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Ten Proposed Mechanism-Based Classification Nodes for MONDO, Derived from dismech

Date: 2026-08-01 Status: Proposal for MONDO review — no MONDO edits made Source KB: dismech (kb/modules/, kb/disorders/, kb/groupings/) MONDO snapshot: local OAK sqlite:obo:mondo, fetched 2026-08-01 — 31,886 labelled MONDO: classes, 3,968 deprecated. See §6 for the fingerprint check and reproduction commands; re-verify before filing any new-term request.

1. Why there is room for this

MONDO already carries a dedicated mechanism axis, MONDO:7770011 disease by molecular mechanism. It is the branch that holds exactly the kind of class the user of a mechanism-based nosology reaches for — "ciliopathy", "RASopathy".

That branch currently has five children:

MONDO ID Label
MONDO:0005308 ciliopathy
MONDO:0021060 RASopathy
MONDO:0019119 muscular channelopathy
MONDO:0021179 proteostasis deficiencies
MONDO:0005574 tauopathy

Five nodes is a very thin axis for ~25,000 disease classes. The gap is not that MONDO lacks mechanism knowledge — 240 MONDO terms carry a RO:0004021 basis_in_disruption_of_process axiom — but that almost all of those axioms sit on single diseases or single enzymes (Fabry disease → GO:0004557 alpha-galactosidase activity) or on very broad metabolic-process containers (amino acid metabolism disease → GO:0006520). The intermediate tier — the "this is one recognisable mechanistic family of ~10–30 diseases that clinicians and researchers name and study as a unit" tier that ciliopathy and RASopathy occupy — is nearly empty.

dismech is a good source for filling it because its kb/modules/ layer was built for precisely this purpose: 118 conserved mechanism modules, each a curated trigger→consequence pathophysiology chain with evidence, and each with disorder entries that declare conforms_to: <module>#<node>. A module with many independent conformers is direct evidence that the mechanism is a real cross-disease family rather than a one-off.

Two structural precedents this proposal leans on

  • RASopathy is logically defined: MONDO:0000001 and (RO:0004021 some GO:0007265), with the MONDO:patterns/basis_in_disruption_of_process design pattern generating the synonym disorder of Ras protein signal transduction. Seven of the ten proposals below can be minted the same way (#2, #3, #4, #5, #6, #7, #9), and each cites a verified GO term. The remaining three (#1, #8, #10) deliberately propose no RO:0004021 axiom — see the next bullet and their individual entries.
  • proteostasis deficiencies (MONDO:0021179) carries no RO:0004021 axiom — it is a textual grouping with asserted children. That is the precedent for proposal #1, whose mechanism (toxic-metabolite accumulation under catabolic stress) is a convergence pattern rather than one GO process, and for proposal #8.

RO:0004021 is direction-agnostic — read the axioms as necessary conditions

This constrains every logical definition below and is stated once here rather than repeated ten times. RO:0004021 basis_in_disruption_of_process says the disease has its basis in a disruption of the named process; it does not encode which direction the process is perturbed. A proposed axiom therefore cannot distinguish gain from loss of function, and will admit disorders that perturb the same process the opposite way from the textual definition:

  • #7 (GO:0007224 smoothened signaling pathway) — the textual definition says "constitutive activation", but the loss-of-signaling disorders satisfy the axiom equally. This KB already contains such counterexamples annotated with GO:0007224: Holoprosencephaly_12_With_or_Without_Pancreatic_Agenesis, Brachydactyly_Type_A1, and Smith-Lemli-Opitz_syndrome.
  • #3 (GO:0008543 FGFR signaling pathway) — the definition says "constitutively active or ligand-hypersensitive", but FGFR loss-of-function disease (Kallmann_Syndrome, FGFR1 LOF) satisfies the axiom.
  • #9 (GO:0016236 macroautophagy) — §3.9's own gap evidence notes that MONDO's existing autophag* terms describe excessive autophagy; those satisfy the axiom too.

Consequence for the new-term requests: either write the textual definitions direction-neutrally, or state explicitly in each NTR that the RO:0004021 axiom is a necessary condition only and that directionality is carried by the textual definition. Do not present these axioms as equivalence axioms. Where MONDO wants direction encoded, a positive/negative regulation of ... GO child (e.g. GO:0045879 negative regulation of smoothened signaling pathway, already used by the dismech module) is the better anchor.

2. How candidates were selected and filtered

Sourcing. Primary source was kb/modules/, ranked by the number of distinct disorder files declaring conforms_to against the module (not raw node counts, which overcount multi-node conformers). Cross-disorder pathophysiology patterns without a module were also considered; none displaced a module-backed candidate.

MONDO exclusion filter (as agreed: exclude only on an exact or near-synonym match; a partial/phenotype-based/anatomy-based MONDO grouping does not disqualify, but must be disclosed). Each candidate was tested three ways against the MONDO snapshot:

  1. Label match — all rdfs:label values.
  2. Synonym match — all exact/related/broad/narrow synonyms.
  3. Definition-text match — all IAO:0000115 definitions, to catch classes whose label hides the mechanism.

All ten proposals returned zero hits on all three passes for their mechanism phrase. The searches that did hit are reported per-node under "MONDO gap evidence", because those adjacent classes are what a MONDO curator will need to reconcile against.

Candidates excluded by the filter (recorded so the work isn't repeated). The Conformers column is distinct-file counts, the same metric used in §3 and §4; the node-occurrence count is shown alongside because the two differ substantially and an earlier draft of this table mistakenly reported nodes:

dismech module Conformers (files) (nodes) Excluded because MONDO already has
lysosomal_substrate_accumulation 44 85 lysosomal storage disease
ciliopathy_dysfunction 28 68 MONDO:0005308 ciliopathy
complex_iv_assembly_deficiency 23 61 mitochondrial complex IV deficiency
congenital_disorder_of_glycosylation 11 26 MONDO:0017740 / CDG classes
microtubule_dependent_neuronal_migration_failure 9 22 MONDO:0100153 tubulinopathy
amyloidogenesis 5 39 MONDO:0019065 amyloidosis (under proteostasis deficiencies)
heme_biosynthesis_porphyria 3 10 porphyria
cranial_suture_premature_fusion 2 5 craniosynostosis
renal_cystogenesis 2 7 cystic kidney disease
drug_hypersensitivity_scar 2 9 MONDO:0005594 severe cutaneous adverse reaction
granuloma_formation 2 7 granulomatous disease classes
er_protein_storage_disease 1 1 MONDO:0027749 serpinopathy

Note that on the corrected metric several excluded modules are smaller than the proposals in §3 — amyloidogenesis has 5 conforming files, fewer than seven of the ten proposals. This does not change any exclusion: every row above was excluded because MONDO already carries an equivalent class, never because of its size. Size is used only to rank the surviving candidates.

3. The ten proposed nodes

Ranked by strength of dismech backing. Each entry gives a proposed label, definition, logical definition, parentage, the mechanism rationale, the candidate member set, and the MONDO gap evidence.

3.1 Intoxication-type inborn error of metabolism

  • Proposed label: intoxication-type inborn error of metabolism
  • Synonyms: intoxication-type inborn error of intermediary metabolism; intoxication-type metabolic disease; toxic-metabolite accumulation disorder
  • Proposed parents: MONDO:7770011 disease by molecular mechanism; MONDO:0019052 inborn errors of metabolism
  • Logical definition: none proposed — follow the MONDO:0021179 proteostasis deficiencies precedent of a textually-defined grouping with asserted children. No single GO process captures "toxic metabolite accumulates behind an enzymatic block and is unmasked by catabolic stress"; forcing GO:0006082 organic acid metabolic process would both over- and under-generate.

Definition. An inborn error of intermediary metabolism in which a deficient enzyme or transporter causes accumulation of an upstream toxic metabolite and/or an energy deficit that is clinically silent at baseline and is unmasked by catabolic stress (intercurrent illness, fasting, surgery, or a protein load), precipitating acute metabolic decompensation — metabolic acidosis, hyperammonemia, and/or hypoglycemia — and consequent acute encephalopathy and multiorgan crisis.

Why this is a genuine mechanism class. The clinically decisive division in metabolic medicine is not which substrate accumulates but how the disease behaves: whether it presents as an acute, potentially reversible crisis requiring emergency protocols (stop protein, reverse catabolism with glucose, scavenge ammonia, dialyse). MONDO currently scatters these disorders across urea cycle disorder, classic organic aciduria, disorder of fatty acid oxidation and ketogenesis, and amino-acid disorders — a substrate partition that cross-cuts the behavioural one, so no MONDO query can currently return "the disorders that decompensate acutely."

Naming caveat — do not label this "Saudubray group 1" without narrowing it. An earlier draft leaned on the Saudubray classification, which is the standard reference for this axis. That attribution is only partly accurate for the member list as curated: Saudubray places fatty-acid-oxidation and ketogenesis defects in the energy-deficiency group, not the intoxication group, yet MONDO:0015515 (CPT II) and MONDO:0011614 (HMG-CoA synthase) are listed below; and MONDO:0018820 (TANGO2) fits neither classical group. Two honest options for the NTR, and MONDO should pick one explicitly:

  1. Keep the broader membership and use a behaviour-based label — e.g. acute metabolic decompensation disorder — dropping the claim of strict Saudubray equivalence. This is the option the member list below actually supports, and is the one recommended here.
  2. Keep the "intoxication-type" label and drop the FAO/ketogenesis members plus TANGO2, aligning the class strictly with Saudubray group 1.

The dismech grouping kb/groupings/Intoxication-Type_Inborn_Errors_of_Metabolism.yaml (added in this PR) has already adopted option 1: its display_name reads "(Acute Metabolic Decompensation)" rather than claiming Saudubray group 1 equivalence, and its grouping_rationale names the three members (MONDO:0015515 CPT II, MONDO:0011614 HMG-CoA synthase, MONDO:0018820 TANGO2) that would have to be reconsidered if option 2 is ever preferred instead. The MONDO label proposed above should be decided the same way.

dismech provenance. kb/modules/metabolic_intoxication_decompensation.yaml — node chain: Enzymatic Block in Intermediary Metabolism → Toxic Metabolite Accumulation and Energy Deficit → Acute Metabolic Decompensation → Acute Metabolic Encephalopathy → Neurological Injury and Multiorgan Crisis. 19 conforming disorder entries — the largest non-excluded module in the KB. Backing dismech grouping: Intoxication-Type_Inborn_Errors_of_Metabolism (added in this PR; 19 members, NECESSARY, skos:broadMatch → MONDO:0019052).

Candidate MONDO members (19). MONDO:0009520 3-hydroxy-3-methylglutaric aciduria · MONDO:0011614 3-hydroxy-3-methylglutaryl-CoA synthase deficiency · MONDO:0018950 3-methylcrotonyl-CoA carboxylase deficiency · MONDO:0009610 3-methylglutaconic aciduria type 1 · MONDO:0008814 arginase deficiency · MONDO:0008815 argininosuccinic aciduria · MONDO:0008760 beta-ketothiolase deficiency · MONDO:0009376 carbamoyl phosphate synthetase I deficiency · MONDO:0014332 hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency · MONDO:0015515 carnitine palmitoyltransferase II deficiency · MONDO:0016602 citrin deficiency · MONDO:0008988 citrullinemia type I · MONDO:0009666 holocarboxylase synthetase deficiency · MONDO:0009475 isovaleric acidemia · MONDO:0009109 lysinuric protein intolerance · MONDO:0009563 maple syrup urine disease · MONDO:0002012 methylmalonic acidemia · MONDO:0010703 ornithine carbamoyltransferase deficiency · MONDO:0018820 recurrent metabolic encephalomyopathic crises-rhabdomyolysis (TANGO2)

Note for curators: MONDO:0018820 (TANGO2) appears in both this proposal and

2 (cardiac channelopathy) — it causes metabolic crises and a

QT-prolonging ventricular arrhythmia. That is biologically correct and an argument for multi-parenting rather than a conflict, exactly as flagged for MONDO:0008222 Andersen-Tawil syndrome in §3.2.

MONDO gap evidence. "intoxication" matches 24 MONDO terms — all are exogenous poisoning (lead, cocaine, botulinum toxin, ackee fruit, digitalis); none is an inborn error. "metabolic decompensation" and "metabolic crisis": 0 hits. "toxic metabolite" in definition text: 0 hits. Substrate-partitioned neighbours that would become siblings, not parents: MONDO:0004739 urea cycle disorder, MONDO:0019215 classic organic aciduria, MONDO:0017713 disorder of fatty acid oxidation and ketogenesis.

3.2 Cardiac channelopathy

  • Proposed label: cardiac channelopathy
  • Synonyms: inherited arrhythmia syndrome; cardiac ion channelopathy; disorder of cardiac muscle cell action potential
  • Proposed parents: MONDO:7770011 disease by molecular mechanism; MONDO:0005267 heart disorder
  • Logical definition: MONDO:0000001 and (RO:0004021 some GO:0086001) — GO:0086001 cardiac muscle cell action potential ✅ verified. (GO:0086009 membrane repolarization ✅ is the alternative if a repolarization-specific axiom is preferred; GO:0086001 is recommended because it also admits the depolarization/pacemaker branch.)

Definition. A disease caused by disturbed function of ion channels or calcium-handling proteins of the cardiomyocyte, altering the cardiac action potential and/or intracellular calcium handling, producing an arrhythmogenic substrate and triggered activity in a structurally normal heart.

Why this is a genuine mechanism class — and the strongest structural argument in this document. MONDO's generic channelopathy class, MONDO:0021016, is obsolete. What survived obsoletion is MONDO:0019119 muscular channelopathy, which sits directly under disease by molecular mechanism with 12 children and its own per-ion-species subclasses (sodium/chloride/calcium/potassium). So MONDO has already accepted the modelling pattern "channelopathy of tissue X" as a mechanism-axis class — it just never minted the cardiac sibling, even though the cardiac channelopathies are, if anything, the better-known half of the field. This proposal is a direct structural completion, not a novel construct.

dismech provenance. kb/modules/cardiac_ion_channel_repolarization.yaml — Cardiac Ion-Channel or Calcium-Handling Variant → Altered Action Potential and Calcium Handling → Arrhythmogenic Substrate and Triggered Activity → Ventricular Tachyarrhythmia → Syncope and Sudden Cardiac Death, with a parallel Sinoatrial Node Pacemaker Dysfunction branch. 12 conforming disorder entries. dismech also carries the Inherited_Arrhythmia_Syndromes grouping with NECESSARY_AND_SUFFICIENT membership criteria — i.e. this class already has a machine-checkable boolean definition on the dismech side.

Candidate MONDO members (12). MONDO:0008222 Andersen-Tawil syndrome · MONDO:0015263 Brugada syndrome · MONDO:0018054 familial atrial fibrillation · MONDO:0012061 familial sick sinus syndrome · MONDO:0019171 familial long QT syndrome · MONDO:0100234 paroxysmal familial ventricular fibrillation · MONDO:0017990 catecholaminergic polymorphic ventricular tachycardia · MONDO:0000453 short QT syndrome · MONDO:0013960 sinoatrial node dysfunction and deafness · MONDO:0010979 Timothy syndrome · MONDO:0013317 torsade-de-pointes syndrome with short coupling interval · MONDO:0018820 TANGO2 deficiency disorder

MONDO gap evidence. "cardiac channelopathy" across labels + synonyms: 0 hits. "cardiac action potential" in definition text: 0 hits. "repolarization" in definition text: 3 hits, all individual diseases (MONDO:0100234, MONDO:0005478 torsades de pointes, and a rabbit model), no grouping. Note for curators: MONDO:0008222 Andersen-Tawil syndrome is currently a child of muscular channelopathy — it is genuinely both, and should become multi-parented rather than moved.

3.3 FGFR-opathy

  • Proposed label: FGFR-opathy
  • Synonyms: FGFR-related disorder; fibroblast growth factor receptor signaling disease; disorder of fibroblast growth factor receptor signal transduction
  • Proposed parents: MONDO:7770011 disease by molecular mechanism; MONDO:0003847 hereditary disease
  • Logical definition: MONDO:0000001 and (RO:0004021 some GO:0008543) — GO:0008543 fibroblast growth factor receptor signaling pathway ✅ verified.

Definition. A hereditary disease caused by a germline variant in a fibroblast growth factor receptor gene (most often FGFR3, less often FGFR2 or FGFR1) that produces a constitutively active or ligand-hypersensitive receptor, with sustained downstream MAPK/ERK and STAT signaling acting on growth-plate chondrocytes and cranial suture osteogenic fronts.

Why this is a genuine mechanism class. This is the closest available analogue to RASopathy anywhere in the ontology and the most obviously missing sibling: a named receptor-tyrosine-kinase signaling family, with a shared gain-of-function direction, a shared downstream cascade (which is literally the RAS-MAPK cascade that RASopathy is defined on), a coherent two-compartment skeletal phenotype, and a shared therapeutic strategy — FGFR-pathway antagonism. That payoff should be stated carefully: the CNP/NPR2 analogue vosoritide is approved for achondroplasia only, and its extension to hypochondroplasia and the craniosynostosis members is under investigation rather than established. The class-level claim is that these disorders share a druggable node, not that any one drug is approved across them. MONDO currently has ~30 FGFR*-related per-gene terms and no class over them.

Why not a child of RASopathy? The shared downstream cascade invites the question. The answer is ontological: GO:0008543 (FGFR signaling pathway) is not a subclass of GO:0007265 (Ras protein signal transduction) in GO, so the axioms do not subsume, and the two classes are distinguished by the lesion (receptor tyrosine kinase vs. RAS-pathway component) rather than by the shared effector arm. They should be siblings on the mechanism axis, not parent and child.

dismech provenance. kb/modules/fgfr_gain_of_function_skeletal_dysplasia.yaml — Constitutive FGFR Activation → Sustained MAPK/STAT Signaling → {Growth-Plate Chondrocyte Dysregulation, Cranial Suture Osteogenic Acceleration} → {Impaired Endochondral Ossification, Premature Suture Fusion}, plus a CNP-NPR2 counter-regulation/therapy node. 11 conforming disorder entries. dismech also carries the FGFR_Related_Skeletal_Dysplasias grouping.

Candidate MONDO members (11). MONDO:0007037 achondroplasia · MONDO:0007041 Apert syndrome · MONDO:0007405 Crouzon syndrome · MONDO:0012833 Crouzon syndrome-acanthosis nigricans syndrome · MONDO:0007793 hypochondroplasia · MONDO:0007400 Jackson-Weiss syndrome · MONDO:0011274 Muenke syndrome · MONDO:0007043 Pfeiffer syndrome · MONDO:0014658 SADDAN · MONDO:0008546 thanatophoric dysplasia type 1 · MONDO:0008547 thanatophoric dysplasia type 2

MONDO gap evidence. "FGFR" matches 30 terms — all per-gene or per-disease (FGFR3-related chondrodysplasia, FGFR1-related Pfeiffer syndrome, FGFR2-related bent bone dysplasia), no cross-gene grouping. "fibroblast growth factor receptor" in definition text: 1 hit (MONDO:0014658 SADDAN), a single disease. Adjacent but non-blocking: MONDO:0019685 FGFR3-related chondrodysplasia is gene-scoped and would become a child.

3.4 Synaptic vesicle cycle disorder

  • Proposed label: synaptic vesicle cycle disorder
  • Synonyms: presynaptic vesicle cycle disease; SV-opathy; disorder of the synaptic vesicle cycle
  • Proposed parents: MONDO:0021017 synaptopathy; MONDO:7770011 disease by molecular mechanism
  • Logical definition: MONDO:0000001 and (RO:0004021 some GO:0099504) — GO:0099504 synaptic vesicle cycle ✅ verified.

Definition. A synaptopathy caused by deficiency of a protein of the presynaptic synaptic vesicle cycle, disrupting vesicle docking and priming, calcium-triggered SNARE-mediated fusion, or vesicle endocytosis and recycling, and producing neurotransmitter release failure.

Why this is a genuine mechanism class. This is the single most productive gene-discovery family in developmental and epileptic encephalopathy of the last decade — STXBP1, SNAP25, STX1B, SYT1, VAMP2, DNM1, UNC13A, SYN1, CPLX1 are curated, reviewed, and increasingly treated as one group, because they converge on one biochemical cycle with step-resolved lesions (docking/priming vs. fusion vs. endocytosis). MONDO scatters every one of them into numbered developmental and epileptic encephalopathy, N classes where the shared presynaptic mechanism is completely invisible.

Relationship to existing MONDO coverage — disclosed. MONDO does have MONDO:0021017 synaptopathy ("a disease caused by dysfunction of synapses"). That term is far broader — it spans pre- and post-synaptic, central and neuromuscular — and currently has exactly one child, MONDO:0020124 neuromuscular junction disease. This proposal is a child of it, not a competitor, and would be its first central-synapse subclass. This passes the agreed filter (no exact/near-synonym), but the parentage should be explicit.

dismech provenance. kb/modules/synaptic_vesicle_cycle.yaml — Synaptic Vesicle Cycle Protein Deficiency → {Impaired Docking and Priming, Impaired Ca²⁺-Triggered SNARE-Mediated Fusion, Impaired Endocytosis and Recycling} → Neurotransmitter Release Failure. 9 conforming disorder entries. dismech also carries the Synaptic_Vesicle_Cycle_Disorders grouping.

Candidate MONDO members (9). MONDO:0012812 developmental and epileptic encephalopathy 4 (STXBP1) · MONDO:0014598 DEE 31A (DNM1) · MONDO:0033372 DEE 63 (CPLX1) · MONDO:0032678 DEE 71 (SNAP25) · MONDO:0014517 generalized epilepsy with febrile seizures plus type 9 (STX1B) · MONDO:0010339 epilepsy X-linked 1 (SYN1) · MONDO:0033864 infantile hypotonia-oculomotor anomalies-hyperkinetic movements (SYT1, Baker-Gordon) · MONDO:0980940 NDD with hypotonia and epilepsy (UNC13A) · MONDO:0032900 NDD with hypotonia and autistic features (VAMP2)

MONDO gap evidence. "synaptic vesicle" across labels + synonyms: 0 hits; in definition text: 0 hits. "synaptopathy" returns only MONDO:0021017 and two DLG4 synonyms (a postsynaptic scaffold gene — different arm).

3.5 Centrosomopathy

  • Proposed label: centrosomopathy
  • Synonyms: centrosome-spindle disorder; disorder of centrosome cycle; mitotic spindle disorder
  • Proposed parents: MONDO:7770011 disease by molecular mechanism; MONDO:0003847 hereditary disease
  • Logical definition: MONDO:0000001 and (RO:0004021 some GO:0007098) — GO:0007098 centrosome cycle ✅ verified. (Alternatives, both ✅ verified, if the intended scope is spindle-centric or centriole-centric: GO:0051225 spindle assembly, GO:0007099 centriole replication.)

Definition. A hereditary disease caused by dysfunction of the centrosome, centriole, or mitotic spindle apparatus, in which perturbed progenitor cell division alters the balance of proliferative versus differentiative divisions and distorts the progenitor pool — most prominently in cortical neurogenesis, producing primary microcephaly, microlissencephaly, and simplified gyration, and in some members a systemic growth defect (primordial dwarfism).

Why this is a genuine mechanism class. "Centrosomopathy" is standard, long-established usage in the developmental neurogenetics literature for the MCPH/MOPD gene families (ASPM, WDR62, CENPJ, CEP152, PCNT, NDE1, KATNB1). It is also the natural structural sibling of two classes MONDO already has: ciliopathy (basal body — the centriole in its non-mitotic role) and tubulinopathy (the microtubule polymer). MONDO has the organelle-in-cilium class and the polymer class but not the organelle-in-mitosis class, which is what leaves ASPM-type primary microcephaly with no mechanistic home.

dismech provenance. kb/modules/neural_progenitor_centrosome_spindle_dysfunction.yaml — Centrosome and Mitotic Spindle Perturbation → Abnormal Progenitor Division and Fate Choice → Progenitor Pool Distortion → Abnormal Cortical Neuron Output and Gyration, with programmed-cell-death and viral-cytopathy branches. 8 conforming disorder entries. Backing dismech grouping: Centrosomopathies (added in this PR; 8 members, NECESSARY, no MONDO mapping because no equivalent term exists). Related but phenotype-scoped groupings: Primary_Microcephaly_Spectrum, Lissencephaly_and_Neuronal_Migration_Disorders.

Candidate MONDO members (5 mapped of 8 dismech conformers). MONDO:0016660 autosomal recessive primary microcephaly · MONDO:0018838 lissencephaly spectrum disorders · MONDO:0008872 microcephalic osteodysplastic primordial dwarfism type II · MONDO:0013785 intellectual disability, autosomal recessive 34 (CRADD) · MONDO:0020491 subcortical band heterotopia (EML1). Three dismech conformers — NDE1-related_Microcephaly_Lissencephaly, KATNB1-related_Cortical_Malformation, TUBB/TUBB5-related_Microcephaly — carry no disease_term; these are candidate MONDO new-term requests in their own right, flagged separately below (§5).

MONDO gap evidence. "centrosomopath", "centriolopath", "centriole", "pericentriolar", "centrosome amplification": 0 hits across labels and synonyms. "centrosome" and "spindle assembly" in definition text: 0 hits. All 95 "spindle" label hits are spindle-cell neoplasms — a homonym, not a conflict.

3.6 Meiotic recombination failure disorder

  • Proposed label: meiotic recombination failure disorder
  • Synonyms: meiotic prophase I failure; synaptonemal complex disorder; disorder of meiotic recombination
  • Proposed parents: MONDO:7770011 disease by molecular mechanism; MONDO:0005039 reproductive system disorder (or MONDO:0005047 infertility disorder)
  • Logical definition: MONDO:0000001 and (RO:0004021 some GO:0007131) — GO:0007131 reciprocal meiotic recombination ✅ verified. (GO:0007130 synaptonemal complex assembly ✅ verified, for a synapsis-scoped variant if MONDO prefers to split the two.)

Definition. A disease caused by disruption of meiotic prophase I chromosome synapsis or homologous recombination in germ cells, producing pachytene-checkpoint arrest and germ-cell apoptosis, and manifesting sex-dimorphically as ovarian follicle depletion with primary ovarian insufficiency in 46,XX individuals and spermatogenic arrest with non-obstructive azoospermia in 46,XY individuals.

Why this is a genuine mechanism class. This class has an unusual and compelling property: one mechanism, two clinical presentations that current nosology files in different places entirely. The same STAG3, SYCE1, HFM1, MCM8/9, HROB lesion causes "premature ovarian failure N" in one sex and "spermatogenic failure N" in the other, and MONDO's numbered series place these in unrelated branches. A mechanism node is the only way to state that they are one disease family. Several members additionally carry a somatic DNA-repair deficiency with cancer predisposition (MCM8/MCM9), which the mechanism node explains and the phenotype-based classes cannot.

dismech provenance. kb/modules/meiotic_prophase_failure.yaml — Meiotic Prophase I Entry and Homolog Pairing → Synaptonemal Complex Assembly → Homologous Recombination Repair of Meiotic DNA Breaks → Pachytene Checkpoint Arrest and Germ Cell Apoptosis → {Ovarian Follicle Depletion/POI, Spermatogenic Arrest/NOA}, plus a Somatic DNA Repair Deficiency and Cancer Predisposition branch. 7 conforming disorder entries. dismech also carries the Meiotic_Gametogenic_Failure grouping.

Candidate MONDO members (6 mapped of 7). MONDO:0014322 premature ovarian failure 9 (HFM1) · MONDO:0971176 ovarian dysgenesis 11 (HROB) · MONDO:0044776 premature ovarian failure 10 (MCM8) · MONDO:0014321 premature ovarian failure 8 (STAG3) · MONDO:1060214 SYCE1-related gametogenic failure · MONDO:0010052 spermatogenic failure 4 (SYCP3). (MCM9-related gametogenic failure unmapped in dismech.)

MONDO gap evidence. "meiotic recombination", "synaptonemal": 0 hits across labels, synonyms, and definitions. "meiotic"/"meiosis": 1 hit, MONDO:0044626 female infertility due to oocyte meiotic arrest — a single sex-specific disease with an RO:0004021 GO:0051321 meiotic cell cycle axiom, which would become a child.

3.7 Hedgehog pathway activation disease

  • Proposed label: Hedgehog pathway activation disease
  • Synonyms: Hedgehog-driven neoplasm; disorder of constitutive smoothened signaling; Hedgehog pathway signaling disease
  • Proposed parents: MONDO:7770011 disease by molecular mechanism
  • Logical definition: MONDO:0000001 and (RO:0004021 some GO:0007224) — GO:0007224 smoothened signaling pathway ✅ verified. Per §1's necessary-condition caveat, this axiom is direction-agnostic and so does not by itself exclude the loss-of-signaling disorders (Greig_Cephalopolysyndactyly, Pallister-Hall_Syndrome, the Holoprosencephaly_9/12 entries, Smith-Lemli-Opitz_syndrome); the activation direction is asserted textually. If MONDO prefers the direction encoded in the axiom, GO:0045879 negative regulation of smoothened signaling pathway — already used by the dismech module — is the better anchor. The label is deliberately narrowed to activation to match the backing dismech grouping Hedgehog_Pathway_Activation_Disorders, which scopes loss-of-signaling out.

Definition. A disease caused by ligand-independent constitutive activation of the Hedgehog signaling pathway, arising either from loss of function of a negative regulator (PTCH1, PTCH2, SUFU) or gain of function of the positive transducer SMO, converging on constitutive GLI transcriptional output and Hedgehog-dependent proliferation.

Why this is a genuine mechanism class. Like RASopathy, this is a named developmental signaling pathway whose disorders are recognised as a unit — and here the therapeutic argument is decisive: the SMO inhibitors vismodegib and sonidegib are approved on the basis of pathway membership, and SUFU-mutant tumours are known to be intrinsically resistant because the lesion is downstream of the drug target. That distinction is a pure mechanism-graph fact and is unrepresentable in a phenotype- or histology-based classification. The class also usefully unifies germline (Gorlin) and somatic (sporadic BCC, SHH-medulloblastoma) disease.

dismech provenance. kb/modules/hedgehog_pathway_activation.yaml — Loss of Hedgehog Pathway Negative Regulation → Constitutive Smoothened Activity → Constitutive GLI Transcriptional Output → Hedgehog-Driven Proliferation and Tumorigenesis. 5 conforming disorder entries. Backing dismech grouping: Hedgehog_Pathway_Activation_Disorders (added in this PR; 5 members, NECESSARY_AND_SUFFICIENT — the only N&S class of the four, since the defining lesion is a discrete molecular state — no MONDO mapping because no equivalent term exists). Note the 5 members are 3 disease-level entities: Gorlin Syndrome plus its own PTCH1- and SUFU-related molecular subdivisions, which the grouping's own member notes concede are not independent diseases.

Candidate MONDO members (5). MONDO:0007187 nevoid basal cell carcinoma syndrome (Gorlin) · MONDO:0958174 basal cell nevus syndrome 1 (PTCH1) · MONDO:0958189 basal cell nevus syndrome 2 (SUFU) · MONDO:0005341 skin basal cell carcinoma · MONDO:0850197 medulloblastoma SHH activated. Strong further candidates not yet in dismech: rhabdomyosarcoma subsets, Curry-Jones syndrome (SMO mosaic), and — as a loss-of-signaling counterpart worth considering for a sibling node rather than this one — holoprosencephaly.

MONDO gap evidence. "hedgehog" across labels + synonyms: 2 hits, both veterinary (ataxia, middle-African hedgehog; cardiomyopathy, hedgehogs) — the animal, not the pathway. "smoothened", "sonic hedgehog", "GLI3": 0 hits. "hedgehog signaling" and "smoothened" in definition text: 0 hits.

3.8 Polyglutamine expansion disease

  • Proposed label: polyglutamine expansion disease
  • Synonyms: polyQ disease; polyglutamine disorder; translated CAG repeat expansion disease
  • Proposed parents: MONDO:0021179 proteostasis deficiencies; MONDO:0005559 neurodegenerative disease
  • Logical definition: none proposed via RO:0004021 — the defining feature is a variant class (a translated CAG/polyQ tract expansion conferring a dominant toxic gain of function), not a disrupted GO process. Recommend a textual grouping in the proteostasis deficiencies style, or a has_material_basis_in pattern if MONDO wishes to model repeat-expansion variant classes generally.

Definition. An autosomal dominant neurodegenerative disease caused by expansion of a translated CAG trinucleotide repeat encoding an elongated polyglutamine tract, which confers a dominant toxic gain of function on the host protein — misfolding and aggregation with neuronal intranuclear inclusions, sequestration of transcriptional co-activators, overload of ubiquitin-proteasome and autophagic clearance, and mitochondrial bioenergetic impairment — producing region-specific selective neuronal loss.

Why this is a genuine mechanism class. "The polyglutamine diseases" is one of the most firmly established mechanism-based groupings in all of neurology — nine diseases (HD, DRPLA, SBMA, SCA1/2/3/6/7/17) taught, reviewed, and drug-screened as one family, with a shared repeat-length/age-of-onset relationship and shared anticipation. MONDO has no term for it and no term for repeat expansion at all. Notably, MONDO already accepted the two structurally identical siblings — MONDO:0000510 synucleinopathy and MONDO:0700038 TDP-43 proteinopathy, both "aggregating protein defines the class" nodes under proteostasis deficiencies — so the modelling precedent is exact.

dismech provenance. kb/modules/polyglutamine_expansion_proteotoxicity.yaml — Translated CAG/PolyQ Repeat Expansion → Misfolded PolyQ Protein Aggregation → {Transcriptional Dysregulation, Proteostasis Network Overload, Mitochondrial and Bioenergetic Dysfunction} → Selective Neuronal Dysfunction and Loss. 4 conforming disorder entries, plus the Polyglutamine_Disorders grouping (grouping_basis: SHARED_MECHANISM).

Candidate MONDO members (4 in dismech; the class is larger). MONDO:0007739 Huntington disease · MONDO:0007182 Machado-Joseph disease (SCA3) · MONDO:0011781 spinocerebellar ataxia type 17 · MONDO:0007435 dentatorubral-pallidoluysian atrophy. Established members not yet curated in dismech that MONDO should include: SCA1, SCA2, SCA6, SCA7, and spinal-bulbar muscular atrophy (Kennedy disease).

MONDO gap evidence. "polyglutamine", "repeat expansion", "trinucleotide", "triplet repeat": 0 hits across labels, synonyms, and definition text. "CAG repeat" in definitions: 0 hits. "proteinopathy": 3 hits, all neighbours (TDP-43 proteinopathy, SQSTM1-related multisystem proteinopathy, proteostasis deficiencies) — the proposed parent and siblings.

3.9 Macroautophagy deficiency disorder

  • Proposed label: macroautophagy deficiency disorder
  • Synonyms: disabled macroautophagy; autophagy deficiency disease; disorder of macroautophagy
  • Proposed parents: MONDO:0021179 proteostasis deficiencies; MONDO:7770011 disease by molecular mechanism
  • Logical definition: MONDO:0000001 and (RO:0004021 some GO:0016236) — GO:0016236 macroautophagy ✅ verified. (GO:0006914 autophagy ✅ verified, if a broader scope including chaperone-mediated autophagy is wanted.)

Definition. A disease caused by decline or disruption of the macroautophagy machinery, impairing lysosomal sequestration and recycling of dysfunctional organelles and aggregated proteins, with consequent failure of cytoplasmic quality control and accumulation of cellular damage.

Why this is a genuine mechanism class. Macroautophagy is the clearance arm of proteostasis, and MONDO:0021179 proteostasis deficiencies explicitly names "degradation or clearance of misfolded proteins" in its own definition — yet all four of its current children (synucleinopathy, amyloidosis, TDP-43 proteinopathy, SQSTM1 multisystem proteinopathy) are aggregating-substrate classes. The machinery side of the parent's own definition has no representative. This node also gives VCP/SQSTM1 multisystem proteinopathy a mechanistic (rather than purely substrate-based) home, and is a designated hallmark of aging (López-Otín et al. 2023), which matters for MONDO's aging-related content.

Caveat, stated honestly: at 5 conformers this is the thinnest of the ten on dismech backing, and its members are common complex diseases (ALS, Parkinson) where autophagy failure is one contributing mechanism among several rather than the defining lesion. MONDO may prefer to scope the initial class tightly to the monogenic autophagy-machinery disorders (EPG5/Vici syndrome, WDR45/BPAN, VCP, SQSTM1, ATG7) and admit the complex diseases only via contributes_to-style relations rather than is_a. That would be a sounder class, and dismech should follow suit.

dismech provenance. kb/modules/disabled_macroautophagy.yaml — Autophagy Machinery Decline → Failure of Cytoplasmic Quality Control → Accumulated Cellular Damage and Age-Related Disease. 5 conforming disorder entries. Backing dismech grouping: Macroautophagy_Deficiency_Disorders (added in this PR; 5 members, NECESSARY, skos:broadMatch → MONDO:0021179, explicitly provisional pending the scoping decision in the caveat above). Note the 5 members are 4 distinct diseases — the VCP-MSP / IBMPFD pair is flagged in-file as substantially overlapping — and, counted at that same disease level, only 2 of the 4 carry no partial-mechanism caveat (3 of the 5 member entries, before the VCP pair collapses).

Candidate MONDO members (5 in dismech). MONDO:0008178 / MONDO:0000507 inclusion body myopathy with Paget disease of bone and frontotemporal dementia (VCP) · MONDO:0008029 Bethlem myopathy · MONDO:0004976 amyotrophic lateral sclerosis · MONDO:0005180 Parkinson disease. Recommended additions per the caveat above: Vici syndrome (EPG5), BPAN (WDR45), ATG7-related disorder. Conversely, MONDO:0008029 Bethlem myopathy is the first member that should drop under the tight-scoping recommendation: it is a COL6 extracellular-matrix defect in which the autophagy block is a downstream consequence rather than a primary lesion in the machinery. Note also that MONDO:0008178 and MONDO:0000507 are two distinct MONDO classes curated as two distinct dismech entries, not one entry with two ids.

MONDO gap evidence. "macroautophagy", "autophagy disorder": 0 hits across labels, synonyms, and definitions. "autophag" matches only 3 individual diseases (X-linked myopathy with excessive autophagy; infantile-onset autophagic vacuolar myopathy; one obsolete term) — and note these are excessive autophagy, the opposite direction, so they are not even candidate members.

3.10 BBSome-opathy

  • Proposed label: BBSome-opathy
  • Synonyms: BBSome complex disorder; BBSome trafficking disorder; disorder of BBSome-dependent ciliary trafficking
  • Proposed parents: MONDO:0005308 ciliopathy
  • Logical definition: no axiom recommended. (GO:0032465 — regulation of cytokinesis — appeared in an earlier draft and is simply wrong for this class; it is named here only so the discarded option is not re-proposed.) Prefer a complex-scoped textual definition, or — if GO gains a suitable term — a BBSome-mediated ciliary trafficking process. GO currently has GO:0034464 BBSome as a cellular component ("a ciliary protein complex involved in cilium biogenesis"), not a process, so the cleanest logical form is MONDO:0000001 and (RO:0004021 some <BBSome-dependent trafficking process>) pending a GO process term; a MONDO new-term request may need a paired GO request.

Definition. A ciliopathy caused by deficiency of a subunit, chaperonin-like assembly factor, or dedicated operator of the BBSome — the obligate eight-subunit complex that escorts signaling receptors and other cargo into and out of the primary cilium — producing failure of BBSome-dependent ciliary cargo trafficking.

Why this is a genuine mechanism class. MONDO's ciliopathy class is large and mechanistically heterogeneous: it lumps the motile-cilia dyskinesias, the transition-zone/IFT disorders, and the BBSome trafficking disorders into one undifferentiated bucket of 36 asserted children. The BBSome is a discrete, well-delimited molecular machine with a defined membership (BBS1, 2, 4, 5, 7, TTC8/8, 9, BBIP1/18; assembly factors MKKS/6, BBS10, BBS12; operators ARL6/3, LZTFL1/17), and its disorders share a distinctive phenotype — obesity, retinal degeneration, polydactyly, renal anomaly — that the transition-zone ciliopathies do not. This is the first natural molecular-machine subdivision of ciliopathy, and would set the pattern for IFT-opathy and transition-zone-opathy siblings.

dismech provenance. kb/modules/bbsome_trafficking.yaml — BBSome Subunit Deficiency / BBS Chaperonin Assembly Defect → Defective BBSome Assembly → BBSome Membrane Recruitment and Retrograde IFT Coupling → BBSome-Dependent Ciliary Cargo Trafficking Failure. 3 conforming disorder entries, plus the dismech BBSome-opathies grouping — which already records the gap explicitly, mapping to MONDO:0005308 ciliopathy with skos:broadMatch and the justification "MONDO has no dedicated 'BBSome machine disorder' node and the parent ciliopathy class is broader than this BBSome-scoped union."

Candidate MONDO members. Direct: MONDO:0015229 Bardet-Biedl syndrome · MONDO:0009367 McKusick-Kaufman syndrome · MONDO:0019200 retinitis pigmentosa (BBSome-related subset — narrow to the TTC8/BBS forms, not the whole class). MONDO's existing per-gene terms make this class immediately populous: MONDO:1040043 BBS1-related ciliopathy, MONDO:1040044 BBS4-related ciliopathy, MONDO:1040045 BBS12-related ciliopathy, MONDO:0700236 BBS9-related ciliopathy, plus the numbered Bardet-Biedl syndrome 1–22 series (restricted to BBSome-component genes; the non-BBSome BBS loci such as CEP290, SDCCAG8, IFT27 should stay under ciliopathy only).

MONDO gap evidence. "BBSome" / "bbsome": 0 hits across labels, synonyms, and definition text — despite MONDO carrying 25+ Bardet-Biedl and BBS*-related ciliopathy terms.

4. Summary table

# Proposed label Logical definition (verified GO) Proposed parent dismech module Conformers MONDO hits (label/syn/def)
1 intoxication-type inborn error of metabolism textual (proteostasis-deficiencies precedent) MONDO:7770011 + IEM metabolic_intoxication_decompensation 19 0 / 0 / 0
2 cardiac channelopathy RO:0004021 some GO:0086001 MONDO:7770011 + heart disorder cardiac_ion_channel_repolarization 12 0 / 0 / 0
3 FGFR-opathy RO:0004021 some GO:0008543 MONDO:7770011 + hereditary disease fgfr_gain_of_function_skeletal_dysplasia 11 0 / 0 / 1 (single disease)
4 synaptic vesicle cycle disorder RO:0004021 some GO:0099504 MONDO:0021017 synaptopathy synaptic_vesicle_cycle 9 0 / 0 / 0
5 centrosomopathy RO:0004021 some GO:0007098 MONDO:7770011 + hereditary disease neural_progenitor_centrosome_spindle_dysfunction 8 0 / 0 / 0
6 meiotic recombination failure disorder RO:0004021 some GO:0007131 MONDO:7770011 + reproductive meiotic_prophase_failure 7 0 / 0 / 0
7 Hedgehog pathway activation disease RO:0004021 some GO:0007224 MONDO:7770011 hedgehog_pathway_activation 5 0 / 0 / 0
8 polyglutamine expansion disease textual (proteostasis-deficiencies style; synucleinopathy/TDP-43 sibling precedent) MONDO:0021179 polyglutamine_expansion_proteotoxicity 4 (+grouping) 0 / 0 / 0
9 macroautophagy deficiency disorder RO:0004021 some GO:0016236 MONDO:0021179 disabled_macroautophagy 5 0 / 0 / 0
10 BBSome-opathy complex-scoped; GO process term needed MONDO:0005308 ciliopathy bbsome_trafficking 3 (+grouping) 0 / 0 / 0

Eight of the ten list MONDO:7770011 among their proposed parents — #1, #2, #3,

4, #5, #6, #7, and #9 — so adopting all ten would take

MONDO:7770011 disease by molecular mechanism from 5 to 13 direct children. Several are deliberately multi-parented: #4 also under MONDO:0021017 synaptopathy, #9 also under MONDO:0021179 proteostasis deficiencies. Only two do not attach to the mechanism axis directly — #8 (under proteostasis deficiencies) and #10 (under MONDO:0005308 ciliopathy).

Of those secondary parents, proteostasis deficiencies and ciliopathy are themselves children of MONDO:7770011, but MONDO:0021017 synaptopathy is not — it currently sits only under MONDO:0005071 nervous system disorder. Whether to place synaptopathy on the mechanism axis as part of adopting #4 is a separate question for MONDO, not something this proposal assumes.

5. Runners-up and side findings

Runners-up — real gaps, held back only by thinner dismech backing. All returned 0 MONDO hits on all three passes:

Candidate dismech module Conformers GO anchor
somite segmentation clock disorder axial_segmentation_serial_homology 3 GO:0001756 somitogenesis ✅
ectodysplasin-NF-κB pathway disease eda_edar_nfkb_ectodermal_appendage 4 GO term needs selection
molecular-mimicry post-infectious autoimmune disease molecular_mimicry_autoimmunity 3 — (only an obsolete MONDO term exists)
epithelial barrier dysfunction disease epithelial_barrier_dysfunction 4+1 —
serial-homology limb/digit patterning disorder limb_digit_patterning_serial_homology 3 —

The segmentation-clock candidate is the strongest of these on the MONDO side despite thin dismech backing: MONDO already has spondylocostal dysostosis 1–6 typed by the exact segmentation-clock genes (DLL3, MESP2, LFNG, HES7, TBX6), so the member set is pre-built and only the parent class is missing.

Side finding — unmapped dismech entries. Assembling the member lists surfaced entries that cannot be aligned to MONDO. Two distinct gaps, which an earlier draft conflated:

  • No top-level disease_term: at all — 19 files across the KB, including NDE1-related_Microcephaly_Lissencephaly, KATNB1-related_Cortical_Malformation, and TUBB_TUBB5-related_Microcephaly (all §3.5 members).
  • A disease_term: with a preferred_term but no bound term: id — e.g. MCM9-related_gametogenic_failure (§3.6), which carries disease_term: {preferred_term: MCM9-related gametogenic failure} and so is not missing the slot, only the identifier. An earlier draft wrongly listed it in the first category.

Measured against the KB at the time of writing (1,795 disorder files): 19 files with no top-level disease_term:, and 17 with no MONDO: identifier anywhere in the file. Both counts move as curation proceeds — re-measure before filing. These are dismech curation gaps (or genuine MONDO new-term candidates) and are worth their own issue, quoting the re-measured numbers rather than these.

6. Reproducing this analysis

Snapshot provenance. Every MONDO claim in this document (the five children of MONDO:7770011, the 240 RO:0004021 axioms, the obsoletion of MONDO:0021016, and all zero-hit results) was computed against a single local snapshot. MONDO publishes no version IRI date in the OAK SQLite build, so the snapshot is identified by fingerprint:

Property Value
Source OAK sqlite:obo:mondo (downloads the then-current release)
Fetched 2026-08-01
Local path $HOME/.data/oaklib/mondo.db (/root/.data/oaklib/mondo.db in this environment)
Labelled MONDO: classes 31,886
Deprecated MONDO: classes 3,968

Re-running against a later release may give different counts. Re-verify before filing any new-term request — the three-pass exclusion check below is the step that matters most, and it is only meaningful if it can actually be re-run.

# 0. Fingerprint the snapshot you are actually using, and compare to the table above.
MONDO_DB="$HOME/.data/oaklib/mondo.db"
uv run python -c "
import sqlite3, sys; c = sqlite3.connect(sys.argv[1])
q = lambda s: c.execute(s).fetchone()[0]
print('labelled classes:', q(\"SELECT count(*) FROM rdfs_label_statement WHERE subject LIKE 'MONDO:%'\"))
print('deprecated      :', q(\"SELECT count(*) FROM statements WHERE predicate='owl:deprecated' AND subject LIKE 'MONDO:%'\"))
" "$MONDO_DB"

# 1. MONDO mechanism axis — direct children of 'disease by molecular mechanism'
uv run python -c "
import sqlite3, sys; c = sqlite3.connect(sys.argv[1])
for r in c.execute(\"\"\"SELECT e.subject, s.value FROM edge e
  LEFT JOIN rdfs_label_statement s ON s.subject = e.subject
  WHERE e.object = 'MONDO:7770011' AND e.predicate = 'rdfs:subClassOf'\"\"\"): print(r)
" "$MONDO_DB"

# 2. Three-pass exclusion check for one mechanism phrase (label / synonym / definition)
uv run python -c "
import sqlite3, sys; c = sqlite3.connect(sys.argv[1]); pat = sys.argv[2].lower()
rows = c.execute(\"\"\"SELECT subject, value FROM statements WHERE value IS NOT NULL
  AND subject LIKE 'MONDO:%' AND predicate IN ('rdfs:label','oio:hasExactSynonym',
  'oio:hasRelatedSynonym','oio:hasBroadSynonym','oio:hasNarrowSynonym','IAO:0000115')\"\"\").fetchall()
hits = {s for s, v in rows if pat in v.lower()}
print(f'{sys.argv[2]!r}: {len(hits)} hit(s)'); [print(' ', h) for h in sorted(hits)[:10]]
" "$MONDO_DB" "BBSome"

# 3. dismech module backing — DISTINCT FILE count (the metric used in §2, §3 and §4)
grep -rl "conforms_to:.*bbsome_trafficking#" kb/disorders/ | wc -l

# 4. GO anchor verification
uv run runoak -i sqlite:obo:go info GO:0086001

7. Suggested next steps

  1. Review and prune. Ten is the requested count, not a claim that all ten are equally ready. #1–#7 are the strong set. #9 needs the scope decision described in its caveat; #10 may need a paired GO process request.
  2. ~~Mint dismech kb/groupings/ entries for the four proposals that lack one.~~ Done in this PR. All ten proposals now have a dismech grouping backing them, so membership is machine-auditable via just check-groupings before anything goes upstream:
Proposal Backing dismech grouping Status
#1 intoxication-type IEM Intoxication-Type_Inborn_Errors_of_Metabolism (19 members, NECESSARY) added here
#2 cardiac channelopathy Inherited_Arrhythmia_Syndromes (N&S criteria) pre-existing
#3 FGFR-opathy FGFR_Related_Skeletal_Dysplasias pre-existing
#4 synaptic vesicle cycle disorder Synaptic_Vesicle_Cycle_Disorders pre-existing
#5 centrosomopathy Centrosomopathies (8 members, NECESSARY) added here
#6 meiotic recombination failure Meiotic_Gametogenic_Failure pre-existing
#7 Hedgehog pathway activation disease Hedgehog_Pathway_Activation_Disorders (5 members, N&S) added here
#8 polyglutamine expansion disease Polyglutamine_Disorders pre-existing
#9 macroautophagy deficiency Macroautophagy_Deficiency_Disorders (5 members, NECESSARY) added here
#10 BBSome-opathy BBSome-opathies (already records the MONDO gap) pre-existing

Note #5's nearest existing groupings — Primary_Microcephaly_Spectrum and Lissencephaly_and_Neuronal_Migration_Disorders — are phenotype-scoped, not centrosome-scoped, which is why Centrosomopathies was minted as a new grouping rather than an edit to either. The four new groupings audit clean (37/37 members SATISFIED, zero violations, no unlisted candidates on the one N&S class). 3. File MONDO new-term requests one per node, each carrying: label, synonyms, textual definition, the RO:0004021 logical definition with its verified GO term, proposed parentage, and the candidate member list from §3. 4. Record skos: mappings back into dismech once terms are minted, following the pattern the BBSome-opathies grouping already uses (skos:broadMatch → MONDO:0005308 with a written justification).