Usher Syndrome (Combined Deaf-Blindness Spectrum)

name: Usher Syndrome
display_name: Usher Syndrome (Combined Deaf-Blindness Spectrum)
creation_date: "2026-09-24T00:00:00Z"
description: >-
  Usher syndrome is the clinical concept of inherited combined deaf-blindness:
  sensorineural hearing loss with progressive retinitis pigmentosa, with or
  without vestibular dysfunction. It is the most common inherited cause of
  combined deaf-blindness, with a reported worldwide prevalence between 4 and 17
  per 100,000.

  It is curated here as a grouping rather than as a disease entry because the
  four member entities do not share a mechanism. They were previously modelled as
  one entry built on a root node called "Usher Protein Complex Loss of Function",
  and there is no such complex: the Usher proteins form at least two structurally
  and temporally distinct assemblies, clarin-1 belongs to neither, and ARSG is a
  lysosomal enzyme unrelated to any of them. In the retina the four arms act in
  different subcellular compartments and, for type 3, in a different cell type
  altogether.

  What the members genuinely share is the clinical convergence - hearing loss plus
  retinitis pigmentosa - and the management that follows from it: early
  communication access, audiologic and retinal surveillance, low-vision
  rehabilitation, and autosomal recessive counselling. That is a shared phenotype
  and a shared care pathway, not a shared mechanism, and grouping_basis says so.

  The numbered type labels are retained because ClinGen and MONDO both curate at
  that identity, but they are historical clinical labels rather than mechanism
  names, and they are an imperfect proxy: a CLRN1 (type 3) family has been
  reported as clinically diagnosable as type 1. Where the two disagree, the
  mechanism decides which entity an entry belongs to.
grouping_basis:
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped on the shared clinical phenotype of inherited combined deaf-blindness,
  NOT on a shared mechanism. This is the unusual case where the mechanistic
  criterion is deliberately refused: the four members are separated precisely
  because their mechanisms differ, and asserting a SHARED_MECHANISM basis here
  would reintroduce at the grouping level the error the split was made to
  correct.

  Membership is stated as NECESSARY, not NECESSARY_AND_SUFFICIENT, on the
  phenotype pair. Sufficiency was written first and then withdrawn on evidence:
  evaluating it surfaced Adult Refsum Disease, PHARC syndrome, NARP syndrome,
  Leber Congenital Amaurosis with Early-Onset Deafness and three further entries
  as satisfying the pair. Those are genuine deaf-blindness phenocopies and the
  clinical differential for this concept, not unlisted members, so the pair
  cannot be sufficient. Membership is curated explicitly instead.

  That leaves the grouping without a computable membership rule, which is an
  honest description of the situation rather than a gap to be closed: "Usher
  syndrome" is a historical clinical category whose boundary against the other
  syndromic deaf-blindness disorders was drawn by convention, and no phenotype
  predicate available here reconstructs it. The criterion is not attempting to
  encode mechanism and should not be read as doing so.

  This grouping deliberately does NOT mirror the MONDO hierarchy. MONDO's own
  proposal for this case (monarch-initiative/mondo#10576) widens the Usher
  definition so features may be variably expressed or absent, and hangs isolated
  retinopathy under Usher syndrome type 2A. That is close to the opposite move:
  MONDO relaxes the parent so a heterogeneous set can sit under it, while dismech
  splits the parent into mechanism entities and demotes the clinical concept to
  this grouping. Both are defensible for what each artifact is for. Anyone
  comparing the two should read the divergence as intentional rather than as a
  synchronization failure.

  There is no umbrella `Disease` entry for Usher syndrome. The previously lumped
  kb/disorders/Usher_Syndrome.yaml was deleted rather than slimmed, per issue
  #4490's rule against leaving an umbrella Disease and a Grouping covering the
  same concept. The cost is real and was accepted: communication support,
  surveillance and counselling are now stated on each member entity rather than
  once.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019501
      label: Usher syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping covers exactly the MONDO Usher syndrome concept. exactMatch
      rather than broadMatch because the grouping is the clinical concept, not a
      subset of it - the split happened below this level, into the four member
      entities, each of which carries its own MONDO term.
membership_criteria:
- description: >-
    Every Usher entity presents with BOTH sensorineural hearing loss AND
    retinitis pigmentosa (rod-cone dystrophy), with or without vestibular
    dysfunction. The conjunction is the whole content of the criterion: either
    phenotype alone is shared with a large part of the KB, and it is their
    co-occurrence that makes a disorder a candidate.

    NECESSARY and not sufficient. The co-occurrence does not by itself make a
    disorder an Usher entity - several disorders in this KB satisfy it and are
    correctly excluded, among them Adult Refsum Disease, PHARC syndrome, NARP
    syndrome and Leber Congenital Amaurosis with Early-Onset Deafness. Those are
    the clinical differential for deaf-blindness rather than members, and each
    is excluded on mechanism. Membership is therefore curated explicitly in the
    members list rather than derived; the evaluator reports the others as
    candidates, which is the correct behaviour and should not be read as missing
    members.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    description: >-
      Both sensory phenotypes, in the same disorder.
    operands:
    - criterion_predicate: HAS_PHENOTYPE
      phenotype_term:
        preferred_term: Sensorineural hearing impairment
        term:
          id: HP:0000407
          label: Sensorineural hearing impairment
      description: >-
        Sensorineural hearing loss of any severity and any course - profound and
        congenital in type 1, sloping and congenital in type 2, progressive and
        postlingual in types 3 and 4.
    - criterion_predicate: HAS_PHENOTYPE
      phenotype_term:
        preferred_term: Rod-cone dystrophy
        term:
          id: HP:0000510
          label: Rod-cone dystrophy
      description: >-
        Progressive rod-cone dystrophy (retinitis pigmentosa), with onset varying
        from adolescence in type 1 to adulthood in type 4.
members:
- member: Usher Syndrome Type 1
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss of a component of the upper tip-link density (UTLD) - the
      tension-bearing complex of the MATURE hair bundle, in which a myosin VIIa
      motor cluster anchored by harmonin and SANS holds the
      cadherin-23/protocadherin-15 tip link under resting tension. Because the
      tip link gates the transduction channel directly, the deficit is complete
      and present at birth: profound congenital hearing loss with constant
      vestibular areflexia.

      In the retina, a conserved network at the CALYCEAL PROCESSES - the
      microvillus-like collar at the base of the outer segment, present in human,
      macaque and frog and absent from mice.
    module: sensorineural_hair_cell_loss
- member: Usher Syndrome Type 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Failure to assemble the ankle-link complex - a TRANSIENT assembly of the
      DEVELOPING hair bundle, in which whirlin and PDZD7 orchestrate usherin and
      ADGRV1 into a condensate by liquid-liquid phase separation. Ankle links are
      not present in mature stereocilia. The deficit is therefore partial: a
      sloping congenital loss worse at high frequencies, with vestibular function
      generally intact.

      In the retina, the PERICILIARY MEMBRANE COMPARTMENT - a ciliary trafficking
      site at the base of the connecting cilium, and a different compartment from
      the type-1 calyceal processes.
    module: sensorineural_hair_cell_loss
- member: Usher Syndrome Type 3
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss of clarin-1, which belongs to NEITHER complex and has no assigned
      biochemical activity; its core supported role is actin filament
      organization. The cochlear deficit is a progressive postnatal hair cell
      loss rather than a structural failure present from the outset, which is the
      mechanistic correlate of the progressive postlingual audiogram.

      The retinal arm diverges furthest of the four: clarin-1 is expressed in
      MÜLLER GLIA, not photoreceptors, in both mouse and human retina, so
      photoreceptor loss is secondary to a glial support failure. Cell-specific
      rescue in zebrafish works from Müller glia and not from rods or cones.
    module: sensorineural_hair_cell_loss
- member: Usher Syndrome Type 4
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Deficiency of arylsulfatase G, a lysosomal enzyme, causing heparan sulfate
      accumulation. Unrelated to the hair-bundle and photoreceptor protein
      networks of the other three members: this is a storage mechanism that
      converges on the same two organs, with a characteristically late-onset
      presentation. It is the clearest demonstration that Usher syndrome is a
      clinical convergence rather than a mechanistic family.
    gene:
      preferred_term: ARSG
      term:
        id: hgnc:24102
        label: ARSG
references:
- reference: PMID:32995707
  title: "Usher syndrome: clinical features, molecular genetics and advancing therapeutics."
- reference: PMID:33193648
  title: "Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy."
- reference: PMID:35353227
  title: "The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification."
notes: >-
  Created 2026-09-24, replacing kb/disorders/Usher_Syndrome.yaml, per the decision
  recorded on issue #10822. That issue and its comments carry the full argument
  and the source citations for the complex memberships summarized in each member's
  differentiating_mechanisms.

  The worldwide prevalence figure in the description (4-17 per 100,000, from
  PMID:32995707) is carried as prose because `Grouping` has no prevalence slot.
  It is deliberately not restated on the four member entities: the source reports
  it for Usher syndrome as a whole, and dividing it four ways would invent numbers
  no source states.

  `differentiating_mechanisms` names `sensorineural_hair_cell_loss` as the module
  for the first three members because that is the module they conform to at the
  shared downstream node. Do not read that as a shared mechanism: the module is a
  convergence point, and the prose in each row is the part that differentiates.
  Type 4 names its gene instead, because its mechanism is lysosomal and reaches
  hair cell loss by a different route.