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Mechanism-Based Disease Classes for MONDO, Round 2: Four New Proposals and a Status Update

Date: 2026-10-23 Builds on: mondo-mechanism-classification-proposal-2026-08-01.md (round 1, PR #7800) Scope: proposal only. No MONDO edits and no new-term requests have been filed.

Summary

Round 1 proposed ten mechanism-based classes for MONDO's MONDO:7770011 disease by molecular mechanism branch, each backed by a dismech mechanism module and a dismech grouping. None of the ten has been created in MONDO since, and the evidence behind every one of them has grown: each module now has more conforming entries than it did in August.

Re-running the round-1 selection over the current module set (198 modules, against 118 in August) finds four further classes that MONDO does not have:

Proposal Proposed label dismech module Germline members in dismech MONDO hits (label / synonym / definition)
11 membrane contact site disorder membrane_contact_site_dysfunction 9 0 / 0 / 1
12 mTORopathy mtorc1_hyperactivation 8 0 / 0 / 1
13 Mendelian disorder of the epigenetic machinery epigenetic_machinery_neurodevelopmental_dysregulation 26 0 / 0 / 0
14 hereditary desmosomopathy desmosomal_adhesion_failure 7 0 / 0 / 2

Numbering continues from round 1 so that "proposal 3" always means the same class. The definition-text hits are single diseases whose definitions mention the mechanism; they are listed under each proposal and none is a class.

Each proposal has a backing dismech grouping, so membership can be audited with just check-groupings before anything goes to MONDO: Membrane_Contact_Site_Disorders (proposal 11), mTORopathies (12), Mendelian_Disorders_of_the_Epigenetic_Machinery (13) and Hereditary_Desmosomopathies (14).

1. Status of the round-1 proposals

Checked against MONDO release 2026-10-06 (see section 5 for the snapshot).

Proposal Proposed label In MONDO? Conformers, Aug 2026 Conformers, Oct 2026
1 intoxication-type inborn error of metabolism no 19 24
2 cardiac channelopathy no 12 21
3 FGFR-opathy no 11 15
4 synaptic vesicle cycle disorder no 9 13
5 centrosomopathy no 8 12
6 meiotic recombination failure disorder no 7 14
7 Hedgehog pathway activation disease no 5 6
8 polyglutamine expansion disease no 4 8
9 macroautophagy deficiency disorder no 5 15
10 BBSome-opathy no 3 3

Conformers are distinct kb/disorders/ and kb/comorbidities/ files declaring conforms_to against the proposal's module, the same metric as round 1. A rise in conformers is not by itself a rise in germline members; for proposal 9 in particular, re-check which of the 15 are monogenic macroautophagy disorders before filing, as round 1's scoping note asked.

One change on the MONDO side. The mechanism branch now has six direct children, not five. The new one is MONDO:1060233 Mediator complex-related neurodevelopmental disorder, a class defined by a shared molecular machine rather than a phenotype. It is a close precedent for proposals 11 and 13.

Direct children of MONDO:7770011 (2026-10-06)
MONDO:0005308 ciliopathy
MONDO:0005574 tauopathy
MONDO:0019119 muscular channelopathy
MONDO:0021060 RASopathy
MONDO:0021179 proteostasis deficiencies
MONDO:1060233 Mediator complex-related neurodevelopmental disorder

2. How the new candidates were selected

The method is round 1's, section 2, unchanged except for one added step.

  1. Rank modules by the number of distinct disorder files conforming to them.
  2. Keep mechanism families. Drop modules that describe a phenotype, a physiological response or a drug mechanism (fibrotic response, seizure excitation-inhibition imbalance, antibiotic targets) rather than a shared molecular lesion.
  3. Exclude on an exact or near-synonym MONDO match in any of three passes: labels, all synonym types, and IAO:0000115 definitions. Adjacent partial matches do not exclude but are disclosed.
  4. New this round: count germline members only. Some modules mix hereditary and acquired conformers; the JAK-STAT module, for example, includes myeloproliferative neoplasms and lymphomas. A class under MONDO:7770011 is about inherited molecular lesions, so each candidate's member list keeps only germline (Mendelian) conformers, and the rest are listed as excluded.

Excluded because MONDO already has the class:

Candidate family dismech module MONDO class
type 1 interferonopathy innate_antiviral_interferon_response MONDO:0700264 type 1 interferonopathy
laminopathy none MONDO:0021106 laminopathy
telomere biology disorder telomere_attrition MONDO:0800467 dyskeratosis congenita and related telomere biology disorder

Excluded for other reasons: nlrp3_inflammasome_activation (7 conformers, mostly acquired: stroke, silicosis, multiple sclerosis, envenomation; the hereditary member, familial cold autoinflammatory syndrome, is already under MONDO's cryopyrin-associated periodic syndrome).

3. The four new proposals

3.1 Proposal 11: membrane contact site disorder

  • Proposed label: membrane contact site disorder
  • Synonyms: organelle contact site disorder; disorder of organelle tethering
  • Definition: A hereditary disease caused by loss or mis-regulation of a protein that tethers two organelle membranes at a membrane contact site, or that transfers lipids or calcium across one, resulting in disturbed lipid supply between organelles, calcium transfer into mitochondria, or organelle morphology and position.
  • Logical definition: textual only. Members fail at different steps: the tether itself (VAPB, ACBD5), lipid transfer across the contact (VPS13A, XK, CERT1) or calcium transfer (WFS1, PDZD8). A single RO:0004021 basis_in_disruption_of_process axiom on GO:0120009 intermembrane lipid transfer would exclude the calcium-transfer members, and one on GO:0140056 organelle localization by membrane tethering would exclude CERT1. The cellular component GO:0044232 organelle membrane contact site is the common factor, so a component-scoped axiom, as for proposal 10, would be the route if MONDO wants one.
  • Proposed parent: MONDO:7770011 disease by molecular mechanism
  • Why it is a family: contact sites are where organelles exchange lipids and calcium without vesicle traffic, and every organelle forms them (PMID:31732717). The disease genes encode the tethers and transfer proteins themselves, and the shared consequence is neural. Field definitions: PMID:30894536.
  • Members (dismech, all germline):
MONDO Disease Gene Organelle pair
MONDO:0100112 acyl-CoA binding domain containing protein 5 deficiency ACBD5 peroxisome-ER
MONDO:0008453 adult-onset proximal spinal muscular atrophy, autosomal dominant VAPB ER to many partners
MONDO:0008695 VPS13A-related neurodegenerative disease (chorea-acanthocytosis) VPS13A ER-mitochondria, ER-lipid droplet
MONDO:0018945 XK-related neurodegenerative disease (McLeod syndrome) XK ER-plasma membrane
MONDO:0014599 intellectual disability, autosomal dominant 34 CERT1 ER-Golgi
MONDO:0018105 Wolfram syndrome WFS1, CISD2 ER-mitochondria
MONDO:0700293 WFS1-related disorder WFS1 ER-mitochondria
MONDO:0859281 intellectual developmental disorder with autism and dysmorphic facies PDZD8 ER-mitochondria, ER-lysosome
MONDO:0014601 autosomal recessive spinocerebellar ataxia 20 SNX14 ER-lipid droplet

Candidates not yet in dismech or not yet conformed: MFN2-related Charcot-Marie-Tooth disease type 2A, SPG87 (TMEM63C), PACS2-related developmental and epileptic encephalopathy, Alkuraya-Kucinskas syndrome (BLTP1), VPS13B-related Cohen syndrome, VPS13C- and VPS13D-related disease. - MONDO gap evidence: "membrane contact site", "organelle contact" and "lipid transfer" return no label or synonym hit. "contact site" appears only in the definition of MONDO:0100112, one of the members. - dismech provenance: kb/modules/membrane_contact_site_dysfunction.yaml and kb/groupings/Membrane_Contact_Site_Disorders.yaml (9 members, all SATISFIED under a NECESSARY module-conformance criterion).

3.2 Proposal 12: mTORopathy

  • Proposed label: mTORopathy
  • Synonyms: mTORC1 hyperactivation disorder; GATORopathy (narrower: the GATOR1-complex members)
  • Definition: A hereditary disease caused by a germline or mosaic variant in a regulator of the mTORC1 pathway that leaves mTORC1 constitutively active, typically producing focal cortical malformation, epilepsy, hamartomas or overgrowth.
  • Logical definition: RO:0004021 some GO:0038202 TORC1 signaling. As round 1 section 1 explains, RO:0004021 does not encode the direction of the change, and the definition text carries "hyperactivation".
  • Proposed parent: MONDO:7770011 disease by molecular mechanism
  • Why it is a family: "mTORopathy" is established clinical usage for the disorders of TSC1/TSC2, PTEN, the GATOR1 complex (DEPDC5, NPRL2, NPRL3) and MTOR itself. They share focal cortical dysplasia, epilepsy responsive to mTOR inhibition, and somatic second-hit mosaicism.
  • Members (dismech, germline):
MONDO Disease Gene
MONDO:0001734 tuberous sclerosis TSC1, TSC2
MONDO:0017623 PTEN hamartoma tumor syndrome PTEN
MONDO:0016063 Cowden disease PTEN
MONDO:0007924 Bannayan-Riley-Ruvalcaba syndrome PTEN
MONDO:0020310 familial focal epilepsy with variable foci DEPDC5, NPRL2, NPRL3
MONDO:0000030 familial sleep-related hypermotor epilepsy (DEPDC5 form) DEPDC5
MONDO:0014201 developmental and epileptic encephalopathy, 18 SZT2
MONDO:0957960 Long-Olsen-Distelmaier syndrome RRAGC

Also in MONDO but not in dismech: MONDO:0100572 MTOR-related overgrowth spectrum and MONDO:0976294 ragopathy. Both are single diseases that would become children.

Excluded from the member list: lymphangioleiomyomatosis and perivascular epithelioid cell neoplasm (TSC-associated neoplasms that also occur sporadically) and Peutz-Jeghers polyp (a lesion, not a disease). DEPDC5-Related_Epilepsy is also left out of the table, but only because its dismech entry is anchored to the broad MONDO:0005384 focal epilepsy, following ClinGen's lumping. It is a germline DEPDC5 disorder, so the GATOR1 arm is better supported than the table alone shows. Boundary case: Peutz-Jeghers syndrome (STK11) acts through AMPK on mTORC1, and its defining features are polyposis and cancer risk rather than the cortical phenotype, so it is listed as a candidate for review rather than a member. - MONDO gap evidence: "mTORopathy" and "GATORopathy" return nothing. "mTORC1" appears only in the definition of MONDO:0976294 ragopathy, a single syndrome under MONDO:0002254 syndromic disease with no children. - dismech provenance: kb/modules/mtorc1_hyperactivation.yaml (13 conforming files, 8 germline members) and kb/groupings/mTORopathies.yaml. The grouping has 9 members: the 8 above plus DEPDC5-Related_Epilepsy, whose broad MONDO anchor matters for a MONDO member list but not for dismech. Sleep-related hypermotor epilepsy is listed as its DEPDC5 subtype only.

3.3 Proposal 13: Mendelian disorder of the epigenetic machinery

  • Proposed label: Mendelian disorder of the epigenetic machinery
  • Synonyms: disorder of the epigenetic machinery; chromatinopathy
  • Definition: A hereditary disease caused by a germline variant in a gene encoding a writer, eraser, reader or remodeler of chromatin marks or DNA methylation, typically presenting as intellectual disability with growth abnormality and characteristic facial features.
  • Logical definition: RO:0004021 some GO:0040029 epigenetic regulation of gene expression
  • Proposed parent: MONDO:7770011 disease by molecular mechanism
  • Why it is a family: this is the largest new family by membership. The disorders share a dosage-sensitive chromatin regulator, overlapping neurodevelopmental phenotypes, and disease-specific DNA methylation signatures ("episignatures") that are used clinically to classify variants.
  • Members (dismech, all germline, 26). Names are the common syndrome names; several MONDO labels are descriptive (for example MONDO:0014558 is "autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome"): MONDO:0016980 ATR-X-related syndrome (ATRX); MONDO:0014558 KAT6A syndrome; MONDO:0015022 BRPF1 syndrome; MONDO:0014205 ASXL3 deficiency (Bainbridge-Ropers syndrome); MONDO:0032922 Beck-Fahrner syndrome (TET3); MONDO:0010537 Borjeson-Forssman-Lehmann syndrome (PHF6); MONDO:0014150 developmental and epileptic encephalopathy 94 (CHD2); MONDO:0014017 CHD8 disorder; MONDO:0015452 Coffin-Siris syndrome (ARID1B, SMARCA4, SMARCB1); MONDO:0030012 Diets-Jongmans syndrome (KDM3B); MONDO:0970951 El Hayek-Chahrour neurodevelopmental disorder (KDM5A); MONDO:0020850 intellectual disability, autosomal recessive 65 (KDM5B); MONDO:0014751 KDM1A disorder; MONDO:0032790 KDM6B disorder; MONDO:0015004 dystonia 28 (KMT2B); MONDO:0016512 Kabuki syndrome (KMT2D, KDM6A); MONDO:0012455 Kleefstra syndrome (EHMT1); MONDO:0014791 Luscan-Lumish syndrome (SETD2); MONDO:0011053 Nicolaides-Baraitser syndrome (SMARCA2); MONDO:0032793 O'Donnell-Luria-Rodan syndrome (KMT2E); MONDO:0019188 Rubinstein-Taybi syndrome (CREBBP, EP300); MONDO:0014336 SETD5 haploinsufficiency; MONDO:0019349 Sotos syndrome (NSD1); MONDO:0010193 Weaver syndrome (EZH2); MONDO:0011518 Wiedemann-Steiner syndrome (KMT2A); MONDO:0016033 Cornelia de Lange syndrome (NIPBL).
  • Boundary to decide: Cornelia de Lange syndrome is a cohesin disorder. Cohesin shapes chromatin architecture and the syndrome has an episignature, but it is also the founding member of the "cohesinopathies", which MONDO does not have either. It can stay here or seed a sibling class.
  • Candidates not yet in dismech: Cohen-Gibson syndrome (MONDO:0060510, EED), a PRC2 disorder in the same family as Weaver syndrome.
  • MONDO gap evidence: "epigenetic machinery", "chromatinopathy", "chromatin regulator" and "chromatin modifier" return nothing in any pass.
  • dismech provenance: kb/modules/epigenetic_machinery_neurodevelopmental_dysregulation.yaml (26 conforming files, all germline) and kb/groupings/Mendelian_Disorders_of_the_Epigenetic_Machinery.yaml (26 members).

3.4 Proposal 14: hereditary desmosomopathy

  • Proposed label: hereditary desmosomopathy
  • Synonyms: desmosomal disease; cardiocutaneous desmosomal disorder (narrower)
  • Definition: A hereditary disease caused by a germline variant in a gene encoding a desmosomal protein, leading to loss of cell-cell adhesion in tissues under mechanical stress: skin, hair, oral mucosa and heart.
  • Logical definition: RO:0004021 some GO:0002934 desmosome organization
  • Proposed parent: MONDO:7770011 disease by molecular mechanism
  • Why it is a family: desmoplakin, plakoglobin, desmoglein and plakophilin variants give an overlapping cardiocutaneous pattern of palmoplantar keratoderma, woolly hair and arrhythmogenic cardiomyopathy, and the skin and hair signs can flag the cardiac risk.
  • Members (dismech, germline):
MONDO Disease Gene
MONDO:0011017 Naxos disease JUP
MONDO:0011581 arrhythmogenic cardiomyopathy with wooly hair and keratoderma DSP
MONDO:0014355 dilated cardiomyopathy with wooly hair, keratoderma, and tooth agenesis DSP
MONDO:0011882 skin fragility-woolly hair-palmoplantar keratoderma syndrome DSP
MONDO:0013034 keratosis palmoplantaris striata 2 DSP
MONDO:0013030 dilated cardiomyopathy 1BB DSG2
MONDO:0030986 blistering, acantholytic, of oral and laryngeal mucosa DSG3

Excluded: the pemphigus diseases (autoimmune attack on desmogleins, not hereditary) and Darier and Hailey-Hailey diseases (ATP2A2 and ATP2C1 calcium pumps; desmosome loss is downstream of the calcium defect). - Adjacent MONDO classes, disclosed: MONDO's arrhythmogenic cardiomyopathy classes are phenotype-defined and include non-desmosomal genes, so they overlap without being equivalent. "desmosom" appears only in the definitions of MONDO:0008017 and MONDO:0011581. - dismech provenance: kb/modules/desmosomal_adhesion_failure.yaml (13 conforming files, 7 germline) and kb/groupings/Hereditary_Desmosomopathies.yaml (7 members). A second HAS_GENE criterion over the desmosomal genes keeps the pemphigus and calcium-pump conformers out.

Runner-up: JAK-STAT gain-of-function inborn error of immunity

jak_stat_pathway_activation has 12 conformers, but most are neoplasms (myeloproliferative neoplasms, NK-cell leukemia, cutaneous T-cell lymphoma). The germline members are STAT6 gain-of-function hyper-IgE syndrome (MONDO:0957807), STAT4 disabling pansclerotic morphea (MONDO:0957497), SOCS1 haploinsufficiency (MONDO:0800130), autoinflammation with immune dysregulation and eosinophilia (MONDO:0033558), and the STAT1 gain-of-function form of chronic mucocutaneous candidiasis (MONDO:0015279, a broader class). MONDO has no JAK-STAT class (0 / 0 / 0 for "JAK-STAT" and "STAT gain"), but five members, one of them a broad class, is too thin to propose yet.

4. Next steps

  1. Review and prune proposals 11 to 14 alongside the round-1 queue. Round 1 was never filed. A single batch to MONDO covering the strongest of both rounds (round-1 proposals 1 to 7 and proposals 11 to 13 here) would let MONDO weigh the mechanism axis as a whole rather than one class at a time.
  2. Backing groupings are in place for proposals 11 to 14, so membership is auditable with just check-groupings, as it was for round 1.
  3. Settle the boundary cases: Peutz-Jeghers syndrome in proposal 12, Cornelia de Lange syndrome in proposal 13, and MFN2-related Charcot-Marie-Tooth disease for proposal 11, which needs a contact-site node in its dismech entry first.
  4. Re-check round-1 proposal 9 against its 15 current conformers before filing.

5. Reproducing this analysis

The MONDO checks used the OAK SQLite build fetched on 2026-10-23 ($HOME/.data/oaklib/mondo.db), fingerprinted as 36,017 labelled MONDO: classes and 3,980 deprecated. OLS reported release 2026-10-06 on the same day. Round 1's snapshot had 31,886 labelled classes, so counts from the two rounds are not directly comparable. Re-run before filing.

The commands are those in round 1, section 6. Round 1's step 3 counts conformers for one module; this command counts them for all modules at once:

python3 - <<'EOF'
import glob, re, collections, os
cnt = collections.defaultdict(set)
for f in glob.glob('kb/disorders/*.yaml') + glob.glob('kb/comorbidities/*.yaml'):
    for m in re.findall(r'conforms_to:\s*"?([A-Za-z0-9_\-]+)', open(f).read()):
        cnt[m].add(f)
for p in sorted(glob.glob('kb/modules/*.yaml')):
    m = os.path.basename(p)[:-5]
    print(f"{len(cnt.get(m, ()))}\t{m}")
EOF

Germline filtering was done by reading each conforming entry's category, genetic block and description; it is a judgement per entry, and the excluded entries are named under each proposal so the call can be checked.