Corneal Dystrophy

Mendelian MONDO:0018102 Pathograph 10 Show in embeddings browser Corneal disease Hereditary eye disease

Corneal dystrophy is the family of inherited, usually bilateral and progressive corneal opacifications that arise without inflammation or a preceding external insult. Abnormal material accumulates in, or the cells of, one layer of the cornea, and because the cornea's optical function depends on transparency, almost any such deposit eventually costs vision. Presentation ranges from lifelong asymptomatic opacity found on examination to recurrent corneal erosions with pain and photophobia, to progressive visual loss requiring keratoplasty. The family is organised by the corneal layer of origin. The International Committee for Classification of Corneal Dystrophies (IC3D) groups them into four anatomic categories: epithelial and subepithelial dystrophies, epithelial-stromal TGFBI dystrophies, stromal dystrophies, and endothelial dystrophies. The epithelial-stromal TGFBI group is the one category defined by a gene rather than purely by depth — allelic variants of TGFBI produce granular, lattice and Reis-Bucklers phenotypes that classical anatomic classification had scattered across layers, and pulling them together was the substantive change of the modern scheme. IC3D also grades each entity by how well established it is as a genuine dystrophy, from category 1 (well characterised clinically, histopathologically and genetically) down to category 4 (a suspected but not confirmed entity). That evidence grade is part of the classification rather than a commentary on it, and several long-standing named dystrophies have been reclassified or dissolved between editions. This root entry carries the family-level material — the anatomic axis, the evidence-grading convention, and the shared route from layer-specific deposition to loss of corneal transparency — together with the gene-defined IC3D category 1 entities that have no dismech entry of their own. Where an entity already has its own file, its detail is not re-derived here: see `TGFBI_Corneal_Dystrophies.yaml`, `Stromal_Corneal_Dystrophy.yaml`, `Fuchs_Endothelial_Corneal_Dystrophy.yaml`, `Posterior_Polymorphous_Corneal_Dystrophy.yaml`, `Schnyder_Corneal_Dystrophy.yaml` and `Pre-descemet_Corneal_Dystrophy.yaml`.

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8
Pathophys.
6
Phenotypes
2
Gaps
10
Pathograph
12
Subtypes
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Subtypes

12
anatomic
Epithelial and Subepithelial Dystrophies MONDO:0000763
IC3D anatomic category 1. Dystrophies of the corneal epithelium, its basement membrane and Bowman layer — epithelial basement membrane dystrophy, Meesmann corneal dystrophy (KRT12/KRT3), Lisch epithelial corneal dystrophy, gelatinous drop-like corneal dystrophy and the epithelial recurrent erosion dystrophies, which include a COL17A1-associated category 1 entity. Recurrent erosion is the characteristic symptom of this layer. No dismech entry yet.
  • MECD1
  • MECD2
  • GDLD
  • ERED
  • LECD
Stromal Dystrophies MONDO:0020213
IC3D anatomic category 3. Dystrophies in which abnormal material accumulates within the corneal stroma without a TGFBI basis — macular corneal dystrophy (CHST6, autosomal recessive), Schnyder corneal dystrophy (UBIAD1, corneal cholesterol and phospholipid deposition), fleck, congenital stromal and central cloudy dystrophy of Francois. Curated in `Stromal_Corneal_Dystrophy.yaml`, with Schnyder held separately in `Schnyder_Corneal_Dystrophy.yaml`.
  • FCD
Endothelial Dystrophies MONDO:0000766
IC3D anatomic category 4. Dystrophies of the corneal endothelium and Descemet membrane — Fuchs endothelial corneal dystrophy, posterior polymorphous corneal dystrophy, congenital hereditary endothelial dystrophy (SLC4A11) and X-linked endothelial corneal dystrophy. Mechanistically distinct from the other three categories: the endothelium is a non-regenerating pump, so its failure causes stromal oedema and loss of transparency rather than deposition of abnormal material. Curated in `Fuchs_Endothelial_Corneal_Dystrophy.yaml` and `Posterior_Polymorphous_Corneal_Dystrophy.yaml`.
  • CHED
genetic
Epithelial-Stromal TGFBI Dystrophies MONDO:0000764
TGFBI hgnc:11771 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TGFBI (hgnc:11771). hgnc:11771 is a gene from the HUGO Gene Nomenclature Committee.
IC3D anatomic category 2, and the one category defined by its gene. Allelic TGFBI variants produce Reis-Bucklers, Thiel-Behnke, lattice and granular corneal dystrophies, whose deposits span the epithelial basement membrane and anterior stroma. Fully curated in `TGFBI_Corneal_Dystrophies.yaml`.
entity
Meesmann corneal dystrophy 1 (KRT12) MONDO:0020791
KRT12 hgnc:6414 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in KRT12 (hgnc:6414). hgnc:6414 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Meesmann corneal dystrophy, the KRT12 form. Autosomal dominant fragility of the anterior corneal epithelium. KRT12 encodes one of the two cornea-specific keratins of the epithelial intermediate filament cytoskeleton, and the disease-causing substitutions fall in the conserved keratin helix boundary motifs where dominant mutations in other keratins are known to compromise cytoskeletal function.
Show evidence (1 reference)
PMID:9171831 SUPPORT Human Clinical
"Heterozygous missense mutations in K3 (E509K) and in K12 (V143L; R135T) completely co-segregated with MCD in the families and were not found in 100 normal unrelated chromosomes."
Co-segregation of a K12 missense variant with Meesmann corneal dystrophy, absent from 100 control chromosomes, is the original evidence that KRT12 causes this entity.
Meesmann corneal dystrophy 2 (KRT3) MONDO:0032904
KRT3 hgnc:6440 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in KRT3 (hgnc:6440). hgnc:6440 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Meesmann corneal dystrophy, the KRT3 form. KRT3 and KRT12 are the two cornea-specific keratins of the epithelial intermediate filament cytoskeleton, and the original gene report found the Meesmann phenotype segregating with either locus in different pedigrees — so the same disease arises from a variant in either gene. KRT3 sits in the type-II keratin cluster on chromosome 12 and KRT12 in the type-I cluster on chromosome 17.
Show evidence (2 references)
PMID:9171831 SUPPORT Human Clinical
"K3 was mapped to the type-II keratin gene cluster on 12q; and K12 to the type-I keratin cluster on 17q using radiation hybrids."
Places KRT3 and KRT12 in the type-II and type-I keratin clusters respectively, which is the basis for treating MECD1 and MECD2 as two loci for one phenotype rather than two diseases.
PMID:9171831 SUPPORT Human Clinical
"we also showed that the phenotype segregated with either the K12 or the K3 locus in two Northern Irish pedigrees"
Segregation with either locus in different pedigrees is the evidence that one phenotype has two loci, which is what MECD1 and MECD2 record.
Gelatinous drop-like corneal dystrophy (TACSTD2) MONDO:0008777
TACSTD2 hgnc:11530 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TACSTD2 (hgnc:11530). hgnc:11530 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
Autosomal recessive severe corneal amyloidosis leading to blindness. Three of the four variants in the original gene report are nonsense and one a frameshift, so the mechanism is loss of the encoded protein; raised, yellowish-grey gelatinous masses severely impair visual acuity by the third decade and lamellar keratoplasty is required in most patients. It is the only recessive entity among the epithelial and subepithelial rows curated here.
Show evidence (2 references)
PMID:10192395 SUPPORT Human Clinical
"Here we report DNA sequencing, cDNA cloning and mutational analyses of four deleterious mutations (Q118X, 632delA, Q207X and S170X) in M1S1 (formerly TROP2 and GA733-1), encoding a gastrointestinal tumour-associated antigen."
Original identification of the GDLD gene. Note the paper names it M1S1, which is HGNC's previous symbol for TACSTD2 (hgnc:11530); three of the four reported variants are nonsense and one a frameshift, so the mechanism is loss of protein.
PMID:10192395 SUPPORT Human Clinical
"By the third decade, raised, yellowish-grey, gelatinous masses severely impair visual acuity, and lamellar keratoplasty is required for most patients."
Source for the appearance of the deposits, the decade by which acuity is severely impaired, and the need for lamellar keratoplasty in most patients.
Epithelial recurrent erosion dystrophy (COL17A1) MONDO:0007381
COL17A1 hgnc:2194 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in COL17A1 (hgnc:2194). hgnc:2194 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Autosomal dominant recurrent breakdown of the corneal epithelium from childhood in the absence of an associated disease. IC3D edition 3 lists the COL17A1-associated form as category 1 and records that its signs and symptoms are similar to the category 4 entities Franceschetti corneal dystrophy, dystrophia Smolandiensis and dystrophia Helsinglandica. Biallelic COL17A1 loss instead causes junctional epidermolysis bullosa, so the dominant corneal phenotype is not simply a milder allelic dose.
Show evidence (2 references)
PMID:38359414 SUPPORT Human Clinical
"Epithelial recurrent erosion dystrophies now include epithelial recurrent erosion dystrophy, category 1 ( COL17A1 mutations, chromosome 10)."
IC3D edition 3 assigns the COL17A1-associated ERED evidence category 1, which is what makes it eligible as a curated entity here under this entry's stated rule of excluding category 3 and 4 entities.
PMID:25676728 SUPPORT Human Clinical
"Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology."
States both the gene and the authors' reading of the allelic mechanism as presumed gain of function, which is why dominant ERED is not the heterozygous state of recessive junctional epidermolysis bullosa.
Lisch epithelial corneal dystrophy (MCOLN1) MONDO:0010425
MCOLN1 hgnc:13356 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MCOLN1 (hgnc:13356). hgnc:13356 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Long reported as X-linked; IC3D edition 3 records that it has since been shown to be autosomal dominant with MCOLN1 variants on chromosome 19. The clinical description is taken from the bound MONDO term's own definition: feather-shaped opacities and microcysts in the corneal epithelium arranged in a band-shaped and sometimes whorled pattern, occasionally with impaired vision. MCOLN1 encodes mucolipin TRP cation channel 1 (HGNC:13356), whose biallelic loss causes mucolipidosis IV — a separate disease, and the only MCOLN1 relationship ClinGen has curated; how the corneal phenotype arises is not established, and no mechanism is asserted here.
Show evidence (1 reference)
PMID:38359414 SUPPORT Human Clinical
"Lisch epithelial corneal dystrophy, previously reported as X-linked, has been discovered to be autosomal dominant ( MCOLN1 mutations, chromosome 19)."
Sole source for both the gene and the correction of the inheritance mode. MONDO still carries "corneal dystrophy, Lisch epithelial, X-linked dominant" as a synonym of MONDO:0010425 while recording the MCOLN1 edge, so the ontology currently asserts both readings at once.
Congenital hereditary endothelial dystrophy (SLC4A11) MONDO:0009019
SLC4A11 hgnc:16438 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SLC4A11 (hgnc:16438). hgnc:16438 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
Autosomal recessive congenital failure of the corneal endothelium, presenting with corneal opacification and nystagmus; the bound MONDO term's definition adds a diffuse ground-glass appearance of the corneas and marked corneal thickening from birth. SLC4A11 encodes a membrane-bound sodium-borate cotransporter; the reported variants act by blocking membrane targeting or through nonsense-mediated decay, so the mechanism is loss of endothelial solute transport rather than deposition of abnormal material. Formerly called CHED2, after the dissolution of autosomal dominant CHED1.
Show evidence (1 reference)
PMID:16767101 SUPPORT Human Clinical
"We describe seven different mutations in the SLC4A11 gene in ten families with autosomal recessive CHED."
Seven variants across ten independent recessive CHED families is the original and still the principal evidence for the gene and for the recessive mode.
Fleck corneal dystrophy (PIKFYVE) MONDO:0007376
PIKFYVE hgnc:23785 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PIKFYVE (hgnc:23785). hgnc:23785 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Autosomal dominant scattering of numerous small white flecks through all layers of the corneal stroma. The bound MONDO term's definition characterises the opacities as asymptomatic and non-progressive with no effect on visual acuity, which is why this row carries no link to visual impairment. PIKFYVE (reported as PIP5K3 when the gene was identified) controls the morphogenesis and function of multivesicular bodies and the sorting of peripheral endosomes; the gene report states that the histological and clinical characteristics of affected patients are consistent with that endosomal sorting role, which is as far as the mechanistic claim goes.
Show evidence (1 reference)
PMID:15902656 SUPPORT Human Clinical
"Sequencing analysis disclosed missense, frameshift, and/or protein-truncating mutations in 8 of 10 families with CFD that were studied"
Variants in eight of ten fleck-dystrophy families establish the gene. The paper calls it PIP5K3, which HGNC records as the previous symbol for PIKFYVE (hgnc:23785).
Punctiform and polychromatic pre-Descemet corneal dystrophy (PRDX3) MONDO:0859248
PRDX3 hgnc:9354 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PRDX3 (hgnc:9354). hgnc:9354 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Autosomal dominant punctate polychromatic opacities immediately anterior to Descemet membrane, typically asymptomatic, caused by PRDX3 variants. IC3D edition 3 groups it with the pre-Descemet corneal dystrophies and grades it category 1, distinguishing it phenotypically from the category 4 entity pre-Descemet corneal dystrophy, which dismech curates separately in `Pre-descemet_Corneal_Dystrophy.yaml`. PRDX3 encodes peroxiredoxin 3 (HGNC:9354); how variants in it produce deep stromal deposits is not established, and no mechanism is asserted here.
Show evidence (1 reference)
PMID:38359414 SUPPORT Human Clinical
"Pre-Descemet corneal dystrophies include category 1, autosomal dominant, punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) ( PRDX3 mutations, chromosome 10)."
Gives the gene, the dominant mode and the category 1 evidence grade in one sentence, and separates PPPCD from the category 4 pre-Descemet entity.
?

Discussions and Knowledge Gaps

2
How should dismech represent an entity whose status as a distinct disease is itself graded by the source classification?
KNOWLEDGE GAP ic3d_evidence_category_is_part_of_the_classification
Attached to
pathophysiology#Layer-Restricted Corneal Deposition or Cellular Failure
IC3D assigns every corneal dystrophy an evidence category from 1 (well characterised clinically, histopathologically and genetically) to 4 (a suspected entity that may not be distinct), and revises those grades between editions. Entities have been dissolved on review — autosomal dominant CHED (CHED1) was found insufficiently distinct and reassigned to posterior polymorphous corneal dystrophy — and others have been promoted as genes were identified. dismech has no slot for "the source classification doubts this is a real disease", so an IC3D category 4 entity and a category 1 entity would be curated identically. This matters because MONDO carries descendants of `MONDO:0018102` that correspond to entities IC3D has since downgraded or merged, and curating them as subtypes would assert more confidence than the source does. No category 3 or 4 entity is curated as a subtype here.
Show evidence (2 references)
PMID:38359414 SUPPORT Human Clinical
"The new information was used to update the anatomic classification and each of the 22 standardized templates including the level of evidence for being a corneal dystrophy"
Establishes that the evidence grade is a maintained part of each entity's standardized template, not an informal aside.
PMID:25564336 SUPPORT Human Clinical
"The so-called autosomal dominant inherited CHED (formerly CHED1) is insufficiently distinct to continue to be considered a unique corneal dystrophy."
A worked instance of an entity being dissolved on review — the concrete case that makes this a curation problem rather than a theoretical one.
Should a disease that MONDO classifies as a corneal dystrophy, but that the source classification for corneal dystrophies does not recognise as one, be curated as a subtype here?
KNOWLEDGE GAP mondo_files_two_non_dystrophies_under_this_family
Attached to
has_subtypes#
Two descendants of MONDO:0018102 are curated neither as entity rows here nor as children of any anatomic category, and the reason is the same for both: the authoritative classification of the corneal dystrophies does not contain them. MONDO:0007848 autosomal dominant keratitis is a direct child of MONDO:0018102 with a PAX6 causal gene edge. Its reported features include corneal vascularization and foveal hypoplasia, neither of which is a corneal dystrophy finding — IC3D defines the dystrophies as non-inflammatory and cornea-restricted — and the gene-identification paper places it with the PAX6 anterior segment malformations rather than with the dystrophies. ClinGen curates PAX6 only as PAX6-related ocular dysgenesis (Definitive, autosomal dominant), and dismech's PAX6 home is Aniridia.yaml. Ruling: out of scope for this family; the concept belongs with the PAX6 ocular dysgenesis spectrum. MONDO:0014089 corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome is filed by MONDO under MONDO:0020212 superficial corneal dystrophy with an NLRP1 causal gene edge. It is a multisystem NLRP1 inflammasome disorder with palmoplantar and laryngeal involvement, and the corneal finding is one feature of a syndrome rather than an isolated dystrophy. The cached full text of IC3D edition 3 (PMID:38359414) contains no occurrence of "dyskeratosis" or of "NLRP1". Ruling: out of scope for this family; it would need its own entry as an NLRP1-related autoinflammatory syndrome, which dismech does not yet have. Both rulings are disagreements with MONDO's placement rather than with its gene edges, which are themselves well supported.
Show evidence (3 references)
PMID:7668281 SUPPORT Human Clinical
"Autosomal dominant keratitis (ADK) is an eye disorder chiefly characterized by corneal opacification and vascularization and by foveal hypoplasia."
The features that put autosomal dominant keratitis outside the corneal dystrophy definition: corneal vascularization, and a retinal malformation.
PMID:7668281 SUPPORT Human Clinical
"The finding that mutations in PAX6 underlie ADK, along with a recent report that mutations in PAX6 also underlie Peters anomaly, implicates PAX6 broadly in human anterior segment malformations."
The gene-identification paper's own placement of the disease, with Peters anomaly among the PAX6 anterior segment malformations rather than among the dystrophies.
PMID:38359414 SUPPORT Human Clinical
"The new information was used to update the anatomic classification and each of the 22 standardized templates including the level of evidence for being a corneal dystrophy"
Establishes that IC3D edition 3 enumerates the corneal dystrophies as a closed set of 22 templated entities, which is what makes an absence from it informative rather than merely an omission.
⚙

Pathophysiology

8
Layer-Restricted Corneal Deposition or Cellular Failure
Each dystrophy begins with an inherited defect expressed in one corneal layer, and the layer determines both the mechanism and the syndrome. In the epithelial, epithelial-stromal and stromal categories the lesion causes abnormal material to accumulate — mutant TGFBI protein in the epithelial-stromal group, abnormally sulphated keratan sulphate in macular dystrophy, cholesterol and phospholipid in Schnyder dystrophy. The endothelial category works differently: the corneal endothelium does not regenerate and functions as a dehydrating pump, so its progressive failure admits fluid into the stroma instead of depositing anything. Curating these as one node reflects a shared consequence, not a shared molecular mechanism.
TGFBI hgnc:11771 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TGFBI (hgnc:11771). hgnc:11771 is a gene from the HUGO Gene Nomenclature Committee. CHST6 hgnc:6938 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CHST6 (hgnc:6938). hgnc:6938 is a gene from the HUGO Gene Nomenclature Committee. UBIAD1 hgnc:30791 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves UBIAD1 (hgnc:30791). hgnc:30791 is a gene from the HUGO Gene Nomenclature Committee. SLC4A11 hgnc:16438 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC4A11 (hgnc:16438). hgnc:16438 is a gene from the HUGO Gene Nomenclature Committee. MCOLN1 hgnc:13356 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MCOLN1 (hgnc:13356). hgnc:13356 is a gene from the HUGO Gene Nomenclature Committee. PRDX3 hgnc:9354 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PRDX3 (hgnc:9354). hgnc:9354 is a gene from the HUGO Gene Nomenclature Committee.
cornea UBERON:0000964 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cornea (UBERON:0000964). UBERON:0000964 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Loss of Corneal Transparency Deposited material scatters light directly; endothelial pump failure does so indirectly by allowing the stroma to imbibe fluid and lose its ordered collagen spacing. Either route degrades the cornea's optical function.
Show evidence (3 references)
PMID:38359414 SUPPORT Human Clinical
"Lisch epithelial corneal dystrophy, previously reported as X-linked, has been discovered to be autosomal dominant ( MCOLN1 mutations, chromosome 19)."
Source for the MCOLN1 gene binding on this node. MCOLN1 and PRDX3 are carried here rather than on layer-specific nodes because the layer is known for each entity (epithelium for Lisch dystrophy, deep stroma for PPPCD) while the mechanism by which either gene produces its deposit is not, so a dedicated mechanism node would assert more than any source states.
PMID:38359414 SUPPORT Human Clinical
"Pre-Descemet corneal dystrophies include category 1, autosomal dominant, punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) ( PRDX3 mutations, chromosome 10)."
Source for the PRDX3 gene binding on this node, and for treating PPPCD as an established entity rather than a category 4 candidate.
PMID:25564336 SUPPORT Human Clinical
"On the basis of revisiting the cellular origin of corneal dystrophy, a modified anatomic classification is proposed consisting of (1) epithelial and subepithelial dystrophies, (2) epithelial-stromal TGFBI dystrophies, (3) stromal dystrophies, and (4) endothelial dystrophies."
States the four-category anatomic classification and, critically, that it was derived by revisiting the cellular origin of each dystrophy — which is what makes the corneal layer the organising principle rather than a descriptive convenience.
Loss of Corneal Transparency
The convergent node. Corneal transparency depends on regular collagen fibril spacing, a deturgesced stroma and an intact smooth epithelium; every dystrophy degrades at least one of these. The result is corneal opacity, with or without stromal oedema depending on whether the endothelium is the affected layer.
cornea UBERON:0000964 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cornea (UBERON:0000964). UBERON:0000964 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Progressive Visual Impairment Requiring Surgical Restoration Once opacity or oedema crosses the visual axis, optical correction cannot compensate and restoring vision requires physically removing or replacing the affected layer.
Show evidence (1 reference)
PMID:38359414 SUPPORT Human Clinical
"Deposition of opaque substances in epithelial, subepithelial, epithelial-stromal TGFBI or stromal corneal dystrophies may also result in vision reduction. Visual loss may also occur in endothelial corneal dystrophies because of corneal epithelial or stromal edema consequent to endothelial dysfunction."
Establishes that loss of vision is the shared endpoint of both routes into this node — opaque deposition in three categories, and edema from endothelial dysfunction in the fourth.
Progressive Visual Impairment Requiring Surgical Restoration
The clinical endpoint. Management escalates from lubricants, hyperosmotic agents and bandage contact lenses, through phototherapeutic or lamellar keratectomy, to keratoplasty. Because the dystrophies are layer-restricted, layer-selective grafts (anterior lamellar for anterior disease, endothelial keratoplasty for endothelial disease) are now preferred over penetrating keratoplasty — the anatomic classification maps directly onto the choice of operation. Recurrence in the graft is possible because the genetic defect persists in the host.
Show evidence (1 reference)
PMID:28583694 SUPPORT Human Clinical
"Anterior lamellar or endothelial keratoplasty are now preferred to penetrating keratoplasty, although the latter still remains the only possible option in some cases."
Documents the preference for lamellar and endothelial keratoplasty over penetrating keratoplasty, while noting the latter remains necessary in some cases.
Cornea-Specific Keratin Filament Fragility
The Meesmann mechanism. The intermediate filament cytoskeleton of the corneal epithelium is built from the cornea-specific pair K3 and K12; a heterozygous substitution in either, falling in a conserved keratin helix boundary motif, leaves the anterior epithelium mechanically fragile. A dominant-negative effect on the filament is the hypothesis the gene report set out to test, and is presented there as such rather than demonstrated. This is the same class of lesion that produces keratinocyte fragility phenotypes in skin keratins, restricted here to the one tissue where K3 and K12 are expressed.
corneal epithelial cell CL:0000575 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves corneal epithelial cell (CL:0000575). CL:0000575 is a cell type from the Cell Ontology.
KRT12 hgnc:6414 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KRT12 (hgnc:6414). hgnc:6414 is a gene from the HUGO Gene Nomenclature Committee. KRT3 hgnc:6440 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KRT3 (hgnc:6440). hgnc:6440 is a gene from the HUGO Gene Nomenclature Committee.
keratin filament GO:0045095 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves keratin filament (GO:0045095). GO:0045095 is a cellular component from the Gene Ontology.
corneal epithelium UBERON:0001772 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in corneal epithelium (UBERON:0001772). UBERON:0001772 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Recurrent Corneal Erosions A mechanically fragile epithelium separates from its bed under ordinary shear. Erosion episodes occur in Meesmann dystrophy, and this edge records that; it does not claim they are the dystrophy's most frequent presentation, which the cited source does not address.
Show evidence (2 references)
PMID:9171831 SUPPORT Human Clinical
"Meesmann's corneal dystrophy (MCD) is an autosomal dominant disorder causing fragility of the anterior corneal epithelium, where K3 and K12 are specifically expressed."
Establishes the node's three claims together: the affected layer is the anterior corneal epithelium, the lesion is fragility, and the two keratins are expressed specifically there.
PMID:9171831 SUPPORT Human Clinical
"All mutations occur in the highly conserved keratin helix boundary motifs, where dominant mutations in other keratins have been found to severely compromise cytoskeletal function, leading to keratinocyte fragility phenotypes."
Supports the dominant-negative reading and the comparison with skin keratin fragility disorders, which is the argument for a cytoskeletal rather than a depositional mechanism.
Epithelial Basement Membrane Adhesion Failure
The ERED mechanism. COL17A1 encodes collagen type XVII alpha 1 chain, and the route from it to recurrent corneal erosion is read here from the allelic contrast rather than asserted directly: biallelic COL17A1 loss causes junctional epidermolysis bullosa, a recessive disorder of epithelial attachment in which recurrent corneal erosions are reported, while dominant COL17A1 variants produce corneal erosion alone. The authors of the ERED gene report read the dominant variants as presumed gain of function rather than as a heterozygous dose of the recessive lesion.
COL17A1 hgnc:2194 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COL17A1 (hgnc:2194). hgnc:2194 is a gene from the HUGO Gene Nomenclature Committee.
corneal epithelium UBERON:0001772 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in corneal epithelium (UBERON:0001772). UBERON:0001772 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Recurrent Corneal Erosions Failure of epithelial attachment at the basement membrane is expressed clinically as repeated epithelial breakdown. The MONDO:0007381 definition characterises ERED by recurrent episodes of epithelial erosions from childhood in the absence of associated diseases; the evidence below reaches the dominant corneal entity by way of the recessive skin disorder, because that is where loss of collagen XVII function has been shown to produce corneal erosion.
Show evidence (2 references)
PMID:25676728 SUPPORT Human Clinical
"Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology."
The gene and the allelic mechanism, stated by the authors as a presumption rather than a demonstration, which is how it is represented here.
PMID:25676728 SUPPORT Human Clinical
"Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases."
Supports the allelic contrast in the description, and independently supports that loss of collagen XVII function produces recurrent corneal erosion.
Subepithelial Corneal Amyloid Deposition
The gelatinous drop-like mechanism. Three nonsense variants and one frameshift in TACSTD2 (reported as M1S1) were found in the original gene study, so the mechanism is loss of the encoded protein; severe corneal amyloidosis follows, presenting as raised yellowish-grey gelatinous masses that severely impair acuity by the third decade. The truncated protein itself aggregates in the perinuclear region of the cell that makes it, where the normal protein is distributed diffusely through the cytoplasm — so the intracellular aggregate and the subepithelial amyloid deposit are recorded as two observations rather than collapsed into one process.
TACSTD2 hgnc:11530 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TACSTD2 (hgnc:11530). hgnc:11530 is a gene from the HUGO Gene Nomenclature Committee.
corneal amyloid fibril formation GO:1990000 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased corneal amyloid fibril formation, annotated with amyloid fibril formation (GO:1990000). GO:1990000 is a biological process from the Gene Ontology. ↑ INCREASED
cornea UBERON:0000964 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cornea (UBERON:0000964). UBERON:0000964 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Corneal Opacity The subepithelial amyloid masses are themselves the opacity, which is why gelatinous drop-like dystrophy is visible as mounded milky-white nodules rather than as diffuse haze.
Loss of Corneal Transparency Amyloid in the visual axis scatters light directly, and the resulting loss of transparency is severe enough that lamellar keratoplasty is required in most patients.
Show evidence (2 references)
PMID:10192395 SUPPORT Human Clinical
"Gelatinous drop-like corneal dystrophy (GDLD; OMIM 204870) is an autosomal recessive disorder characterized by severe corneal amyloidosis leading to blindness, with an incidence of 1 in 300,000 in Japan."
Names corneal amyloidosis as the defining lesion, which is what the amyloid fibril formation binding on this node asserts, and gives the recessive mode.
PMID:10192395 SUPPORT Human Clinical
"Protein expression analysis revealed aggregation of the mutated, truncated protein in the perinuclear region, whereas the normal protein was distributed diffusely in the cytoplasm with a homogenous or fine granular pattern."
Supports the distinction drawn in the description between intracellular aggregation of the truncated gene product and the extracellular amyloid deposit.
Corneal Stromal Endosomal Sorting Defect
The fleck dystrophy mechanism. PIKFYVE (identified as PIP5K3) governs the morphogenesis and function of multivesicular bodies and the sorting of peripheral endosomes carrying cargo destined for lysosomes; missense, frameshift and protein-truncating variants leave discrete white flecks scattered through the full thickness of the stroma. The node is named for the compartment rather than for a cell type: the gene report goes no further than saying the histological and clinical findings are consistent with a role in endosomal sorting.
PIKFYVE hgnc:23785 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PIKFYVE (hgnc:23785). hgnc:23785 is a gene from the HUGO Gene Nomenclature Committee.
multivesicular body sorting of endosomal cargo GO:0032509 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal multivesicular body sorting of endosomal cargo, annotated with endosome transport via multivesicular body sorting pathway (GO:0032509). GO:0032509 is a biological process from the Gene Ontology. ⚠ ABNORMAL
corneal stroma UBERON:0001777 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in corneal stroma, annotated with substantia propria of cornea (UBERON:0001777). UBERON:0001777 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Corneal Opacity The flecks are discrete stromal opacities distributed through every layer, and they are the whole of the corneal finding in this dystrophy.
Show evidence (2 references)
PMID:15902656 SUPPORT Human Clinical
"PIP5K3 is a member of the phosphoinositide 3-kinase family and regulates the sorting and traffic of peripheral endosomes that contain lysosomally directed fluid phase cargo, by controlling the morphogenesis and function of multivesicular bodies."
The multivesicular-body sorting binding on this node is taken from this sentence, which names both the pathway and the gene's role in it.
PMID:15902656 SUPPORT Human Clinical
"The histological and clinical characteristics of patients with CFD are consistent with biochemical studies of PIP5K3 that indicate a role in endosomal sorting."
The authors' own statement of how far the mechanistic claim goes: the phenotype is consistent with an endosomal sorting role, not demonstrated to follow from it.
Corneal Endothelial Sodium-Borate Cotransport Failure
The congenital hereditary endothelial dystrophy mechanism, and the one lesion in this entry whose route to lost transparency is oedema rather than deposition. SLC4A11 encodes a membrane-bound sodium-borate cotransporter; the recessive variants cause loss of function either by blocking its membrane targeting or through nonsense-mediated decay. The consequence is corneal opacification, and IC3D edition 3 states the route for the endothelial category as a whole: visual loss follows corneal epithelial or stromal edema consequent to endothelial dysfunction, rather than deposition of abnormal material. This entity is congenital, which separates it from the endothelial dystrophies of later life.
corneal endothelial cell CL:0000132 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves corneal endothelial cell (CL:0000132). CL:0000132 is a cell type from the Cell Ontology.
SLC4A11 hgnc:16438 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC4A11 (hgnc:16438). hgnc:16438 is a gene from the HUGO Gene Nomenclature Committee.
borate transmembrane transport GO:0035445 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased borate transmembrane transport (GO:0035445). GO:0035445 is a biological process from the Gene Ontology. ↓ DECREASED
corneal endothelium UBERON:0001985 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in corneal endothelium (UBERON:0001985). UBERON:0001985 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Corneal Opacity A non-functioning endothelial pump lets the stroma imbibe fluid, and the cornea is diffusely opacified from birth rather than acquiring opacity progressively.
Loss of Corneal Transparency Endothelial failure reaches the family's convergent node by the oedema route rather than the deposition route, which is the mechanistic divergence this entry's trigger node already flags.
Show evidence (2 references)
PMID:16767101 SUPPORT Human Clinical
"Mutations in SLC4A11, which encodes a membrane-bound sodium-borate cotransporter, cause loss of function of the protein either by blocking its membrane targeting or nonsense-mediated decay."
Gives both the transported solute, which is what the borate transport binding asserts, and the two routes to loss of function stated in the description.
PMID:16767101 SUPPORT Human Clinical
"Congenital hereditary endothelial dystrophy (CHED) is a heritable, bilateral corneal dystrophy characterized by corneal opacification and nystagmus."
Identifies the affected layer as the endothelium and names corneal opacification as the clinical consequence.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Corneal Dystrophy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Corneal Dystrophy Ophthalmic HP:0001131 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Corneal dystrophy (HP:0001131), qualified as course progressive. HP:0001131 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Corneal Opacity Ophthalmic HP:0007957 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Corneal opacity (HP:0007957). HP:0007957 is a phenotype from the Human Phenotype Ontology.
Recurrent Corneal Erosions Ophthalmic HP:0000495 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent corneal erosions (HP:0000495), qualified as temporality recurrent. HP:0000495 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Corneal Stromal Edema Ophthalmic HP:0012040 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Corneal stromal edema (HP:0012040). HP:0012040 is a phenotype from the Human Phenotype Ontology.
Visual Impairment Ophthalmic HP:0000505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visual impairment (HP:0000505), qualified as course progressive. HP:0000505 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Photophobia Ophthalmic HP:0000613 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Photophobia (HP:0000613). HP:0000613 is a phenotype from the Human Phenotype Ontology.
📊

Prevalence

1
General population
Point Prevalence 90.0 per 100,000 >1 in 1,000
Reported as approximately 0.09% of the population, normalised here to 90 per 100,000. Covers the corneal dystrophies as a class; individual entities range from relatively common (epithelial basement membrane dystrophy, Fuchs) to fewer than a dozen reported families.
Show evidence (1 reference)
PMID:28583694 SUPPORT Human Clinical
"Corneal dystrophies affect approximately 0.09% of the population."
Gives a class-level population prevalence figure for the corneal dystrophies.
{ }

Source YAML

click to show 
name: Corneal Dystrophy
creation_date: '2026-08-19T12:00:00Z'
category: Mendelian
description: >
  Corneal dystrophy is the family of inherited, usually bilateral and progressive
  corneal opacifications that arise without inflammation or a preceding external
  insult. Abnormal material accumulates in, or the cells of, one layer of the cornea,
  and because the cornea's optical function depends on transparency, almost any such
  deposit eventually costs vision. Presentation ranges from lifelong asymptomatic
  opacity found on examination to recurrent corneal erosions with pain and photophobia,
  to progressive visual loss requiring keratoplasty.

  The family is organised by the corneal layer of origin. The International Committee
  for Classification of Corneal Dystrophies (IC3D) groups them into four anatomic
  categories: epithelial and subepithelial dystrophies, epithelial-stromal TGFBI
  dystrophies, stromal dystrophies, and endothelial dystrophies. The
  epithelial-stromal TGFBI group is the one category defined by a gene rather than
  purely by depth — allelic variants of TGFBI produce granular, lattice and
  Reis-Bucklers phenotypes that classical anatomic classification had scattered across
  layers, and pulling them together was the substantive change of the modern scheme.

  IC3D also grades each entity by how well established it is as a genuine dystrophy,
  from category 1 (well characterised clinically, histopathologically and genetically)
  down to category 4 (a suspected but not confirmed entity). That evidence grade is
  part of the classification rather than a commentary on it, and several long-standing
  named dystrophies have been reclassified or dissolved between editions.

  This root entry carries the family-level material — the anatomic axis, the
  evidence-grading convention, and the shared route from layer-specific deposition to
  loss of corneal transparency — together with the gene-defined IC3D category 1 entities
  that have no dismech entry of their own. Where an entity already has its own file, its
  detail is not re-derived here: see `TGFBI_Corneal_Dystrophies.yaml`,
  `Stromal_Corneal_Dystrophy.yaml`, `Fuchs_Endothelial_Corneal_Dystrophy.yaml`,
  `Posterior_Polymorphous_Corneal_Dystrophy.yaml`,
  `Schnyder_Corneal_Dystrophy.yaml` and `Pre-descemet_Corneal_Dystrophy.yaml`.
disease_term:
  preferred_term: corneal dystrophy
  term:
    id: MONDO:0018102
    label: corneal dystrophy
synonyms:
- hereditary corneal dystrophy
- corneal dystrophies
categories:
- Ophthalmic Disorder
- Hereditary Eye Disease
parents:
- Corneal disease
- Hereditary eye disease

has_subtypes:
- name: Epithelial and Subepithelial
  display_name: Epithelial and Subepithelial Dystrophies
  classification: anatomic
  description: >-
    IC3D anatomic category 1. Dystrophies of the corneal epithelium, its basement
    membrane and Bowman layer — epithelial basement membrane dystrophy, Meesmann
    corneal dystrophy (KRT12/KRT3), Lisch epithelial corneal dystrophy, gelatinous
    drop-like corneal dystrophy and the epithelial recurrent erosion dystrophies,
    which include a COL17A1-associated category 1 entity. Recurrent erosion is the
    characteristic symptom of this layer. No dismech entry yet.
  subtype_term:
    preferred_term: epithelial and subepithelial corneal dystrophy
    term:
      id: MONDO:0000763
      label: epithelial and subepithelial corneal dystrophy
  children:
  - MECD1
  - MECD2
  - GDLD
  - ERED
  - LECD
- name: Epithelial-Stromal TGFBI
  display_name: Epithelial-Stromal TGFBI Dystrophies
  classification: genetic
  description: >-
    IC3D anatomic category 2, and the one category defined by its gene. Allelic TGFBI
    variants produce Reis-Bucklers, Thiel-Behnke, lattice and granular corneal
    dystrophies, whose deposits span the epithelial basement membrane and anterior
    stroma. Fully curated in `TGFBI_Corneal_Dystrophies.yaml`.
  subtype_term:
    preferred_term: epithelial-stromal TGFBI dystrophy
    term:
      id: MONDO:0000764
      label: epithelial-stromal TGFBI dystrophy
  genes:
  - preferred_term: TGFBI
    term:
      id: hgnc:11771
      label: TGFBI
- name: Stromal
  display_name: Stromal Dystrophies
  classification: anatomic
  description: >-
    IC3D anatomic category 3. Dystrophies in which abnormal material accumulates within
    the corneal stroma without a TGFBI basis — macular corneal dystrophy (CHST6,
    autosomal recessive), Schnyder corneal dystrophy (UBIAD1, corneal cholesterol and
    phospholipid deposition), fleck, congenital stromal and central cloudy dystrophy of
    Francois. Curated in `Stromal_Corneal_Dystrophy.yaml`, with Schnyder held separately
    in `Schnyder_Corneal_Dystrophy.yaml`.
  subtype_term:
    preferred_term: stromal corneal dystrophy
    term:
      id: MONDO:0020213
      label: stromal corneal dystrophy
  children:
  - FCD
- name: Endothelial
  display_name: Endothelial Dystrophies
  classification: anatomic
  description: >-
    IC3D anatomic category 4. Dystrophies of the corneal endothelium and Descemet
    membrane — Fuchs endothelial corneal dystrophy, posterior polymorphous corneal
    dystrophy, congenital hereditary endothelial dystrophy (SLC4A11) and X-linked
    endothelial corneal dystrophy. Mechanistically distinct from the other three
    categories: the endothelium is a non-regenerating pump, so its failure causes
    stromal oedema and loss of transparency rather than deposition of abnormal
    material. Curated in `Fuchs_Endothelial_Corneal_Dystrophy.yaml` and
    `Posterior_Polymorphous_Corneal_Dystrophy.yaml`.
  subtype_term:
    preferred_term: corneal endothelial dystrophy
    term:
      id: MONDO:0000766
      label: corneal endothelial dystrophy
  children:
  - CHED
- name: MECD1
  display_name: Meesmann corneal dystrophy 1 (KRT12)
  classification: entity
  description: >-
    Meesmann corneal dystrophy, the KRT12 form. Autosomal dominant fragility of the
    anterior corneal epithelium. KRT12 encodes one of the two cornea-specific keratins of
    the epithelial intermediate filament cytoskeleton, and the disease-causing substitutions
    fall in the conserved keratin helix boundary motifs where dominant mutations in other
    keratins are known to compromise cytoskeletal function.
  subtype_term:
    preferred_term: corneal dystrophy, Meesmann, 1
    term:
      id: MONDO:0020791
      label: corneal dystrophy, Meesmann, 1
  genes:
  - preferred_term: KRT12
    term:
      id: hgnc:6414
      label: KRT12
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:9171831
    reference_title: "Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous missense mutations in K3 (E509K) and in K12 (V143L; R135T) completely co-segregated with MCD in the families and were not found in 100 normal unrelated chromosomes."
    explanation: >-
      Co-segregation of a K12 missense variant with Meesmann corneal dystrophy, absent
      from 100 control chromosomes, is the original evidence that KRT12 causes this
      entity.
- name: MECD2
  display_name: Meesmann corneal dystrophy 2 (KRT3)
  classification: entity
  description: >-
    Meesmann corneal dystrophy, the KRT3 form. KRT3 and KRT12 are the two
    cornea-specific keratins of the epithelial intermediate filament cytoskeleton, and the
    original gene report found the Meesmann phenotype segregating with either locus in
    different pedigrees — so the same disease arises from a variant in either gene. KRT3
    sits in the type-II keratin cluster on chromosome 12 and KRT12 in the type-I cluster on
    chromosome 17.
  subtype_term:
    preferred_term: corneal dystrophy, Meesmann, 2
    term:
      id: MONDO:0032904
      label: corneal dystrophy, Meesmann, 2
  genes:
  - preferred_term: KRT3
    term:
      id: hgnc:6440
      label: KRT3
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:9171831
    reference_title: "Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "K3 was mapped to the type-II keratin gene cluster on 12q; and K12 to the type-I keratin cluster on 17q using radiation hybrids."
    explanation: >-
      Places KRT3 and KRT12 in the type-II and type-I keratin clusters respectively,
      which is the basis for treating MECD1 and MECD2 as two loci for one phenotype
      rather than two diseases.
  - reference: PMID:9171831
    reference_title: "Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we also showed that the phenotype segregated with either the K12 or the K3 locus in two Northern Irish pedigrees"
    explanation: >-
      Segregation with either locus in different pedigrees is the evidence that one
      phenotype has two loci, which is what MECD1 and MECD2 record.
- name: GDLD
  display_name: Gelatinous drop-like corneal dystrophy (TACSTD2)
  classification: entity
  description: >-
    Autosomal recessive severe corneal amyloidosis leading to blindness. Three of the four
    variants in the original gene report are nonsense and one a frameshift, so the mechanism
    is loss of the encoded protein; raised, yellowish-grey gelatinous masses severely impair
    visual acuity by the third decade and lamellar keratoplasty is required in most
    patients. It is the only recessive entity among the epithelial and subepithelial rows
    curated here.
  subtype_term:
    preferred_term: gelatinous drop-like corneal dystrophy
    term:
      id: MONDO:0008777
      label: gelatinous drop-like corneal dystrophy
  genes:
  - preferred_term: TACSTD2
    term:
      id: hgnc:11530
      label: TACSTD2
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:10192395
    reference_title: Identification of the gene responsible for gelatinous drop-like corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report DNA sequencing, cDNA cloning and mutational analyses of four deleterious mutations (Q118X, 632delA, Q207X and S170X) in M1S1 (formerly TROP2 and GA733-1), encoding a gastrointestinal tumour-associated antigen."
    explanation: >-
      Original identification of the GDLD gene. Note the paper names it M1S1, which is
      HGNC's previous symbol for TACSTD2 (hgnc:11530); three of the four reported
      variants are nonsense and one a frameshift, so the mechanism is loss of protein.
  - reference: PMID:10192395
    reference_title: Identification of the gene responsible for gelatinous drop-like corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By the third decade, raised, yellowish-grey, gelatinous masses severely impair visual acuity, and lamellar keratoplasty is required for most patients."
    explanation: >-
      Source for the appearance of the deposits, the decade by which acuity is severely
      impaired, and the need for lamellar keratoplasty in most patients.
- name: ERED
  display_name: Epithelial recurrent erosion dystrophy (COL17A1)
  classification: entity
  description: >-
    Autosomal dominant recurrent breakdown of the corneal epithelium from childhood in the
    absence of an associated disease. IC3D edition 3 lists the COL17A1-associated form as
    category 1 and records that its signs and symptoms are similar to the category 4
    entities Franceschetti corneal dystrophy, dystrophia Smolandiensis and dystrophia
    Helsinglandica. Biallelic COL17A1 loss instead causes junctional epidermolysis
    bullosa, so the dominant corneal phenotype is not simply a milder allelic dose.
  subtype_term:
    preferred_term: epithelial recurrent erosion dystrophy
    term:
      id: MONDO:0007381
      label: epithelial recurrent erosion dystrophy
  genes:
  - preferred_term: COL17A1
    term:
      id: hgnc:2194
      label: COL17A1
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:38359414
    reference_title: IC3D Classification of Corneal Dystrophies-Edition 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epithelial recurrent erosion dystrophies now include epithelial recurrent erosion dystrophy, category 1 ( COL17A1 mutations, chromosome 10)."
    explanation: >-
      IC3D edition 3 assigns the COL17A1-associated ERED evidence category 1, which is
      what makes it eligible as a curated entity here under this entry's stated rule of
      excluding category 3 and 4 entities.
  - reference: PMID:25676728
    reference_title: "Mutations in collagen, type XVII, alpha 1 (COL17A1) cause epithelial recurrent erosion dystrophy (ERED)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology."
    explanation: >-
      States both the gene and the authors' reading of the allelic mechanism as
      presumed gain of function, which is why dominant ERED is not the heterozygous
      state of recessive junctional epidermolysis bullosa.
- name: LECD
  display_name: Lisch epithelial corneal dystrophy (MCOLN1)
  classification: entity
  description: >-
    Long reported as X-linked; IC3D edition 3 records that it has since been shown to be
    autosomal dominant with MCOLN1 variants on chromosome 19. The clinical description is
    taken from the bound MONDO term's own definition: feather-shaped opacities and microcysts
    in the corneal epithelium arranged in a band-shaped and sometimes whorled pattern,
    occasionally with impaired vision. MCOLN1 encodes mucolipin TRP cation channel 1
    (HGNC:13356), whose biallelic loss causes mucolipidosis IV — a separate disease, and the
    only MCOLN1 relationship ClinGen has curated; how the corneal phenotype arises is not
    established, and no mechanism is asserted here.
  subtype_term:
    preferred_term: Lisch epithelial corneal dystrophy
    term:
      id: MONDO:0010425
      label: Lisch epithelial corneal dystrophy
  genes:
  - preferred_term: MCOLN1
    term:
      id: hgnc:13356
      label: MCOLN1
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:38359414
    reference_title: IC3D Classification of Corneal Dystrophies-Edition 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lisch epithelial corneal dystrophy, previously reported as X-linked, has been discovered to be autosomal dominant ( MCOLN1 mutations, chromosome 19)."
    explanation: >-
      Sole source for both the gene and the correction of the inheritance mode. MONDO
      still carries "corneal dystrophy, Lisch epithelial, X-linked dominant" as a
      synonym of MONDO:0010425 while recording the MCOLN1 edge, so the ontology
      currently asserts both readings at once.
  review_notes: >-
    The MCOLN1 attribution was checked rather than assumed. MCOLN1 is at 19p13.2
    (HGNC:13356, retrieved 2026-09-24), an autosome, which contradicts MONDO's retained
    X-linked synonym; ClinGen curates MCOLN1 only against mucolipidosis type IV
    (Definitive, AR) and has no corneal-dystrophy assertion. IC3D edition 3 resolves
    the contradiction in favour of autosomal dominant MCOLN1, so the gene edge is
    supported and the stale synonym is the defect.
- name: CHED
  display_name: Congenital hereditary endothelial dystrophy (SLC4A11)
  classification: entity
  description: >-
    Autosomal recessive congenital failure of the corneal endothelium, presenting with
    corneal opacification and nystagmus; the bound MONDO term's definition adds a diffuse
    ground-glass appearance of the corneas and marked corneal thickening from birth.
    SLC4A11 encodes a membrane-bound sodium-borate cotransporter; the reported
    variants act by blocking membrane targeting or through nonsense-mediated decay, so
    the mechanism is loss of endothelial solute transport rather than deposition of
    abnormal material. Formerly called CHED2, after the dissolution of autosomal
    dominant CHED1.
  subtype_term:
    preferred_term: congenital hereditary endothelial dystrophy of cornea
    term:
      id: MONDO:0009019
      label: congenital hereditary endothelial dystrophy of cornea
  genes:
  - preferred_term: SLC4A11
    term:
      id: hgnc:16438
      label: SLC4A11
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:16767101
    reference_title: Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe seven different mutations in the SLC4A11 gene in ten families with autosomal recessive CHED."
    explanation: >-
      Seven variants across ten independent recessive CHED families is the original and
      still the principal evidence for the gene and for the recessive mode.
- name: FCD
  display_name: Fleck corneal dystrophy (PIKFYVE)
  classification: entity
  description: >-
    Autosomal dominant scattering of numerous small white flecks through all layers of the
    corneal stroma. The bound MONDO term's definition characterises the opacities as
    asymptomatic and non-progressive with no effect on visual acuity, which is why this row
    carries no link to visual impairment. PIKFYVE (reported as PIP5K3 when the gene was
    identified) controls the
    morphogenesis and function of multivesicular bodies and the sorting of peripheral
    endosomes; the gene report states that the histological and clinical characteristics of
    affected patients are consistent with that endosomal sorting role, which is as far as
    the mechanistic claim goes.
  subtype_term:
    preferred_term: fleck corneal dystrophy
    term:
      id: MONDO:0007376
      label: fleck corneal dystrophy
  genes:
  - preferred_term: PIKFYVE
    term:
      id: hgnc:23785
      label: PIKFYVE
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:15902656
    reference_title: Mutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing analysis disclosed missense, frameshift, and/or protein-truncating mutations in 8 of 10 families with CFD that were studied"
    explanation: >-
      Variants in eight of ten fleck-dystrophy families establish the gene. The paper
      calls it PIP5K3, which HGNC records as the previous symbol for PIKFYVE
      (hgnc:23785).
- name: PPPCD
  display_name: Punctiform and polychromatic pre-Descemet corneal dystrophy (PRDX3)
  classification: entity
  description: >-
    Autosomal dominant punctate polychromatic opacities immediately anterior to Descemet
    membrane, typically asymptomatic, caused by PRDX3 variants. IC3D edition 3 groups it
    with the pre-Descemet corneal dystrophies and grades it category 1, distinguishing it
    phenotypically from the category 4 entity pre-Descemet corneal dystrophy, which
    dismech curates separately in `Pre-descemet_Corneal_Dystrophy.yaml`. PRDX3 encodes
    peroxiredoxin 3 (HGNC:9354); how variants in it produce deep stromal deposits is not
    established, and no mechanism is asserted here.
  subtype_term:
    preferred_term: corneal dystrophy, punctiform and polychromatic pre-descemet
    term:
      id: MONDO:0859248
      label: corneal dystrophy, punctiform and polychromatic pre-descemet
  genes:
  - preferred_term: PRDX3
    term:
      id: hgnc:9354
      label: PRDX3
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:38359414
    reference_title: IC3D Classification of Corneal Dystrophies-Edition 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pre-Descemet corneal dystrophies include category 1, autosomal dominant, punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) ( PRDX3 mutations, chromosome 10)."
    explanation: >-
      Gives the gene, the dominant mode and the category 1 evidence grade in one
      sentence, and separates PPPCD from the category 4 pre-Descemet entity.
  review_notes: >-
    Not listed as a child of any of the four anatomic categories here. MONDO files
    MONDO:0859248 as a direct child of MONDO:0018102 rather than under stromal or
    pre-Descemet corneal dystrophy, while IC3D edition 3 groups PPPCD with the
    pre-Descemet dystrophies; rather than pick one, the row is left unparented and the
    discrepancy recorded.

prevalence:
- population: General population
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 90.0
  notes: >-
    Reported as approximately 0.09% of the population, normalised here to 90 per
    100,000. Covers the corneal dystrophies as a class; individual entities range from
    relatively common (epithelial basement membrane dystrophy, Fuchs) to fewer than a
    dozen reported families.
  evidence:
  - reference: PMID:28583694
    reference_title: Corneal dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Corneal dystrophies affect approximately 0.09% of the population."
    explanation: >-
      Gives a class-level population prevalence figure for the corneal dystrophies.

pathophysiology:
- name: Layer-Restricted Corneal Deposition or Cellular Failure
  biological_scale: TISSUE
  role: trigger
  description: >-
    Each dystrophy begins with an inherited defect expressed in one corneal layer, and
    the layer determines both the mechanism and the syndrome. In the epithelial,
    epithelial-stromal and stromal categories the lesion causes abnormal material to
    accumulate — mutant TGFBI protein in the epithelial-stromal group, abnormally
    sulphated keratan sulphate in macular dystrophy, cholesterol and phospholipid in
    Schnyder dystrophy. The endothelial category works differently: the corneal
    endothelium does not regenerate and functions as a dehydrating pump, so its
    progressive failure admits fluid into the stroma instead of depositing anything.
    Curating these as one node reflects a shared consequence, not a shared molecular
    mechanism.
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  genes:
  - preferred_term: TGFBI
    term:
      id: hgnc:11771
      label: TGFBI
  - preferred_term: CHST6
    term:
      id: hgnc:6938
      label: CHST6
  - preferred_term: UBIAD1
    term:
      id: hgnc:30791
      label: UBIAD1
  - preferred_term: SLC4A11
    term:
      id: hgnc:16438
      label: SLC4A11
  - preferred_term: MCOLN1
    term:
      id: hgnc:13356
      label: MCOLN1
  - preferred_term: PRDX3
    term:
      id: hgnc:9354
      label: PRDX3
  evidence:
  - reference: PMID:38359414
    reference_title: IC3D Classification of Corneal Dystrophies-Edition 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lisch epithelial corneal dystrophy, previously reported as X-linked, has been discovered to be autosomal dominant ( MCOLN1 mutations, chromosome 19)."
    explanation: >-
      Source for the MCOLN1 gene binding on this node. MCOLN1 and PRDX3 are carried here
      rather than on layer-specific nodes because the layer is known for each entity
      (epithelium for Lisch dystrophy, deep stroma for PPPCD) while the mechanism by
      which either gene produces its deposit is not, so a dedicated mechanism node would
      assert more than any source states.
  - reference: PMID:38359414
    reference_title: IC3D Classification of Corneal Dystrophies-Edition 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pre-Descemet corneal dystrophies include category 1, autosomal dominant, punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) ( PRDX3 mutations, chromosome 10)."
    explanation: >-
      Source for the PRDX3 gene binding on this node, and for treating PPPCD as an
      established entity rather than a category 4 candidate.
  - reference: PMID:25564336
    reference_title: IC3D classification of corneal dystrophies--edition 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On the basis of revisiting the cellular origin of corneal dystrophy, a modified anatomic classification is proposed consisting of (1) epithelial and subepithelial dystrophies, (2) epithelial-stromal TGFBI dystrophies, (3) stromal dystrophies, and (4) endothelial dystrophies."
    explanation: >-
      States the four-category anatomic classification and, critically, that it was
      derived by revisiting the cellular origin of each dystrophy — which is what makes
      the corneal layer the organising principle rather than a descriptive convenience.
  downstream:
  - target: Loss of Corneal Transparency
    causal_link_type: DIRECT
    description: >-
      Deposited material scatters light directly; endothelial pump failure does so
      indirectly by allowing the stroma to imbibe fluid and lose its ordered collagen
      spacing. Either route degrades the cornea's optical function.
    evidence:
    - reference: PMID:38359414
      reference_title: IC3D Classification of Corneal Dystrophies-Edition 3.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Deposition of opaque substances in epithelial, subepithelial, epithelial-stromal TGFBI or stromal corneal dystrophies may also result in vision reduction. Visual loss may also occur in endothelial corneal dystrophies because of corneal epithelial or stromal edema consequent to endothelial dysfunction."
      explanation: >-
        Covers both arms of this edge separately: deposited opaque material reduces
        vision in the epithelial, epithelial-stromal TGFBI and stromal categories, while
        in the endothelial category visual loss instead follows epithelial or stromal
        edema consequent to endothelial dysfunction.

- name: Loss of Corneal Transparency
  biological_scale: TISSUE
  role: central_effector
  description: >-
    The convergent node. Corneal transparency depends on regular collagen fibril
    spacing, a deturgesced stroma and an intact smooth epithelium; every dystrophy
    degrades at least one of these. The result is corneal opacity, with or without
    stromal oedema depending on whether the endothelium is the affected layer.
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  evidence:
  - reference: PMID:38359414
    reference_title: IC3D Classification of Corneal Dystrophies-Edition 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deposition of opaque substances in epithelial, subepithelial, epithelial-stromal TGFBI or stromal corneal dystrophies may also result in vision reduction. Visual loss may also occur in endothelial corneal dystrophies because of corneal epithelial or stromal edema consequent to endothelial dysfunction."
    explanation: >-
      Establishes that loss of vision is the shared endpoint of both routes into this
      node — opaque deposition in three categories, and edema from endothelial
      dysfunction in the fourth.
  downstream:
  - target: Progressive Visual Impairment Requiring Surgical Restoration
    causal_link_type: DIRECT
    description: >-
      Once opacity or oedema crosses the visual axis, optical correction cannot
      compensate and restoring vision requires physically removing or replacing the
      affected layer.
    evidence:
    - reference: PMID:28583694
      reference_title: Corneal dystrophies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Anterior lamellar or endothelial keratoplasty are now preferred to penetrating keratoplasty, although the latter still remains the only possible option in some cases."
      explanation: >-
        Supports the layer-selective half of this claim: restoring vision means
        replacing the affected layer, and lamellar or endothelial keratoplasty is now
        preferred over penetrating keratoplasty for that reason.

- name: Progressive Visual Impairment Requiring Surgical Restoration
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The clinical endpoint. Management escalates from lubricants, hyperosmotic agents and
    bandage contact lenses, through phototherapeutic or lamellar keratectomy, to
    keratoplasty. Because the dystrophies are layer-restricted, layer-selective grafts
    (anterior lamellar for anterior disease, endothelial keratoplasty for endothelial
    disease) are now preferred over penetrating keratoplasty — the anatomic
    classification maps directly onto the choice of operation. Recurrence in the graft
    is possible because the genetic defect persists in the host.
  evidence:
  - reference: PMID:28583694
    reference_title: Corneal dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anterior lamellar or endothelial keratoplasty are now preferred to penetrating keratoplasty, although the latter still remains the only possible option in some cases."
    explanation: >-
      Documents the preference for lamellar and endothelial keratoplasty over
      penetrating keratoplasty, while noting the latter remains necessary in some cases.

- name: Cornea-Specific Keratin Filament Fragility
  biological_scale: CELLULAR
  role: trigger
  description: >-
    The Meesmann mechanism. The intermediate filament cytoskeleton of the corneal
    epithelium is built from the cornea-specific pair K3 and K12; a heterozygous
    substitution in either, falling in a conserved keratin helix boundary motif, leaves the
    anterior epithelium mechanically fragile. A dominant-negative effect on the filament is
    the hypothesis the gene report set out to test, and is presented there as such rather
    than demonstrated. This is the same class of lesion that produces keratinocyte fragility
    phenotypes in skin keratins, restricted here to the one tissue where K3 and K12 are
    expressed.
  cell_types:
  - preferred_term: corneal epithelial cell
    term:
      id: CL:0000575
      label: corneal epithelial cell
  cellular_components:
  - preferred_term: keratin filament
    term:
      id: GO:0045095
      label: keratin filament
  locations:
  - preferred_term: corneal epithelium
    term:
      id: UBERON:0001772
      label: corneal epithelium
  genes:
  - preferred_term: KRT12
    term:
      id: hgnc:6414
      label: KRT12
  - preferred_term: KRT3
    term:
      id: hgnc:6440
      label: KRT3
  evidence:
  - reference: PMID:9171831
    reference_title: "Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Meesmann's corneal dystrophy (MCD) is an autosomal dominant disorder causing fragility of the anterior corneal epithelium, where K3 and K12 are specifically expressed."
    explanation: >-
      Establishes the node's three claims together: the affected layer is the anterior
      corneal epithelium, the lesion is fragility, and the two keratins are expressed
      specifically there.
  - reference: PMID:9171831
    reference_title: "Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All mutations occur in the highly conserved keratin helix boundary motifs, where dominant mutations in other keratins have been found to severely compromise cytoskeletal function, leading to keratinocyte fragility phenotypes."
    explanation: >-
      Supports the dominant-negative reading and the comparison with skin keratin
      fragility disorders, which is the argument for a cytoskeletal rather than a
      depositional mechanism.
  downstream:
  - target: Recurrent Corneal Erosions
    causal_link_type: DIRECT
    description: >-
      A mechanically fragile epithelium separates from its bed under ordinary shear.
      Erosion episodes occur in Meesmann dystrophy, and this edge records that; it does
      not claim they are the dystrophy's most frequent presentation, which the cited
      source does not address.
    evidence:
    - reference: PMID:9171831
      reference_title: "Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Meesmann's corneal dystrophy (MCD) is an autosomal dominant disorder causing fragility of the anterior corneal epithelium, where K3 and K12 are specifically expressed."
      explanation: >-
        Names epithelial fragility as the disorder's defining lesion; recurrent erosion
        is that fragility expressed clinically.
- name: Epithelial Basement Membrane Adhesion Failure
  biological_scale: TISSUE
  role: trigger
  description: >-
    The ERED mechanism. COL17A1 encodes collagen type XVII alpha 1 chain, and the route
    from it to recurrent corneal erosion is read here from the allelic contrast rather than
    asserted directly: biallelic COL17A1 loss causes junctional epidermolysis bullosa, a
    recessive disorder of epithelial attachment in which recurrent corneal erosions are
    reported, while dominant COL17A1 variants produce corneal erosion alone. The authors of
    the ERED gene report read the dominant variants as presumed gain of function rather than
    as a heterozygous dose of the recessive lesion.
  locations:
  - preferred_term: corneal epithelium
    term:
      id: UBERON:0001772
      label: corneal epithelium
  genes:
  - preferred_term: COL17A1
    term:
      id: hgnc:2194
      label: COL17A1
  evidence:
  - reference: PMID:25676728
    reference_title: "Mutations in collagen, type XVII, alpha 1 (COL17A1) cause epithelial recurrent erosion dystrophy (ERED)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology."
    explanation: >-
      The gene and the allelic mechanism, stated by the authors as a presumption rather
      than a demonstration, which is how it is represented here.
  - reference: PMID:25676728
    reference_title: "Mutations in collagen, type XVII, alpha 1 (COL17A1) cause epithelial recurrent erosion dystrophy (ERED)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases."
    explanation: >-
      Supports the allelic contrast in the description, and independently supports that
      loss of collagen XVII function produces recurrent corneal erosion.
  downstream:
  - target: Recurrent Corneal Erosions
    causal_link_type: DIRECT
    description: >-
      Failure of epithelial attachment at the basement membrane is expressed clinically
      as repeated epithelial breakdown. The MONDO:0007381 definition characterises ERED
      by recurrent episodes of epithelial erosions from childhood in the absence of
      associated diseases; the evidence below reaches the dominant corneal entity by way
      of the recessive skin disorder, because that is where loss of collagen XVII
      function has been shown to produce corneal erosion.
    evidence:
    - reference: PMID:25676728
      reference_title: "Mutations in collagen, type XVII, alpha 1 (COL17A1) cause epithelial recurrent erosion dystrophy (ERED)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases."
      explanation: >-
        Directly links loss of collagen XVII function to recurrent corneal erosions in
        the recessive skin phenotype, the same tissue consequence this edge asserts.
    - reference: PMID:25676728
      reference_title: "Mutations in collagen, type XVII, alpha 1 (COL17A1) cause epithelial recurrent erosion dystrophy (ERED)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden."
      explanation: >-
        Grounds the edge in the dominant corneal disease itself rather than only in the
        recessive skin disorder: the cohort in which COL17A1 was identified had a
        dominantly inherited recurrent erosion dystrophy.

- name: Subepithelial Corneal Amyloid Deposition
  biological_scale: TISSUE
  role: trigger
  description: >-
    The gelatinous drop-like mechanism. Three nonsense variants and one frameshift in
    TACSTD2 (reported as M1S1) were found in the original gene study, so the mechanism is
    loss of the encoded protein; severe corneal amyloidosis follows, presenting as raised
    yellowish-grey gelatinous masses that severely impair acuity by the third decade. The
    truncated protein itself aggregates in the perinuclear region of the cell that makes it,
    where the normal protein is distributed diffusely through the cytoplasm — so the
    intracellular aggregate and the subepithelial amyloid deposit are recorded as two
    observations rather than collapsed into one process.
  biological_processes:
  - preferred_term: corneal amyloid fibril formation
    modifier: INCREASED
    term:
      id: GO:1990000
      label: amyloid fibril formation
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  genes:
  - preferred_term: TACSTD2
    term:
      id: hgnc:11530
      label: TACSTD2
  evidence:
  - reference: PMID:10192395
    reference_title: Identification of the gene responsible for gelatinous drop-like corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gelatinous drop-like corneal dystrophy (GDLD; OMIM 204870) is an autosomal recessive disorder characterized by severe corneal amyloidosis leading to blindness, with an incidence of 1 in 300,000 in Japan."
    explanation: >-
      Names corneal amyloidosis as the defining lesion, which is what the amyloid fibril
      formation binding on this node asserts, and gives the recessive mode.
  - reference: PMID:10192395
    reference_title: Identification of the gene responsible for gelatinous drop-like corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Protein expression analysis revealed aggregation of the mutated, truncated protein in the perinuclear region, whereas the normal protein was distributed diffusely in the cytoplasm with a homogenous or fine granular pattern."
    explanation: >-
      Supports the distinction drawn in the description between intracellular
      aggregation of the truncated gene product and the extracellular amyloid deposit.
  downstream:
  - target: Corneal Opacity
    causal_link_type: DIRECT
    description: >-
      The subepithelial amyloid masses are themselves the opacity, which is why gelatinous
      drop-like dystrophy is visible as mounded milky-white nodules rather than as diffuse
      haze.
    evidence:
    - reference: PMID:10192395
      reference_title: Identification of the gene responsible for gelatinous drop-like corneal dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "By the third decade, raised, yellowish-grey, gelatinous masses severely impair visual acuity, and lamellar keratoplasty is required for most patients."
      explanation: >-
        Describes the deposits as raised gelatinous masses that impair acuity, which is
        corneal opacity in the sense this phenotype node carries.
  - target: Loss of Corneal Transparency
    causal_link_type: DIRECT
    description: >-
      Amyloid in the visual axis scatters light directly, and the resulting loss of
      transparency is severe enough that lamellar keratoplasty is required in most
      patients.
    evidence:
    - reference: PMID:10192395
      reference_title: Identification of the gene responsible for gelatinous drop-like corneal dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "By the third decade, raised, yellowish-grey, gelatinous masses severely impair visual acuity, and lamellar keratoplasty is required for most patients."
      explanation: >-
        Impairment of visual acuity severe enough to require keratoplasty is the loss of
        corneal optical function this node converges on.

- name: Corneal Stromal Endosomal Sorting Defect
  biological_scale: CELLULAR
  role: trigger
  description: >-
    The fleck dystrophy mechanism. PIKFYVE (identified as PIP5K3) governs the
    morphogenesis and function of multivesicular bodies and the sorting of peripheral
    endosomes carrying cargo destined for lysosomes; missense, frameshift and
    protein-truncating variants leave discrete white flecks scattered through the full
    thickness of the stroma. The node is named for the compartment rather than for a cell
    type: the gene report goes no further than saying the histological and clinical
    findings are consistent with a role in endosomal sorting.
  biological_processes:
  - preferred_term: multivesicular body sorting of endosomal cargo
    modifier: ABNORMAL
    term:
      id: GO:0032509
      label: endosome transport via multivesicular body sorting pathway
  locations:
  - preferred_term: corneal stroma
    term:
      id: UBERON:0001777
      label: substantia propria of cornea
  genes:
  - preferred_term: PIKFYVE
    term:
      id: hgnc:23785
      label: PIKFYVE
  evidence:
  - reference: PMID:15902656
    reference_title: Mutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PIP5K3 is a member of the phosphoinositide 3-kinase family and regulates the sorting and traffic of peripheral endosomes that contain lysosomally directed fluid phase cargo, by controlling the morphogenesis and function of multivesicular bodies."
    explanation: >-
      The multivesicular-body sorting binding on this node is taken from this sentence,
      which names both the pathway and the gene's role in it.
  - reference: PMID:15902656
    reference_title: Mutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The histological and clinical characteristics of patients with CFD are consistent with biochemical studies of PIP5K3 that indicate a role in endosomal sorting."
    explanation: >-
      The authors' own statement of how far the mechanistic claim goes: the phenotype is
      consistent with an endosomal sorting role, not demonstrated to follow from it.
  downstream:
  - target: Corneal Opacity
    causal_link_type: DIRECT
    description: >-
      The flecks are discrete stromal opacities distributed through every layer, and they
      are the whole of the corneal finding in this dystrophy.
    evidence:
    - reference: PMID:15902656
      reference_title: Mutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "fleck corneal dystrophy (CFD) is a rare, autosomal dominant corneal dystrophy characterized by numerous small white flecks scattered in all layers of the stroma."
      explanation: >-
        Names the flecks and their distribution through the stroma, which is the whole of
        what this edge asserts. No edge is drawn from this node to visual impairment, but
        that omission rests on the MONDO:0007376 definition rather than on this paper: the
        cited abstract says nothing about visual acuity.

- name: Corneal Endothelial Sodium-Borate Cotransport Failure
  biological_scale: CELLULAR
  role: trigger
  description: >-
    The congenital hereditary endothelial dystrophy mechanism, and the one lesion in this
    entry whose route to lost transparency is oedema rather than deposition. SLC4A11 encodes a membrane-bound sodium-borate
    cotransporter; the recessive variants cause loss of function either by blocking its
    membrane targeting or through nonsense-mediated decay. The consequence is corneal
    opacification, and IC3D edition 3 states the route for the endothelial category as a
    whole: visual loss follows corneal epithelial or stromal edema consequent to endothelial
    dysfunction, rather than deposition of abnormal material. This entity is congenital,
    which separates it from the endothelial dystrophies of later life.
  cell_types:
  - preferred_term: corneal endothelial cell
    term:
      id: CL:0000132
      label: corneal endothelial cell
  biological_processes:
  - preferred_term: borate transmembrane transport
    modifier: DECREASED
    term:
      id: GO:0035445
      label: borate transmembrane transport
  locations:
  - preferred_term: corneal endothelium
    term:
      id: UBERON:0001985
      label: corneal endothelium
  genes:
  - preferred_term: SLC4A11
    term:
      id: hgnc:16438
      label: SLC4A11
  evidence:
  - reference: PMID:16767101
    reference_title: Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in SLC4A11, which encodes a membrane-bound sodium-borate cotransporter, cause loss of function of the protein either by blocking its membrane targeting or nonsense-mediated decay."
    explanation: >-
      Gives both the transported solute, which is what the borate transport binding
      asserts, and the two routes to loss of function stated in the description.
  - reference: PMID:16767101
    reference_title: Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital hereditary endothelial dystrophy (CHED) is a heritable, bilateral corneal dystrophy characterized by corneal opacification and nystagmus."
    explanation: >-
      Identifies the affected layer as the endothelium and names corneal opacification as
      the clinical consequence.
  downstream:
  - target: Corneal Opacity
    causal_link_type: DIRECT
    description: >-
      A non-functioning endothelial pump lets the stroma imbibe fluid, and the cornea is
      diffusely opacified from birth rather than acquiring opacity progressively.
    evidence:
    - reference: PMID:16767101
      reference_title: Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Congenital hereditary endothelial dystrophy (CHED) is a heritable, bilateral corneal dystrophy characterized by corneal opacification and nystagmus."
      explanation: >-
        States corneal opacification as the characteristic finding of the endothelial
        dystrophy this node models.
  - target: Loss of Corneal Transparency
    causal_link_type: DIRECT
    description: >-
      Endothelial failure reaches the family's convergent node by the oedema route rather
      than the deposition route, which is the mechanistic divergence this entry's trigger
      node already flags.
    evidence:
    - reference: PMID:38359414
      reference_title: IC3D Classification of Corneal Dystrophies-Edition 3.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Visual loss may also occur in endothelial corneal dystrophies because of corneal epithelial or stromal edema consequent to endothelial dysfunction."
      explanation: >-
        States the oedema route from endothelial dysfunction to visual loss, which is
        exactly the arm of the convergent node this edge enters by.
phenotypes:
- category: Ophthalmic
  name: Corneal Dystrophy
  description: >-
    Inherited, non-inflammatory, usually bilateral corneal opacification — the defining
    finding of the family.
  phenotype_term:
    preferred_term: Corneal dystrophy
    term:
      id: HP:0001131
      label: Corneal dystrophy
    clinical_course: PROGRESSIVE
- category: Ophthalmic
  name: Corneal Opacity
  description: Loss of corneal clarity from deposited material or stromal oedema.
  phenotype_term:
    preferred_term: Corneal opacity
    term:
      id: HP:0007957
      label: Corneal opacity
- category: Ophthalmic
  name: Recurrent Corneal Erosions
  description: >-
    Repeated breakdown of the corneal epithelium causing pain, photophobia and foreign
    body sensation. Characteristic of the epithelial and epithelial-stromal categories
    rather than of the family as a whole.
  phenotype_term:
    preferred_term: Recurrent corneal erosions
    term:
      id: HP:0000495
      label: Recurrent corneal erosions
    temporality: RECURRENT
- category: Ophthalmic
  name: Corneal Stromal Edema
  description: >-
    Fluid accumulation in the corneal stroma from endothelial pump failure; specific to
    the endothelial category.
  phenotype_term:
    preferred_term: Corneal stromal edema
    term:
      id: HP:0012040
      label: Corneal stromal edema
- category: Ophthalmic
  name: Visual Impairment
  description: Progressive reduction in visual acuity as opacity encroaches on the visual axis.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
    clinical_course: PROGRESSIVE
- category: Ophthalmic
  name: Photophobia
  description: Light sensitivity, most prominent during epithelial erosion episodes.
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia

discussions:
- discussion_id: ic3d_evidence_category_is_part_of_the_classification
  kind: KNOWLEDGE_GAP
  attaches_to:
  - "pathophysiology#Layer-Restricted Corneal Deposition or Cellular Failure"
  prompt: >-
    How should dismech represent an entity whose status as a distinct disease is itself
    graded by the source classification?
  rationale: >-
    IC3D assigns every corneal dystrophy an evidence category from 1 (well characterised
    clinically, histopathologically and genetically) to 4 (a suspected entity that may
    not be distinct), and revises those grades between editions. Entities have been
    dissolved on review — autosomal dominant CHED (CHED1) was found insufficiently
    distinct and reassigned to posterior polymorphous corneal dystrophy — and others
    have been promoted as genes were identified. dismech has no slot for "the source
    classification doubts this is a real disease", so an IC3D category 4 entity and a
    category 1 entity would be curated identically. This matters because MONDO carries
    descendants of `MONDO:0018102` that correspond to entities IC3D has since
    downgraded or merged, and curating them as subtypes would assert more confidence
    than the source does. No category 3 or 4 entity is curated as a subtype here.
  evidence:
  - reference: PMID:38359414
    reference_title: IC3D Classification of Corneal Dystrophies-Edition 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The new information was used to update the anatomic classification and each of the 22 standardized templates including the level of evidence for being a corneal dystrophy"
    explanation: >-
      Establishes that the evidence grade is a maintained part of each entity's
      standardized template, not an informal aside.
  - reference: PMID:25564336
    reference_title: IC3D classification of corneal dystrophies--edition 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The so-called autosomal dominant inherited CHED (formerly CHED1) is insufficiently distinct to continue to be considered a unique corneal dystrophy."
    explanation: >-
      A worked instance of an entity being dissolved on review — the concrete case that
      makes this a curation problem rather than a theoretical one.

- discussion_id: mondo_files_two_non_dystrophies_under_this_family
  kind: KNOWLEDGE_GAP
  attaches_to:
  - "has_subtypes#"
  prompt: >-
    Should a disease that MONDO classifies as a corneal dystrophy, but that the source
    classification for corneal dystrophies does not recognise as one, be curated as a
    subtype here?
  rationale: >-
    Two descendants of MONDO:0018102 are curated neither as entity rows here nor as
    children of any anatomic category, and the reason is the same for both: the
    authoritative classification of the corneal dystrophies does not contain them.

    MONDO:0007848 autosomal dominant keratitis is a direct child of MONDO:0018102 with a
    PAX6 causal gene edge. Its reported features include corneal vascularization and
    foveal hypoplasia, neither of which is a corneal dystrophy finding — IC3D defines the
    dystrophies as non-inflammatory and cornea-restricted — and the gene-identification
    paper places it with the PAX6 anterior segment malformations rather than with the
    dystrophies. ClinGen curates PAX6 only as PAX6-related ocular dysgenesis (Definitive,
    autosomal dominant), and dismech's PAX6 home is Aniridia.yaml. Ruling: out of scope
    for this family; the concept belongs with the PAX6 ocular dysgenesis spectrum.

    MONDO:0014089 corneal intraepithelial dyskeratosis-palmoplantar
    hyperkeratosis-laryngeal dyskeratosis syndrome is filed by MONDO under MONDO:0020212
    superficial corneal dystrophy with an NLRP1 causal gene edge. It is a multisystem
    NLRP1 inflammasome disorder with palmoplantar and laryngeal involvement, and the
    corneal finding is one feature of a syndrome rather than an isolated dystrophy. The
    cached full text of IC3D edition 3 (PMID:38359414) contains no occurrence of
    "dyskeratosis" or of "NLRP1". Ruling: out of scope for this family; it would need its
    own entry as an NLRP1-related autoinflammatory syndrome, which dismech does not yet
    have.

    Both rulings are disagreements with MONDO's placement rather than with its gene
    edges, which are themselves well supported.
  evidence:
  - reference: PMID:7668281
    reference_title: Mutation of the PAX6 gene in patients with autosomal dominant keratitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal dominant keratitis (ADK) is an eye disorder chiefly characterized by corneal opacification and vascularization and by foveal hypoplasia."
    explanation: >-
      The features that put autosomal dominant keratitis outside the corneal dystrophy
      definition: corneal vascularization, and a retinal malformation.
  - reference: PMID:7668281
    reference_title: Mutation of the PAX6 gene in patients with autosomal dominant keratitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The finding that mutations in PAX6 underlie ADK, along with a recent report that mutations in PAX6 also underlie Peters anomaly, implicates PAX6 broadly in human anterior segment malformations."
    explanation: >-
      The gene-identification paper's own placement of the disease, with Peters anomaly
      among the PAX6 anterior segment malformations rather than among the dystrophies.
  - reference: PMID:38359414
    reference_title: IC3D Classification of Corneal Dystrophies-Edition 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The new information was used to update the anatomic classification and each of the 22 standardized templates including the level of evidence for being a corneal dystrophy"
    explanation: >-
      Establishes that IC3D edition 3 enumerates the corneal dystrophies as a closed set
      of 22 templated entities, which is what makes an absence from it informative rather
      than merely an omission.
notes: >
  Scope. A thin root over an already-populated subtree. It binds MONDO:0018102 and
  carries the IC3D anatomic axis, the shared route to loss of corneal transparency, and
  the layer-to-operation correspondence once. Entity-level mechanism, genetics and
  management stay in the existing entries.

  Subtype axis. `has_subtypes` follows the IC3D four-category anatomic classification,
  and each category is bound to the MONDO term that denotes it — MONDO happens to carry
  intermediate terms matching three of the four categories exactly, and
  `MONDO:0000766` corneal endothelial dystrophy for the fourth. Three of the four
  categories already have curated dismech entries.

  Second axis: gene-defined entities. Eight IC3D entities are now carried as
  `classification: entity` rows beside the four anatomic categories, each bound to its
  own MONDO term and its causal gene. They are not a second, competing partition: the
  anatomic rows name them through `children`, so MECD1, MECD2, GDLD, ERED and LECD sit
  under the epithelial and subepithelial category, FCD under stromal, and CHED under
  endothelial. PPPCD is deliberately left unparented — MONDO files `MONDO:0859248` as a
  direct child of `MONDO:0018102` while IC3D groups PPPCD with the pre-Descemet
  dystrophies, and the row records that rather than resolving it. The entities chosen are
  those whose gene is established and which have no dismech entry of their own; the
  epithelial and subepithelial category still has no dedicated file, and these five rows
  are what stands in for one.

  Genes reach the pathograph, and by layer. Five mechanism nodes carry the layer-specific
  lesions — keratin filament fragility (KRT12, KRT3), basement membrane adhesion failure
  (COL17A1), subepithelial amyloid deposition (TACSTD2), corneal stromal endosomal sorting
  (PIKFYVE) and endothelial sodium-borate cotransport failure (SLC4A11) — rather than one
  flat gene list, because in this family the layer is the mechanism. They run in parallel
  with the family-level trigger node, which states the shared shape and carries the IC3D
  classification evidence; the five state what actually goes wrong in each layer. MCOLN1
  and PRDX3 are bound on the family-level node instead, because for Lisch dystrophy and
  PPPCD the affected layer is known and the mechanism is not.

  No disease-level `genetic:` section. A flat per-gene list at this level would assert a
  single genetic architecture for a family that has four, and each gene's detail belongs
  either to its entity row here or to the child entry that owns the entity.

  Unlisted siblings checked. All 57 distinct descendants of MONDO:0018102 were enumerated
  through the ontology hierarchy and each queried for a causal gene edge, rather than only
  the ten concepts named in the gap list. Three further
  descendants carry one. `MONDO:0007097` Finnish type amyloidosis (GSN) is already curated as
  its own entry and held in the `Hereditary_Systemic_Amyloidoses` grouping — it is a systemic
  amyloidosis whose corneal lattice is one feature, so it is correctly not a member of this
  family's subtype list. `MONDO:0012401` congenital stromal corneal dystrophy (DCN) is
  curated as the `CSCD` subtype of `Stromal_Corneal_Dystrophy.yaml`. `MONDO:0007375`
  epithelial basement membrane dystrophy (TGFBI) is bound nowhere in dismech and is the one
  real remaining gap in this subtree; it is not added here because its natural home is
  `TGFBI_Corneal_Dystrophies.yaml`, whose subtype list it is missing from, and because most
  cases of that dystrophy are not familial. `MONDO:0010426` X-linked endothelial corneal
  dystrophy has no gene edge and no dismech binding.

  MONDO carries a fifth intermediate that overlaps the IC3D categories. `MONDO:0020212`
  superficial corneal dystrophy is a direct child of `MONDO:0018102` holding twelve
  descendants that mostly also sit under the epithelial and subepithelial or epithelial-stromal
  TGFBI categories, and `MONDO:0007381` epithelial recurrent erosion dystrophy sits under it
  alone — so ERED is not reachable from `MONDO:0000763`, the term bound to the epithelial and
  subepithelial category here. The ERED row is nevertheless listed as a child of that category
  because IC3D places it there. `MONDO:0020214` posterior corneal dystrophy overlaps
  `MONDO:0000766` in the same way.

  Two concepts MONDO files under corneal dystrophy that are not curated here.
  `MONDO:0007848` autosomal dominant keratitis (PAX6) and `MONDO:0014089` corneal
  intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis
  syndrome (NLRP1) are both descendants of `MONDO:0018102`, and neither appears anywhere
  in IC3D edition 3 — searching the cached full text of PMID:38359414 for "keratitis"
  returns only a reference title from 1890, and for "dyskeratosis" and "NLRP1" returns
  nothing at all. See the `mondo_files_two_non_dystrophies_under_this_family` discussion.

  Honest limit on the shared pathograph. The endothelial category reaches loss of
  transparency by a mechanistically different route from the other three — pump failure
  and stromal oedema rather than deposition of abnormal material. The trigger node says
  so explicitly rather than papering over it with a single "abnormal accumulation"
  claim. If that divergence later proves to warrant separate chains, the endothelial
  arm is the natural place to split.

  Not curated. No treatments section: management is layer- and severity-driven and is
  described at the consequence node, and the specific agents are not dystrophy-specific.
  IC3D category 3 and 4 entities are deliberately excluded from `has_subtypes`; see the
  `ic3d_evidence_category_is_part_of_the_classification` discussion.