Somatic Mosaic Disorders (Post-zygotic Genetic Architecture)

name: Somatic Mosaic Disorders
display_name: Somatic Mosaic Disorders (Post-zygotic Genetic Architecture)
creation_date: "2026-09-05T00:00:00Z"
description: >-
  A curated union of dismech entries whose disease, or a recognized arm of it,
  is caused by a variant that arose after fertilization and is therefore present
  in some cells and absent from others. Membership is keyed on the mode of
  inheritance itself: each member carries at least one curated inheritance block
  bound to the HPO term Typified by somatic mosaicism (HP:0001442), attesting a
  post-zygotic, DNA-level mosaic origin. This is a genetic-architecture grouping
  assembled below the level of the classifications taxonomies; members otherwise
  share nothing, spanning segmental overgrowth (AKT1, PIK3CA), malformations of
  cortical development (PI3K-AKT-mTOR activators and repressors, SLC35A2),
  vascular and pigmentary anomalies (GNAQ, GNA11, TEK, KRAS), skeletal dysplasia
  (GNAS), endocrine tumours (EPAS1, GLI3, PRKACA), keratinization (mevalonate
  pathway second hits), pancreatic islet lesions (11p15 loss), and acquired
  clonal haematopoiesis (UBA1, PIGA). Mechanistic heterogeneity is the point,
  not a defect: what the members have in common is that the causal lesion is a
  clone, the disease distribution follows that clone, and the disorder is not
  transmitted through the germline.
grouping_basis:
- OTHER
grouping_rationale: >-
  Grouped on a shared non-Mendelian genetic architecture (post-zygotic somatic
  mosaicism), not a shared mechanism, gene family, or phenotype, in the same way
  Digenic and Oligogenic Disorders is grouped on multi-locus inheritance. The
  grouping exists to make the mosaic architecture auditable and queryable: before
  it was assembled, the flagship mosaic disorders encoded the same claim four
  different ways (an HP:0001442 block, a block bound to Sporadic, a free-text
  "Not applicable" block, or prose alone), so no query could recover the set.
  The convention the members now follow is an inheritance block bound to
  HP:0001442 with its own snippet-backed evidence, plus variant_origin SOMATIC
  on the causal gene. Two tiers are admitted and each member's row says which:
  disorders in which post-zygotic mosaicism is the mechanism (Proteus syndrome,
  Sturge-Weber syndrome, fibrous dysplasia, VEXAS), and disorders with a
  recognized, separately curated mosaic arm alongside a germline form (tuberous
  sclerosis complex, porokeratosis, focal hyperinsulinism, the MOGHE arm of
  SLC35A2 disease). Acquired clonal disorders of adult life (VEXAS, paroxysmal
  nocturnal hemoglobinuria) are deliberately in scope: a somatic variant in one
  haematopoietic stem cell that expands into a clone leaves the patient a
  mosaic of mutant and normal blood cells, which is post-zygotic mosaicism by
  the term's own definition, differing from the congenital members only in
  timing and lineage. The criteria are NECESSARY, not NECESSARY_AND_SUFFICIENT,
  because HP:0001442 is also bound in the knowledge base for two things that are
  not somatic mosaic disorders in this sense: a single mosaic proband in an
  otherwise germline dominant disorder (Neurodevelopmental Disorder with
  Hypotonia and Speech Delay, an EIF4A2 case report) and parental germline
  mosaicism explaining apparent sporadic recurrence (KCNH1 Associated Disorder).
  Those entries correctly carry the term and are deliberately not members; a
  qualifying non-member is therefore a lead to triage against the two tiers, not
  an automatic addition. Functional mosaicism from X inactivation (CHILD
  syndrome) is excluded outright and carries no HP:0001442 binding, since the
  term names DNA-level post-zygotic mosaicism and the CHILD entry's own
  inheritance block says that is not what it describes.
membership_criteria:
- description: >-
    Every member has at least one curated inheritance block bound to Typified by
    somatic mosaicism (HP:0001442), attesting that the disease, or a recognized
    arm of it, arises from a post-zygotic variant confined to a clone of cells.
    The criteria are NECESSARY only: carrying the term is required for
    membership but does not by itself confer it, because the term is also used
    for incidental mosaic probands and for parental germline mosaicism.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_INHERITANCE
    description: Typified by somatic mosaicism (HP:0001442).
    inheritance_term:
      preferred_term: Somatic mosaicism
      term:
        id: HP:0001442
        label: Typified by somatic mosaicism
members:
- member: Proteus syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Obligate mosaic. A post-zygotic AKT1 p.E17K activating variant confined to a
      subset of cells; mosaic lesion distribution and sporadic occurrence are
      diagnostic criteria, and germline transmission has never been observed.
    gene:
      preferred_term: AKT1
      term:
        id: hgnc:391
        label: AKT1
- member: CLOVES Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Obligate mosaic. Post-zygotic activating PIK3CA variants at 3-30% allele
      fraction in affected tissue from multiple embryonic lineages; the
      canonical PIK3CA-related overgrowth spectrum member.
    gene:
      preferred_term: PIK3CA
      term:
        id: hgnc:8975
        label: PIK3CA
- member: angioosteohypertrophic syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Obligate mosaic (Klippel-Trenaunay spectrum). Somatic PIK3CA activation
      confined to malformed lymphatic and venous tissue, with five recurrent
      hotspot variants accounting for most cases.
    gene:
      preferred_term: PIK3CA
      term:
        id: hgnc:8975
        label: PIK3CA
- member: Hemimegalencephaly
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Obligate brain-restricted mosaic. De novo somatic gain-of-function
      variants in PIK3CA, AKT3, MTOR, RHEB or AKT1, or germline-plus-somatic
      two-hit loss of an mTOR repressor, arising in a neural progenitor and
      producing a mosaic variant gradient across one hemisphere.
- member: Focal Cortical Dysplasia Type II
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Obligate brain-restricted mosaic mTORopathy. Somatic activator variants or
      two-hit repressor loss in as few as a thousand cortical neurons; the
      smallest-clone member of the grouping and the reason lesional tissue, not
      blood, is the diagnostic substrate.
- member: Hypothalamic Hamartoma with Gelastic Seizures
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Obligate lesion-restricted mosaic. Somatic GLI3 loss-of-function or PRKACA
      variants confined to the hamartoma; the sporadic counterpart of the
      germline GLI3 Pallister-Hall syndrome.
    gene:
      preferred_term: GLI3
      term:
        id: hgnc:4319
        label: GLI3
- member: Sturge-Weber Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Obligate mosaic. A somatic GNAQ p.R183Q (rarely GNA11) activating variant
      at 1-18% allele fraction in affected tissue; the developmental timing of
      the event sets the extent from isolated port-wine stain to full
      leptomeningeal syndrome.
    gene:
      preferred_term: GNAQ
      term:
        id: hgnc:4390
        label: GNAQ
- member: Nevus of Ota
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Obligate mosaic. Low-level post-zygotic GNAQ or GNA11 activation in dermal
      melanocytic tissue, undetectable in blood (GNA11 in a minority); the pigmentary sibling of the
      GNAQ vascular anomalies.
    gene:
      preferred_term: GNAQ
      term:
        id: hgnc:4390
        label: GNAQ
- member: Blue Rubber Bleb Nevus Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Obligate mosaic with a double-hit architecture. Multifocal venous
      malformations arise from cis double somatic TEK (TIE2) mutations in an
      endothelial-lineage clone.
    gene:
      preferred_term: TEK
      term:
        id: hgnc:11724
        label: TEK
- member: Brain arteriovenous malformation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Sporadic lesions are somatic mosaic. Activating KRAS (or BRAF) variants in
      lesional endothelium and absent from paired blood; the germline AVMs of
      hereditary hemorrhagic telangiectasia are a distinct entity and not the
      basis of membership.
    gene:
      preferred_term: KRAS
      term:
        id: hgnc:6407
        label: KRAS
- member: Encephalocraniocutaneous Lipomatosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Obligate mosaic. Post-zygotic activating FGFR1 (occasionally KRAS)
      variants distributed across neural-crest and mesenchymal derivatives.
    gene:
      preferred_term: FGFR1
      term:
        id: hgnc:3688
        label: FGFR1
- member: Fibrous Dysplasia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Obligate mosaic. Early post-zygotic activating GNAS variants in skeletal
      progenitors; lesion burden tracks the mosaic distribution, and germline
      transmission has never been confirmed. McCune-Albright syndrome, the
      extraskeletal extension of the same clone, is a has_subtypes row on this
      entry and is covered through it.
    gene:
      preferred_term: GNAS
      term:
        id: hgnc:4392
        label: GNAS
- member: Pacak-Zhuang syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Obligate mosaic. Early post-zygotic gain-of-function EPAS1 (HIF2A)
      variants producing paragangliomas, somatostatinomas and polycythemia with
      no affected relatives.
    gene:
      preferred_term: EPAS1
      term:
        id: hgnc:3374
        label: EPAS1
- member: VEXAS Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Acquired clonal mosaic of adult life. Somatic UBA1 p.Met41 variants in
      haematopoietic stem cells, present in blood and marrow and absent from
      fibroblasts; the autoinflammatory member of the clonal-haematopoiesis pair.
    gene:
      preferred_term: UBA1
      term:
        id: hgnc:12469
        label: UBA1
- member: Paroxysmal Nocturnal Hemoglobinuria
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Acquired clonal mosaic of adult life. A somatic loss-of-function PIGA
      variant in a single haematopoietic stem cell expands under immune
      selection, leaving the patient a mosaic of GPI-deficient and normal blood
      cells.
    gene:
      preferred_term: PIGA
      term:
        id: hgnc:8957
        label: PIGA
- member: Porokeratosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Mosaic arm of a germline disorder. A germline mevalonate-pathway variant is
      unmasked by a post-zygotic second hit, embryonic in linear porokeratosis
      and lesion-by-lesion in DSAP; localized forms can be purely somatic.
- member: Hyperinsulinemic Hypoglycemia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Mosaic arm of a germline disorder. Focal congenital hyperinsulinism
      requires a paternally inherited K-ATP channel variant plus somatic loss of
      the maternal 11p15 region within the islet lesion; the diffuse form is
      germline recessive.
- member: Tuberous Sclerosis Complex
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Mosaic arm of a germline disorder. Most conventionally mutation-negative
      cases are low-level post-zygotic TSC1/TSC2 mosaics with milder phenotypes;
      the predominant mode is autosomal dominant.
- member: SLC35A2-congenital disorder of glycosylation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Mosaic arm of a germline disorder. The MOGHE arm is a brain-restricted
      post-zygotic loss-of-function clone diagnosed on resected epileptogenic
      tissue, alongside the X-linked multisystem form.
    gene:
      preferred_term: SLC35A2
      term:
        id: hgnc:11022
        label: SLC35A2
notes: >-
  Candidates not yet bound and therefore not listed: Schnitzler syndrome
  (myeloid-lineage NLRP3 mosaicism in a
  minority), CINCA/NOMID (mosaic NLRP3 in mutation-negative cases), congenital
  melanocytic nevus (NRAS), craniofacial microsomia, and clonal haematopoiesis
  of indeterminate potential, which has no entry. Isolated mosaic aneuploidies
  (mosaic Turner or trisomy) are chromosomal-segregation mosaics and were not
  assessed for this grouping. Mosaic Variegated Aneuploidy Syndrome is
  deliberately absent: it is autosomal recessive, and its mosaicism is a
  downstream phenotype of germline BUB1B loss rather than a post-zygotic causal
  variant.