Congenital hereditary endothelial dystrophy of cornea

Summary

Congenital hereditary endothelial dystrophy of cornea (MONDO:0009019) is a disease caused by SLC4A11 (GenCC Strong), with 2 cohort genes and 8 clinical trials. Top therapeutic interventions include loteprednol etabonate, nepafenac, and ripasudil.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: SLC4A11 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 94
• Phenotypes (HPO): 9
• Clinical trials: 8

Clinical features

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0011487	Increased corneal thickness	Very frequent (80-99%)
HP:0007957	Corneal opacity	Very frequent (80-99%)
HP:0011490	Abnormal Descemet membrane morphology	Very frequent (80-99%)
HP:0012040	Corneal stromal edema	Very frequent (80-99%)
HP:0000622	Blurred vision	Frequent (30-79%)
HP:0007663	Reduced visual acuity	Frequent (30-79%)
HP:0031792	Irregular astigmatism	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital hereditary endothelial dystrophy of cornea
Mondo ID	MONDO:0009019
MeSH	C536439
OMIM	217700
Orphanet	293603
DOID	DOID:0060649
UMLS	C1857569
MedGen	387857
GARD	0006196
Is cancer (heuristic)	no

Also known as: autosomal recessive CHED · autosomal recessive congenital hereditary endothelial dystrophy · CHED · CHED2 · CHED2, formerly · CHEDII · congenital hereditary endothelial dystrophy of cornea · congenital hereditary endothelial dystrophy of the cornea · congenital hereditary endothelial dystrophy type 2 · corneal dystrophy, congenital hereditary endothelial · corneal endothelial dystrophy · corneal endothelial dystrophy 2 · corneal endothelial dystrophy 2, autosomal recessive · corneal endothelial dystrophy 2, autosomal recessive, formerly · corneal endothelial dystrophy type 2 · corneal endothelial dystrophy, autosomal recessive · infantile hereditary endothelial dystrophy

Data availability: 94 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › corneal disorder › corneal dystrophy › corneal endothelial dystrophy › congenital hereditary endothelial dystrophy of cornea

Related subtypes (3): Fuchs’ endothelial dystrophy, X-linked endothelial corneal dystrophy, posterior polymorphous corneal dystrophy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

94 retrieved; paginated sample, class counts are floors:

22 benign, 20 likely pathogenic, 15 uncertain significance, 14 pathogenic/likely pathogenic, 14 pathogenic, 8 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066524	NM_001174089.2(SLC4A11):c.2306_2307del (p.Tyr769fs)	SLC4A11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072511	NM_001174089.2(SLC4A11):c.425_432dup (p.Arg145fs)	SLC4A11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1304	NM_001174089.2(SLC4A11):c.2216G>A (p.Arg739Gln)	SLC4A11	Pathogenic	criteria provided, single submitter
1305	NM_001174089.2(SLC4A11):c.1418C>T (p.Ser473Leu)	SLC4A11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1306	NM_001174089.2(SLC4A11):c.1343G>A (p.Gly448Asp)	SLC4A11	Pathogenic	criteria provided, single submitter
1307	NM_001174089.2(SLC4A11):c.1765C>T (p.Arg589Ter)	SLC4A11	Pathogenic	criteria provided, multiple submitters, no conflicts
1308	NM_001174089.2(SLC4A11):c.305_308del (p.Lys102fs)	SLC4A11	Pathogenic	no assertion criteria provided
1309	NM_001174089.2(SLC4A11):c.2557C>T (p.Arg853Cys)	SLC4A11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1310	NM_001174089.2(SLC4A11):c.2019-16_2019-6delinsGGCCGGCCGG	SLC4A11	Pathogenic	no assertion criteria provided
1311	NM_001174089.2(SLC4A11):c.2558G>A (p.Arg853His)	SLC4A11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1312	NM_001174089.2(SLC4A11):c.425_432del (p.Arg142fs)	SLC4A11	Pathogenic	criteria provided, multiple submitters, no conflicts
1316	NM_001174089.2(SLC4A11):c.2480T>C (p.Leu827Pro)	SLC4A11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1351232	NM_001174089.2(SLC4A11):c.671G>A (p.Trp224Ter)	SLC4A11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1356826	NM_001174089.2(SLC4A11):c.2185_2192dup (p.Ile732fs)	SLC4A11	Pathogenic	criteria provided, multiple submitters, no conflicts
1453845	NM_001174089.2(SLC4A11):c.1282+1G>A	SLC4A11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1504281	NM_001174089.2(SLC4A11):c.2558+1G>A	SLC4A11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1711855	NM_001174089.2(SLC4A11):c.1418C>G (p.Ser473Trp)	SLC4A11	Pathogenic	criteria provided, single submitter
1711856	NM_001174089.2(SLC4A11):c.2366dup (p.Ala790fs)	SLC4A11	Pathogenic	criteria provided, single submitter
208613	NM_001174089.2(SLC4A11):c.425_433delinsC (p.Arg142fs)	SLC4A11	Pathogenic	criteria provided, multiple submitters, no conflicts
2803216	NM_001174089.2(SLC4A11):c.2140del (p.Arg714fs)	SLC4A11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2906617	NM_001174089.2(SLC4A11):c.1189G>A (p.Gly397Arg)	SLC4A11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
649470	NM_001174089.2(SLC4A11):c.2215C>T (p.Arg739Trp)	SLC4A11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
664579	NM_001174089.2(SLC4A11):c.2158G>T (p.Glu720Ter)	SLC4A11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
666996	NM_001174089.2(SLC4A11):c.1110C>A (p.Cys370Ter)	SLC4A11	Pathogenic	criteria provided, multiple submitters, no conflicts
855486	NM_001174089.2(SLC4A11):c.2192+1G>A	SLC4A11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
855644	NM_001174089.2(SLC4A11):c.764C>T (p.Thr255Met)	SLC4A11	Pathogenic	criteria provided, multiple submitters, no conflicts
941893	NM_001174089.2(SLC4A11):c.62C>A (p.Ser21Ter)	SLC4A11	Pathogenic	criteria provided, multiple submitters, no conflicts
962167	NM_001174089.2(SLC4A11):c.2140C>T (p.Arg714Ter)	SLC4A11	Pathogenic	criteria provided, multiple submitters, no conflicts
1068021	NM_001174089.2(SLC4A11):c.1201G>A (p.Gly401Arg)	SLC4A11	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068065	NM_001174089.2(SLC4A11):c.1201G>C (p.Gly401Arg)	SLC4A11	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SLC4A11	Strong	Autosomal recessive	corneal dystrophy-perceptive deafness syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC4A11	Orphanet:1490	Corneal dystrophy-perceptive deafness syndrome
SLC4A11	Orphanet:293603	Congenital hereditary endothelial dystrophy type II
SLC4A11	Orphanet:98974	Fuchs endothelial corneal dystrophy
KRT3	Orphanet:98954	Meesmann corneal dystrophy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC4A11	HGNC:16438	ENSG00000088836	Q8NBS3	Solute carrier family 4 member 11	gencc,clinvar
KRT3	HGNC:6440	ENSG00000186442	P12035	Keratin, type II cytoskeletal 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC4A11	Solute carrier family 4 member 11	Multifunctional transporter with an impact in cell morphology and differentiation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC4A11	Other/Unknown	no		HCO3_transpt_euk, HCO3_transpt-like_TM_dom, PTrfase/Anion_transptr
KRT3	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephros cortex	1
nasal cavity epithelium	1
olfactory segment of nasal mucosa	1
gingiva	1
gingival epithelium	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC4A11	197	broad	marker	nasal cavity epithelium, olfactory segment of nasal mucosa, metanephros cortex
KRT3	35	tissue_specific	marker	gingiva, gingival epithelium, tendon of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT3	1,241
SLC4A11	846

Intra-cohort edges

A	B	Sources
KRT3	SLC4A11	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC4A11	Q8NBS3	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KRT3	P12035	66.82

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the cornified envelope	1	87.8×	0.027	KRT3
Keratinization	1	55.7×	0.027	KRT3
Developmental Biology	1	14.5×	0.069	KRT3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
borate transport	1	8426.0×	0.002	SLC4A11
fluid transport	1	2808.7×	0.003	SLC4A11
regulation of mesenchymal stem cell differentiation	1	2106.5×	0.003	SLC4A11
monoatomic ion homeostasis	1	1203.7×	0.004	SLC4A11
monoatomic anion transport	1	702.2×	0.004	SLC4A11
cellular hypotonic response	1	702.2×	0.004	SLC4A11
intracellular monoatomic cation homeostasis	1	561.7×	0.004	SLC4A11
intermediate filament cytoskeleton organization	1	468.1×	0.005	KRT3
bicarbonate transport	1	401.2×	0.005	SLC4A11
regulation of mitochondrial membrane potential	1	271.8×	0.006	SLC4A11
proton transmembrane transport	1	156.0×	0.010	SLC4A11
sodium ion transport	1	135.9×	0.010	SLC4A11
intermediate filament organization	1	120.4×	0.010	KRT3
keratinization	1	117.0×	0.010	KRT3
epithelial cell differentiation	1	87.8×	0.013	KRT3
transmembrane transport	1	84.3×	0.013	SLC4A11
cellular response to oxidative stress	1	77.3×	0.013	SLC4A11

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC4A11	0	0
KRT3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SLC4A11, KRT3

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC4A11	0	—
KRT3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	3
PHASE1	3
PHASE4	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05136443	PHASE4	COMPLETED	Loteprednol Etabonate 0.25% for Prevention of Cornea Transplant Rejection
NCT03575130	PHASE2	UNKNOWN	Ripasudil 0.4% Eye Drops in Fuchs Endothelial Corneal Dystrophy
NCT04520321	PHASE1/PHASE2	COMPLETED	A Phase 1/ Phase 2 Study of TTHX1114(NM141)
NCT04812067	PHASE2	COMPLETED	A Safety and Efficacy Trial of TTHX1114 in People With CED
NCT04843839	PHASE2	UNKNOWN	CHED - Congenital Hereditary Endothelial Dystrophy: New Paradigm Shift in Therapy Using Topical Eye Drops
NCT05636579	PHASE1	RECRUITING	Study to Assess Safety and Tolerability of Multiple Doses of EO2002
NCT04191629	PHASE1	UNKNOWN	Phase 1 Study to Evaluate the Safety and Tolerability of EO1404 in the Treatment of Corneal Edema
NCT04894110	PHASE1	COMPLETED	Study of Safety and Tolerability of EO2002 in the Treatment of Corneal Edema

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LOTEPREDNOL ETABONATE	4	1
NEPAFENAC	4	1
RIPASUDIL	3	2
VEHICLE	0	1