Digenic and Oligogenic Disorders (Multi-Locus Inheritance)

name: Digenic and Oligogenic Disorders
display_name: Digenic and Oligogenic Disorders (Multi-Locus Inheritance)
creation_date: "2026-07-03T00:00:00Z"
description: >-
  A curated union of dismech entries in which disease can arise from the
  combined action of variants at two loci (digenic) or a small number of loci
  (oligogenic/triallelic), rather than a single Mendelian locus. Membership is
  keyed on the mode of inheritance itself: each member carries at least one
  curated inheritance block bound to the HPO digenic (HP:0010984) or oligogenic
  (HP:0010983) mode-of-inheritance term. This is a genetic-architecture grouping
  assembled below the level of the classifications taxonomies; members otherwise
  share nothing, spanning the retina, kidney, liver, cochlea, thyroid, heart and
  great vessels, forebrain, gonad, enteric nervous system, skeleton, skeletal
  muscle, gingiva, neural crest, cilia and the immunoproteasome. Mechanistic
  heterogeneity is the point, not a defect: the only thing a member has in
  common with its siblings is the shape of its genetic architecture.
grouping_basis:
- OTHER
grouping_rationale: >-
  Grouped on a shared non-Mendelian genetic architecture (digenic or oligogenic
  inheritance), not a shared mechanism, gene family, or phenotype. The members
  are deliberately mechanistically heterogeneous — the point of the grouping is
  to make the multi-locus inheritance pattern itself auditable and queryable
  across the knowledge base, and to anchor the curation design pattern (see the
  PRPH2-Related Retinopathy exemplar: a digenic block bound to HP:0010984 with a
  double-heterozygote evidence snippet). The criteria are
  NECESSARY_AND_SUFFICIENT: because membership is keyed on the curated mode of
  inheritance and on nothing else, an entry carrying such a block is a member by
  definition. Carrying the block for only a minority subtype while remaining
  predominantly monogenic (Alport syndrome, DFNB1 hearing loss, Bartter type 4B)
  is not a reason to withhold sufficiency — those entries are already members on
  exactly that basis, and it is the grouping's job to make the minority
  architecture visible. Declaring the criteria defining is what lets
  `evaluate_grouping` report a qualifying non-member as a candidate; while they
  were NECESSARY only, five qualifying entries accumulated unlisted.
membership_criteria:
- description: >-
    Every member has at least one curated inheritance block with a digenic
    (HP:0010984) or oligogenic (HP:0010983) mode of inheritance — i.e., disease
    can require the combined action of variants at two or a few loci. The
    criteria are also SUFFICIENT: a dismech entry that curates such a block is
    by that fact a multi-locus disorder and belongs here, so any qualifying
    non-member is reported as a candidate rather than being missed.
  criteria_semantics: NECESSARY_AND_SUFFICIENT
  logic:
    operator: OR
    operands:
    - criterion_predicate: HAS_INHERITANCE
      description: Digenic inheritance (HP:0010984).
      inheritance_term:
        preferred_term: Digenic inheritance
        term:
          id: HP:0010984
          label: Digenic inheritance
    - criterion_predicate: HAS_INHERITANCE
      description: Oligogenic inheritance (HP:0010983).
      inheritance_term:
        preferred_term: Oligogenic inheritance
        term:
          id: HP:0010983
          label: Oligogenic inheritance
members:
- member: PRPH2-Related Retinopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic retinitis pigmentosa (RP7): disease emerges only in double
      heterozygotes for PRPH2/peripherin-RDS and ROM1, the canonical curation
      exemplar for the digenic inheritance pattern.
- member: GJB2-GJB6 Digenic Nonsyndromic Hearing Loss
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic DFNB1 deafness: a GJB2 (connexin 26) mutation in trans with the
      del(GJB6-D13S1830) connexin 30 deletion, converging on loss of cochlear
      gap-junction potassium recycling.
- member: Alport Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic collagen IV disease: pathogenic variants in two collagen IV genes
      (COL4A3 plus COL4A4, or COL4A5 with COL4A3/COL4A4), alongside the classic
      X-linked/AR/AD Mendelian forms.
- member: Usher Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic contribution of a heterozygous PDZD7 variant together with a
      second Usher gene (ADGRV1/GPR98 or USH2A); PDZD7 also acts as a retinal
      disease modifier.
- member: Facioscapulohumeral Muscular Dystrophy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      FSHD2 is digenic: disease requires an SMCHD1 (or other chromatin-modifier)
      mutation together in trans with an FSHD-permissive 4qA D4Z4 haplotype
      carrying the DUX4 polyadenylation signal.
- member: MITF Waardenburg-Tietz Spectrum
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic Waardenburg syndrome type 2 with ocular albinism from a
      heterozygous MITF mutation combined with the hypomorphic TYR R402Q allele
      — a transcription factor interacting with a target gene it regulates.
- member: Meckel Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic inheritance across the shared ciliopathy gene set (e.g., TMEM67
      with KIF14 in trans), in addition to the predominant autosomal recessive
      transmission.
- member: 46,XY partial gonadal dysgenesis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic gonadal dysgenesis: a deleterious DHX37 variant co-occurring with
      a pathogenic NR5A1 variant, reported in a Brazilian 46,XY DSD series. A
      separate oligogenic-modifier arm proposes rare co-inherited OTX2 or PROP1
      alleles modulating the penetrance of NR5A1 splice variants, so this entry
      spans both the digenic and the modifier ends of the multi-locus spectrum.
- member: Atrial Standstill
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic cardiac channelopathy in which a rare coding SCN5A variant
      combines with common regulatory GJA5/connexin-40 promoter polymorphisms.
      Distinctive among the members in that the second locus is a common
      regulatory variant rather than a second rare coding lesion, which is the
      proposed explanation for the incomplete penetrance of the SCN5A allele.
      Curated as a family-specific model, not as the mode of inheritance for
      atrial standstill as a whole.
- member: Axenfeld-Rieger_syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic anterior-segment dysgenesis from co-segregating PITX2 and FOXC1
      mutations. Mechanistically the closest analogue to the MITF/TYR member:
      the two loci are cross-regulating transcription factors, and the double
      heterozygote is markedly more severe than either single heterozygote,
      consistent with loss of the compensatory arm rather than simple additivity.
- member: Hereditary Gingival Fibromatosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic GINGF3-locus fibromatosis requiring both ZNF513 p.R250W and KIF3C
      p.R410H. The only member whose digenic requirement is corroborated by a
      knock-in animal model rather than by human co-segregation alone: neither
      single-gene mouse (heterozygous or homozygous) develops gingival
      fibromatosis, and only the double mutant does.
- member: Bartter syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic renal tubulopathy: type 4B requires loss of function in both
      CLCNKA and CLCNKB. Unusual among the members in that each locus is
      independently disease-associated in its own right - CLCNKB alone gives
      classic type 3 Bartter syndrome - so the second locus converts a milder
      monogenic tubulopathy into the antenatal, deafness-associated form rather
      than being required for any phenotype at all.
- member: Cerebellar Ataxia-Hypogonadism Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic by co-segregating HOMOZYGOUS mutations at two loci (RNF216 and
      OTUD4) in a consanguineous family, rather than by the double-heterozygote
      pattern that characterizes PRPH2/ROM1 and PITX2/FOXC1. The two loci are
      opposing arms of one ubiquitination cycle - an E3 ligase and a
      deubiquitinase - making this the clearest members' example of two hits on
      a single molecular cycle.
- member: Short-Rib Polydactyly Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic diallelic skeletal ciliopathy: single heterozygous hits in NEK1
      and DYNC2H1 summing across the shared ciliary transport machinery, the
      same load-sharing logic curated for Meckel syndrome and Bardet-Biedl
      syndrome. Evidence is one family in the NEK1 discovery report and is
      curated PARTIAL.
- member: Proteasome-Associated Autoinflammatory Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic interferonopathy in which the two loci are drawn from
      mechanistically DIFFERENT halves of one machine: a heterozygous variant in
      an inducible proteasome subunit paired with a variant in a constitutive
      subunit, across six patients in four independent families. The phenotype
      tracks additive loss of total proteasome activity rather than failure of
      either subunit class, which is why the discovery study named the mechanism
      additive loss of function. Distinctive among the members for recurring
      across four families rather than one, and for coexisting with recessive
      and dominant arms of the same disease.
- member: Congenital Hypothyroidism
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic thyroid dysgenesis: a thyroid DEVELOPMENT gene variant paired with
      a DUOX2/DUOXA2 H2O2-generation variant - one lesion impairing gland
      formation, the other hormone synthesis in the gland that forms. The
      least biased ascertainment behind any multi-locus claim in this grouping:
      a prospective nationwide newborn-screening cohort rather than referred
      pedigrees, with the digenic arm at 5.5% of genotyped patients nearly
      matching the 6.8% monogenic yield, supported by familial segregation and
      in vitro functional assay rather than co-occurrence alone.
- member: Bardet-Biedl syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Oligogenic (triallelic) inheritance in a subset of families, where a
      variant at a second BBS locus is required for a primarily autosomal
      recessive ciliopathy to manifest.
- member: Hirschsprung Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Oligogenic/non-Mendelian architecture with epistasis between the two major
      genes RET and EDNRB; single-locus mutations are neither necessary nor
      sufficient.
- member: Kallmann Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Oligogenic inheritance across isolated GnRH-deficiency genes (ANOS1/KAL1,
      FGFR1, FGF8, PROKR2, and others), which co-contribute to variable
      expressivity.
- member: FGFR1-Related Hypogonadotropic Hypogonadism
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Oligogenic inheritance in which FGFR1 variants act with variants in other
      IGD/CHH genes as digenic/oligogenic contributors, explaining intrafamilial
      variability.
- member: Autosomal Recessive Non-Syndromic Intellectual Disability
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Multi-locus recessive inheritance in consanguineous pedigrees: about 6.6%
      of 121 large Pakistani families segregated pathogenic variants at more
      than one locus, so the phenotype is the sum of two or more independent
      recessive lesions. Unlike the epistatic members (Hirschsprung, PRPH2/ROM1)
      the loci are not required to interact — the significance is diagnostic,
      since stopping at the first convincing homozygous variant leaves part of
      the phenotype unexplained and misstates the recurrence risk.
- member: SHH Holoprosencephaly Spectrum
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Oligogenic holoprosencephaly, and the only member whose multi-locus claim
      has been tested against control populations: oligogenic
      combinations were significantly enriched in patients against two
      independent control populations (P < 10-9), with recurrent contributions
      from FAT1, NDST1, COL2A1 and SCUBE2 converging on SHH signalling and the
      primary cilium. It coexists with a classic autosomal dominant SHH arm, so
      the oligogenic model addresses the families a single driver cannot explain
      rather than replacing the dominant one.
- member: Dextro-Transposition of the Great Arteries
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Oligogenic/complex inheritance confined to the familial laterality-gene
      stratum, where multiple mutations across ZIC3, NODAL, FOXH1, CFC1 and GDF1
      segregate together and place d-TGA in the heterotaxy spectrum. The member
      whose multi-locus arm is the smallest fraction of its disease: most d-TGA
      is sporadic with no identified locus, so the block is scoped to those
      pedigrees rather than to the malformation as a whole.
- member: Rotor Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Digenic conjugated hyperbilirubinaemia: disease requires simultaneous loss
      of both SLCO1B1 and SLCO1B3, because the OATP1B1 and OATP1B3 sinusoidal
      uptake transporters they encode are functionally redundant and loss of
      either alone is silent — requirement, not severity. The member whose
      digenic architecture is most easily mistaken for a monogenic one: the two
      loci are adjacent on chromosome 12 and so do not segregate independently,
      commonly being removed together by a single homozygous deletion, which is
      why the entry also carries an autosomal recessive block. Distinguishes
      Rotor from Dubin-Johnson syndrome, whose conjugated hyperbilirubinaemia
      arises at a single locus (ABCC2).
references:
- reference: PMID:38731822
  title: >-
    Digenic Inheritance in Rare Disorders and Mitochondrial Disease - Crossing
    the Frontier to a More Comprehensive Understanding of Etiology.
- reference: PMID:35411390
  title: >-
    Scaling up oligogenic diseases research with OLIDA: the Oligogenic Diseases
    Database.
- reference: PMID:42555244
  title: "Oligogenic inheritance in epilepsy: A systematic exome-wide analysis."
- reference: PMID:40037090
  title: >-
    Oligogenic analysis across broad phenotypes of 46,XY differences in sex
    development associated with NR5A1/SF-1 variants: findings from the
    international SF1next study.
- reference: PMID:40855356
  title: >-
    Novel COL4A3-COL4A5 variants and digenic inheritance in pediatric Alport
    syndrome from Southwestern China.
discussions:
- discussion_id: digenic_claims_survive_systematic_replication
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Every multi-locus claim grouped here rests on one family or a small series.
    When the same question is asked systematically at cohort scale, do any of
    these two-locus combinations survive - and if the honest answer is "not yet
    demonstrated", what evidence bar should a dismech digenic/oligogenic
    inheritance block have to clear?
  rationale: >-
    This is the grouping's central epistemic risk, and it cuts against the
    grouping rather than for it. The members are curated from
    double-heterozygote reports, single consanguineous pedigrees, and
    family-specific models - exactly the study designs that a systematic screen
    is meant to test. The one such screen we can cite did not replicate:
    Duerinckx et al. took Epi25 exome data from 422 epilepsy patients and 5308
    non-epileptic individuals, ran the cohort-based oligogenic analysis on the
    240 patients left after capture-kit and ancestry filtering, found 12 gene
    combinations significantly overrepresented in cases, and then discarded
    every one of them on manual curation. A statistically enriched combination is not a
    disease mechanism. The asymmetry matters for curation policy: a positive
    single-family digenic report is publishable and reaches us, while the
    negative cohort result that would retire it usually is not framed as being
    about that disease at all. Note this does not argue the members are wrong -
    GINGF3 has a knock-in mouse showing neither single mutation suffices, and
    RP7 has held since 1994 - but it does argue that "reported as digenic" and
    "established as digenic" are different claims that this grouping currently
    does not distinguish.
  evidence:
  - reference: PMID:42555244
    reference_title: "Oligogenic inheritance in epilepsy: A systematic exome-wide analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Manual curation of each of the variant combinations and phenotypes could
      not definitively confirm pathogenicity, and all combinations were finally
      discarded.
    explanation: >-
      A systematic exome-wide oligogenic screen in a large epilepsy cohort
      confirmed no oligogenic combination, which is the strongest current
      evidence that statistical enrichment does not translate into curatable
      two-locus causation.
  - reference: PMID:38731822
    reference_title: "Digenic Inheritance in Rare Disorders and Mitochondrial Disease-Crossing the Frontier to a More Comprehensive Understanding of Etiology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Digenic inheritance is the simplest instance of a non-Mendelian disorder,
      characterized by the functional interplay of variants in two
      disease-contributing genes.
    explanation: >-
      Review framing digenic inheritance as functional interplay between two
      genes, which is the standard the members should be held to and which
      statistical co-occurrence alone does not meet.
  proposed_experiments:
  - experiment_id: digenic_grouping_evidence_tiering
    name: Tier every member's multi-locus claim by evidence class
    description: >-
      Classify each member's digenic/oligogenic block by the strongest design
      supporting it - functional/animal corroboration that a single locus is
      insufficient (Hereditary Gingival Fibromatosis), multi-family human
      co-segregation (PRPH2/ROM1, GJB2/GJB6), single-family co-segregation
      (Axenfeld-Rieger, Cerebellar Ataxia-Hypogonadism, Short-Rib Polydactyly),
      or cohort-level statistical association only. The tier, not the presence
      of the block, is what a consumer of this grouping needs.
  - experiment_id: digenic_grouping_negative_result_sweep
    name: Search each member for a published negative replication
    description: >-
      For each member, search specifically for the study that looked for the
      second locus and did not find it, and curate it as REFUTE evidence on the
      inheritance block. Done for Bardet-Biedl syndrome (PMID:22353939); not yet
      attempted for the other members.
- discussion_id: digenic_grouping_coverage_against_olida
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    OLIDA curates 916 oligogenic variant combinations across 159 distinct
    diseases; this grouping holds 23 members. Which of that gap is dismech
    scope, and should the grouping be populated from OLIDA rather than
    incidentally from whichever disease a curator happened to be working on?
  rationale: >-
    The grouping's membership is currently a byproduct of unrelated curation:
    an entry joined because someone curating retinal dystrophy, or hearing
    loss, or Bartter syndrome, happened to bind an inheritance term. That
    produces a real but unrepresentative sample of multi-locus disease, and it
    is why five qualifying entries sat unlisted until this review. OLIDA is the
    obvious external frame - it applies an explicit curation protocol with a
    per-combination confidence score derived from the genetic and functional
    evidence, which is precisely the evidence tiering the sibling discussion
    asks for, and it supersedes the older ad hoc DIDA protocol. Two things must
    be decided before importing from it. First, scope: an OLIDA entry is a
    variant COMBINATION, while a dismech member is a DISEASE, so 916
    combinations do not imply 916 members and the 159 diseases are the relevant
    denominator. Second, the confidence floor: importing low-confidence
    combinations would import exactly the unreplicated single-family claims the
    sibling discussion warns about. Recent literature shows where the
    uncurated mass sits - severe obesity, amyotrophic lateral sclerosis,
    hereditary spastic paraplegia, congenital heart defects, keratoconus and
    congenital hypothyroidism all carry current oligogenic claims and none is a
    member here.
  evidence:
  - reference: PMID:35411390
    reference_title: "Scaling up oligogenic diseases research with OLIDA: the Oligogenic Diseases Database."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The application of this protocol on the oligogenic literature generated a
      new repository containing 916 oligogenic variant combinations linked to
      159 distinct diseases.
    explanation: >-
      Establishes the size and shape of the external reference set against
      which this grouping's coverage should be measured.
  proposed_experiments:
  - experiment_id: digenic_grouping_olida_crosswalk
    name: Crosswalk OLIDA's disease list against kb/disorders
    description: >-
      DONE. Implemented as `scripts/olida_crosswalk.py`, output at
      `research/olida_crosswalk.md`. Against the live OLIDA API (218 diseases,
      up from the 159 in the 2022 paper): 14 already bound, 85 curated in
      dismech but unbound, 119 with no dismech entry. The 85 are the cheap
      list - an entry already exists, so only an inheritance block and its
      evidence are needed. Congenital Hypothyroidism came off that list and
      into this grouping in the same pass, as the worked example that it is
      cheap.

      The confidence floor question the rationale raises now has a worked
      answer, and it is not "import above a score". Cystinuria carries OLIDA's
      MAXIMUM confidence score, yet the International Cystinuria Consortium's
      own report says digenic inheritance is an exception, found in two of 164
      families, contributing only to aminoaciduria values rather than to the
      stone-forming disease. Cystinuria is therefore recorded as an explicit
      non-member on that entry. A high OLIDA score means the COMBINATION is
      well evidenced, not that the DISEASE requires two loci - which is the
      distinction this grouping turns on. Any import must read the primary
      literature, not the score.
- discussion_id: digenic_hpo_term_semantics_mismatch
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    HP:0010984 defines digenic inheritance as "a type of multifactorial
    inheritance", and HP:0010983 records that literature usage of "oligogenic"
    is not uniform. Is the HPO mode-of-inheritance subtree the right key for
    this grouping, given that its two terms conflate deterministic two-locus
    Mendelian disease with polygenic susceptibility?
  rationale: >-
    The grouping is keyed entirely on two HPO terms, so their semantics are the
    grouping's semantics. Both are siblings under HP:0001426 Non-Mendelian
    inheritance, and HPO glosses each as "a type of multifactorial inheritance
    governed by the simultaneous action of" two or a few loci. That gloss fits
    the susceptibility end of the members - Hirschsprung disease, Kallmann
    syndrome, the oligogenic 46,XY DSD arm - but misdescribes the deterministic
    end: RP7 in a PRPH2/ROM1 double heterozygote and the GINGF3 ZNF513/KIF3C
    genotype are fully penetrant two-locus Mendelian disease with no
    multifactorial component, and calling them multifactorial is simply wrong.
    HPO's own note on HP:0010983, that it is recommended for three loci but
    that usage in the literature is not uniform, concedes the boundary is soft.
    The practical consequence is that a consumer filtering dismech on
    HP:0010984 gets a set whose members differ in kind, and the grouping cannot
    currently express that difference because the mode of inheritance is the
    only thing it records. Resolution probably lies in an additional axis
    (deterministic two-locus versus modifier/susceptibility) rather than in
    different ontology terms, since no better terms exist.
  proposed_experiments:
  - experiment_id: digenic_grouping_determinism_axis
    name: Split the members on determinism, not on locus count
    description: >-
      Partition the members into deterministic two-locus disease (both loci
      required, neither sufficient) versus modifier/susceptibility architecture
      (a second locus shifting penetrance or severity), and test whether that
      axis predicts anything the HPO term does not - replication rate,
      availability of functional corroboration, or usefulness in diagnostic
      reporting. Atrial Standstill is the clearest test case, since its second
      locus is a common regulatory polymorphism rather than a rare coding
      lesion.
- discussion_id: digenic_grouping_boundary_severity_versus_requirement
  kind: INTERPRETATION
  status: OPEN
  prompt: >-
    Most dismech entries that use the word "digenic" describe a second locus
    that makes an existing disease worse, not one the disease needs. Where
    should this grouping's boundary sit, and how should the entries on the far
    side of it be marked so the decision is not silently reversed?
  rationale: >-
    A sweep of every kb/disorders entry mentioning digenic, oligogenic or
    triallelic inheritance found 31 that used one of those words without
    binding a term. Three warranted binding. Most of the rest are passing
    mentions - a reference title, an out-of-scope aside - but a hard core of
    them are considered rejections, and those are not weak evidence: they are a
    different claim. In CMH3 a TPM1 variant causes disease and an MYH7 second
    hit worsens it; in familial defective apolipoprotein B-100 each locus
    causes hypercholesterolaemia alone, so the double heterozygote is a dosage
    effect on one clearance step; in primary hyperoxaluria type 3 the quoted
    "triallelic inheritance" is a severity difference between two sisters; in
    cystinuria the type AB genotype raises aminoaciduria without causing the
    stone disease. The working rule adopted here is REQUIREMENT, NOT SEVERITY:
    bind the term when the phenotype does not appear without both loci, and
    decline when either locus suffices and the second only shifts the dial.

    Three boundary cases are worth naming because they look like the rule and
    are not. Chromosome 18p deletion syndrome carries a genuine digenic claim,
    but it belongs to FSHD2 - a different disease, already a member on that
    mechanism - and 18p deletion is itself a de novo chromosomal event.
    Joubert syndrome cites a paper whose title advertises digenic inheritance,
    but the digenic case in it is the Meckel one, which Meckel syndrome
    already cites. Brugada syndrome names an "oligogenic" subtype whose
    evidence is that 70-85% of cases are genetically unresolved, which is an
    absence of a monogenic explanation rather than a demonstration of
    co-transmitted loci, and whose common-variant-burden component would be
    polygenic (HP:0010982) if anything.

    The open part is what to do about visibility. A decline currently lives as
    prose in the declining entry, which the grouping cannot see and no tool
    checks - the mirror image of the problem this review fixed on the positive
    side, where an unbound term made a real member invisible. Entries carrying
    the reasoning today: Hypertrophic_Cardiomyopathy_3,
    Familial_Defective_Apolipoprotein_B-100, Primary_Hyperoxaluria_Type_3,
    Cystinuria, Chromosome_18p_Deletion_Syndrome and Brugada_Syndrome, plus
    the pre-existing declines in Familial_Nonmedullary_Thyroid_Carcinoma,
    RDH5-Related_Retinopathy and BBSome-Related_Retinitis_Pigmentosa.
  proposed_experiments:
  - experiment_id: digenic_grouping_structured_decline
    name: Give a considered non-membership somewhere structured to live
    description: >-
      Decide whether an explicit non-membership assertion belongs in the schema
      - a negated criteria leaf, an excluded-members list on the grouping, or a
      discussion on the disease entry with a resolvable pointer - so that a
      curator who binds HP:0010984 to one of these entries in future collides
      with the earlier reasoning instead of silently overturning it. Nine
      entries already carry a decline in prose, which is enough of a pattern to
      model.