RASopathies (RAS-MAPK pathway syndromes)

name: RASopathies
display_name: RASopathies (RAS-MAPK pathway syndromes)
creation_date: "2026-07-14T00:00:00Z"
description: >-
  The RASopathies are a clinically and genetically heterogeneous group of
  developmental disorders caused by germline (or, rarely, mosaic) mutations in
  genes encoding components and regulators of the RAS-MAPK signal transduction
  pathway. Despite distinct causal genes, the members converge on dysregulated
  RAS-MAPK (ERK) signaling — in most members constitutive up-regulation, but in
  Noonan syndrome with multiple lentigines a catalytically-impaired
  (dominant-negative) SHP2 that produces tissue-specific dysregulation rather
  than uniform pathway activation — and share a recognizable
  phenotypic spectrum: distinctive craniofacial features, congenital heart
  defects (frequently pulmonary valve stenosis and hypertrophic
  cardiomyopathy), cutaneous and pigmentary abnormalities, short stature,
  variable neurocognitive involvement, and an increased predisposition to
  specific malignancies.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PATHWAY
grouping_rationale: >-
  Grouped on a shared pathogenic mechanism: every member results from a germline
  genetic lesion that dysregulates signal throughput of the RAS-MAPK (ERK)
  cascade. In most members this is an increase, whether by gain of function in a
  positive pathway component (e.g. PTPN11/SHP2, HRAS, BRAF, SHOC2) or by loss of
  function of a negative regulator (e.g. the RAS-GAP neurofibromin in NF1). The
  criterion is deliberately written as *dysregulated* rather than *increased*
  RAS-MAPK output because Noonan syndrome with multiple lentigines — a
  RASopathy by every nosology including MONDO — is caused by
  catalytically-impaired, dominant-negative SHP2 alleles whose cardiac
  consequence is Akt/mTOR hyperactivation with agonist-evoked ERK signalling
  instead abrogated. A criterion requiring uniform pathway up-regulation would
  exclude it, so the shared endpoint is modelled as abnormal RAS-MAPK output,
  not unidirectional activation. The members are deliberately kept as separate
  Disease entries rather than merged, because they differ in the specific
  mutated gene, the direction of the molecular lesion (activating oncogene-like
  gain of function vs. tumor-suppressor loss of function vs. dominant-negative
  catalytic impairment), the mode and site of
  the mutation, and the resulting phenotypic and tumor-risk profile. This is a
  grouping over distinct entities, not a lumping of them into one disease.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0021060
      label: RASopathy
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds to the MONDO RASopathy class. exactMatch
      records the intended conceptual alignment; MONDO RASopathy descendants
      without DisMech entries are curation gaps rather than evidence that the
      grouping concept is only a close match.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        All 6 listed members are is-a descendants of MONDO:0021060
        (verified against sqlite:obo:mondo): Noonan syndrome
        (MONDO:0018997), Costello syndrome (MONDO:0009026),
        cardiofaciocutaneous syndrome (MONDO:0015280), neurofibromatosis
        type 1 (MONDO:0018975), Noonan syndrome-like disorder with loose
        anagen hair (MONDO:0011899), and Noonan syndrome with multiple
        lentigines (MONDO:0007893). Juvenile myelomonocytic leukemia
        (MONDO:0011908) is a RAS-MAPK-driven myeloid neoplasm strongly
        associated with the RASopathies (and predisposed to by NF1 and
        germline CBL/Noonan mutations) but is NOT an is-a descendant of
        MONDO:0021060, so it is discussed in the notes as a related entity
        rather than listed as a formal member. Additional MONDO RASopathy
        descendants without DisMech entries should be surfaced as curation
        gaps from this exact mapping.
membership_criteria:
- description: >-
    A disorder belongs to the RASopathies if it is classified as a RASopathy
    AND its pathophysiology involves dysregulated signalling through the
    RAS-MAPK (ERK) cascade — i.e. a germline lesion that abnormally alters
    RAS-MAPK pathway output, whether by gain of function in a positive
    component, loss of function of a negative regulator, or a dominant-negative
    allele that reroutes pathway output (NSML).
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - criterion_predicate: HAS_CLASSIFICATION
      classification: RASopathy
      description: >-
        Carries the RASopathy nosology assignment on its Disease entry, in
        either the `parents:` or the `categories:` free-text nosology slot.
        Both slots count: DisMech has no single canonical nosology slot, so
        `groupings.py` reads this criterion against `parents:`, `categories:`
        and the structured `classifications:` block alike. (Until 2026-08-20
        the evaluator returned UNKNOWN for HAS_CLASSIFICATION and this conjunct
        had to be audited by hand; it is now checked by `just check-groupings`.)
        Verified 2026-08-07: all six members now
        carry the singular `RASopathy` string in `parents:` — Costello and
        cardiofaciocutaneous syndrome were normalized from the plural
        `RASopathies`, and neurofibromatosis type 1, which already carried
        `RASopathy` under `categories:`, had it added to `parents:` as well so
        the tag is declared in the same slot across the union.
    - operator: OR
      description: >-
        Dysregulation of the MAPK (ERK) cascade downstream of RAS — in most
        members constitutive up-regulation — modelled with any of the
        equivalent RAS-MAPK biological-process terms.
      operands:
      - criterion_predicate: HAS_BIOLOGICAL_PROCESS
        description: Increased signalling through the MAPK cascade.
        biological_processes:
        - preferred_term: MAPK cascade
          term:
            id: GO:0000165
            label: MAPK cascade
          modifier: INCREASED
      - criterion_predicate: HAS_BIOLOGICAL_PROCESS
        description: Positive regulation of the MAPK cascade.
        biological_processes:
        - preferred_term: positive regulation of MAPK cascade
          term:
            id: GO:0043410
            label: positive regulation of MAPK cascade
      - criterion_predicate: HAS_BIOLOGICAL_PROCESS
        description: Increased RAS protein signal transduction upstream of MAPK.
        biological_processes:
        - preferred_term: Ras protein signal transduction
          term:
            id: GO:0007265
            label: Ras protein signal transduction
          modifier: INCREASED
      - criterion_predicate: HAS_BIOLOGICAL_PROCESS
        description: >-
          Abnormal (not necessarily increased) ERK1/ERK2 cascade output. This
          branch is what admits the dominant-negative NSML arm, whose entry
          models the shared endpoint as an ABNORMAL rather than INCREASED
          ERK1/ERK2 cascade.
        biological_processes:
        - preferred_term: ERK1 and ERK2 cascade
          term:
            id: GO:0070371
            label: ERK1 and ERK2 cascade
          modifier: ABNORMAL
members:
- member: Noonan Syndrome
  member_type: DISEASE
  display_name: Noonan syndrome
  differentiating_mechanisms:
  - description: >-
      The prototypical and most common RASopathy. Most often caused by germline
      gain-of-function mutations in PTPN11 (encoding the protein tyrosine
      phosphatase SHP2), a positive regulator of RAS-MAPK signalling, with a
      broad allelic series across other pathway genes (SOS1, RAF1, RIT1, KRAS,
      LZTR1, and others). Distinguished clinically by pulmonary valve stenosis,
      hypertrophic cardiomyopathy, short stature, and a characteristic facial
      gestalt.
    gene:
      preferred_term: PTPN11
      term:
        id: hgnc:9644
        label: PTPN11
    modifier: INCREASED
- member: Costello Syndrome
  member_type: DISEASE
  display_name: Costello syndrome
  differentiating_mechanisms:
  - description: >-
      Caused by germline activating mutations in the proto-oncogene HRAS,
      placing the lesion at the level of the RAS GTPase itself. Distinguished
      by coarse facial features, deep palmar/plantar creases, papillomata, and
      the highest tumor-predisposition risk among the classic RASopathies
      (notably rhabdomyosarcoma, neuroblastoma, and bladder carcinoma).
    gene:
      preferred_term: HRAS
      term:
        id: hgnc:5173
        label: HRAS
    modifier: INCREASED
- member: Cardiofaciocutaneous Syndrome
  member_type: DISEASE
  display_name: Cardiofaciocutaneous syndrome
  differentiating_mechanisms:
  - description: >-
      Most commonly caused by germline mutations in BRAF (with a minority in
      MAP2K1/MAP2K2 or KRAS), placing the lesion at the RAF/MEK kinase tier of
      the cascade. Distinguished by prominent ectodermal and cutaneous
      involvement (sparse curly hair, ichthyosis, keratosis pilaris) and
      generally more severe intellectual disability than Noonan syndrome.
    gene:
      preferred_term: BRAF
      term:
        id: hgnc:1097
        label: BRAF
    modifier: INCREASED
- member: Noonan Syndrome with Multiple Lentigines
  member_type: DISEASE
  display_name: Noonan syndrome with multiple lentigines (NSML, formerly LEOPARD syndrome)
  differentiating_mechanisms:
  - description: >-
      The dominant-negative RASopathy, and the member that fixes the direction
      of the grouping's mechanism criterion. NSML shares PTPN11 with Noonan
      syndrome but not the direction of the lesion: the recurrent NSML alleles
      map to the SHP2 catalytic PTP domain and are catalytically *impaired*,
      acting as dominant negatives, whereas Noonan PTPN11 alleles are
      activating. The DisMech entry accordingly models the shared endpoint as
      an ABNORMAL (GO:0070371 ERK1 and ERK2 cascade) rather than INCREASED
      cascade, with cardiac Akt/mTOR hyperactivation and agonist-evoked ERK
      signalling instead abrogated. Minority RAF1 (LPRD2) and BRAF (LPRD3)
      arms are conventional activating kinase alleles, so the entry carries
      both directions. Distinguished clinically by progressive multiple
      lentigines and by concentric hypertrophic cardiomyopathy, which is far
      more prominent than in classic Noonan syndrome.
    gene:
      preferred_term: PTPN11
      term:
        id: hgnc:9644
        label: PTPN11
    modifier: DYSREGULATED
- member: Neurofibromatosis Type 1
  member_type: DISEASE
  display_name: Neurofibromatosis type 1
  differentiating_mechanisms:
  - description: >-
      The tumor-suppressor RASopathy: caused by loss-of-function mutations in
      NF1, encoding the RAS-GAP neurofibromin. Loss of neurofibromin's
      GTPase-activating activity raises RAS-GTP levels and RAS-MAPK output —
      the same pathway endpoint as the gain-of-function members but by an
      opposite (loss-of-negative-regulator) mechanism. Distinguished by
      café-au-lait macules, cutaneous and plexiform neurofibromas, Lisch
      nodules, optic pathway gliomas, and a two-hit tumor-predisposition
      profile.
    gene:
      preferred_term: NF1
      term:
        id: hgnc:7765
        label: NF1
    modifier: INCREASED
- member: Noonan Syndrome-like Disorder with Loose Anagen Hair
  member_type: DISEASE
  display_name: Noonan syndrome-like disorder with loose anagen hair (NS/LAH)
  differentiating_mechanisms:
  - description: >-
      A distinct Noonan-spectrum RASopathy. NSLH1 is caused by the recurrent
      SHOC2 p.Ser2Gly substitution, which introduces an aberrant N-terminal
      myristoylation site and mislocalizes the SHOC2 phosphatase complex,
      dysregulating RAS-MAPK signalling; NSLH2 is caused by PPP1CB mutations.
      Distinguished by the characteristic easily pluckable, slow-growing loose
      anagen hair alongside the shared Noonan-like facies and cardiac features.
    gene:
      preferred_term: SHOC2
      term:
        id: hgnc:15454
        label: SHOC2
    modifier: INCREASED
notes: >-
  Worked example of a RAS-MAPK pathway grouping. Members reference existing
  Disease entries by name and were selected as the germline developmental
  RASopathies currently present in the KB that are also is-a descendants of the
  MONDO RASopathy class. Related RAS-MAPK entities intentionally NOT listed as
  formal members: (1) Juvenile Myelomonocytic Leukemia — a RAS-MAPK-driven
  myeloid neoplasm strongly linked to the RASopathies (predisposed to by NF1
  and by germline Noonan/CBL mutations) but classified in MONDO as a myeloid
  leukemia rather than as an is-a descendant of MONDO:0021060; (2)
  Capillary Malformation-Arteriovenous Malformation Syndrome (RASA1), a
  RAS-GAP disorder that — like JMML — is NOT an is-a descendant of
  MONDO:0021060 (MONDO:0012016 verified 2026-08-07), and whose DisMech entry
  additionally carries no RASopathy nosology tag in either `parents:`
  (`Vascular disorder`) or `categories:`. Both grounds are stated because the
  membership criteria and the mapping consistency claim are independent: the
  MONDO fact is what keeps the skos:exactMatch honest, and the missing tag is
  what makes the NECESSARY HAS_CLASSIFICATION conjunct genuinely false of it
  rather than merely unrecorded — a distinction that only holds now that every
  listed member declares the tag; (3) NF1 Microdeletion Syndrome
  (MONDO:0013357), which IS an
  is-a descendant of MONDO:0021060 (verified 2026-08-06) and DOES satisfy the
  classification conjunct (`categories:` includes `RASopathy`), but is modelled
  in DisMech as a contiguous-gene-deletion severity variant of an existing
  member — its `parents:` is `neurofibromatosis type 1`. Its exclusion
  therefore rests on nesting alone, not on any failed criterion: listing both
  it and NF1 would make the union partly nested, so it is held as a candidate
  pending a decision on whether this grouping admits subtype-level entries.
  Entities (1) and (2) become candidate additions if MONDO reclassifies them
  and their entries declare the RASopathy nosology tag alongside a RAS-MAPK
  mechanism node. Legius syndrome
  (SPRED1), neurofibromatosis-Noonan syndrome and CBL-related disorder from
  issue #6206 were still absent from `kb/disorders/` as of 2026-08-06 and
  should be added here when they land. A future
  refinement could add a CONFORMS_TO_MODULE criterion once a dedicated
  RAS-MAPK dysregulation mechanism module exists.