostasis, producing
      short stature, hypotonia, skeletal dysplasia, joint hypermobility, and
      connective-tissue fragility.
    gene:
      preferred_term: B4GALT7
      term:
        id: hgnc:930
        label: B4GALT7
- member: Musculocontractural Ehlers-Danlos Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      CHST14 (D4ST1) and DSE (DS-epi1) defects block consecutive steps of
      dermatan sulfate biosynthesis, so the glycosaminoglycan chain of decorin
      is replaced by chondroitin sulfate and collagen fibril assembly fails.
      Distinguished from the other EDS members by a two-arm phenotype pairing
      congenital malformation (multiple congenital contractures with adducted
      thumbs and talipes equinovarus, a characteristic craniofacial gestalt)
      with progressive connective-tissue fragility. Shares a
      glycosaminoglycan-biosynthesis mechanism class with spondylodysplastic
      EDS, but acts on dermatan-sulfate chain modification rather than on the
      common tetrasaccharide linker.
    gene:
      preferred_term: CHST14
      term:
        id: hgnc:24464
        label: CHST14
- member: Cardiac Valvular Ehlers-Danlos Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic COL1A2 null variants activate nonsense-mediated decay and
      abolish the proalpha2(I) chain, so type I collagen is assembled as an
      alpha1(I) homotrimer. Distinguished by moderate-to-severe progressive
      cardiac valve disease affecting the mitral valve first, on a background of
      joint hypermobility and skin hyperextensibility, and by the
      characteristic absence of bone fragility that separates it from the
      recessive osteogenesis imperfecta also caused by biallelic COL1A2
      variants.
    gene:
      preferred_term: COL1A2
      term:
        id: hgnc:2198
        label: COL1A2
notes: >-
  Exclude Marfan syndrome, Loeys-Dietz syndrome, osteogenesis imperfecta, cutis
  laxa, arterial tortuosity syndrome, and hypermobility spectrum disorder unless
  a separate disease entry is explicitly curated as an EDS or EDS-related
  subtype. High-value future subtype entries include COL5A2 classical EDS,
  TNXB/AEBP1 classical-like EDS, PLOD1/FKBP14 kyphoscoliotic EDS, ADAMTS2
  dermatosparaxis EDS, COL1A1/COL1A2 arthrochalasia EDS, C1R/C1S periodontal
  EDS, and COL12A1 myopathic EDS.

  Mechanism-class note: two members now share a glycosaminoglycan-biosynthesis
  mechanism class — spondylodysplastic EDS (B4GALT7/B3GALT6 common
  tetrasaccharide linker) and musculocontractural EDS (CHST14/DSE
  dermatan-sulfate chain modification). They are a candidate pair for factoring
  out a shared GAG-biosynthesis mechanism module in kb/modules/; no such module
  exists yet, so neither entry declares a conforms_to edge.