Posterior polymorphous corneal dystrophy

Summary

Posterior polymorphous corneal dystrophy (MONDO:0020364) is a disease caused by GRHL2 (GenCC Strong), with 5 cohort genes and 3 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Czech Republic) [Orphanet-validated]
• Causal gene: GRHL2 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 61
• Phenotypes (HPO): 20
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1	Czech Republic	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0011490	Abnormal Descemet membrane morphology	Very frequent (80-99%)
HP:0011491	Reduced number of corneal endothelial cells	Very frequent (80-99%)
HP:0000483	Astigmatism	Occasional (5-29%)
HP:0000646	Amblyopia	Occasional (5-29%)
HP:0007663	Reduced visual acuity	Occasional (5-29%)
HP:0011483	Anterior synechiae of the anterior chamber	Occasional (5-29%)
HP:0012040	Corneal stromal edema	Occasional (5-29%)
HP:0025358	Uveal ectropion	Occasional (5-29%)
HP:0032122	Very low visual acuity	Occasional (5-29%)
HP:0100692	Increased corneal curvature	Occasional (5-29%)
HP:0000501	Glaucoma	Very rare (<1-4%)
HP:0000565	Esotropia	Very rare (<1-4%)
HP:0000613	Photophobia	Very rare (<1-4%)
HP:0000622	Blurred vision	Very rare (<1-4%)
HP:0000632	Lacrimation abnormality	Very rare (<1-4%)
HP:0007906	Ocular hypertension	Very rare (<1-4%)
HP:0007957	Corneal opacity	Very rare (<1-4%)
HP:0009918	Ectopia pupillae	Very rare (<1-4%)
HP:0200026	Ocular pain	Very rare (<1-4%)
HP:0200065	Chorioretinal degeneration	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	posterior polymorphous corneal dystrophy
Mondo ID	MONDO:0020364
OMIM	122000
Orphanet	98973
DOID	DOID:0060457
ICD-11	935421185
UMLS	C0339284
MedGen	87382
GARD	0016882
Is cancer (heuristic)	no

Also known as: corneal dystrophy, posterior polymorphous · posterior polymorphous dystrophy · PPCD · Schlichting dystrophy

Data availability: 61 ClinVar variants · 6 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › corneal disorder › corneal dystrophy › corneal endothelial dystrophy › posterior polymorphous corneal dystrophy

Related subtypes (3): Fuchs’ endothelial dystrophy, congenital hereditary endothelial dystrophy of cornea, X-linked endothelial corneal dystrophy

Subtypes (4): posterior polymorphous corneal dystrophy 1, posterior polymorphous corneal dystrophy 2, posterior polymorphous corneal dystrophy 3, corneal dystrophy, posterior polymorphous, 4

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

61 retrieved; paginated sample, class counts are floors:

28 uncertain significance, 17 benign, 7 benign/likely benign, 4 conflicting classifications of pathogenicity, 3 likely benign, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
374184	NM_001174096.2(ZEB1):c.976C>T (p.Arg326Ter)	ZEB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1300210	NM_001174096.2(ZEB1):c.623dup (p.Tyr208Ter)	ZEB1	Likely pathogenic	criteria provided, single submitter
337958	NM_014588.6(VSX1):c.740C>G (p.Pro247Arg)	VSX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337959	NM_014588.6(VSX1):c.731A>G (p.His244Arg)	VSX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337970	NM_014588.6(VSX1):c.173C>T (p.Pro58Leu)	VSX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
5248	NM_014588.6(VSX1):c.479G>A (p.Gly160Asp)	VSX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337943	NM_014588.5(VSX1):c.*820T>C	VSX1	Uncertain significance	criteria provided, single submitter
337944	NM_014588.6(VSX1):c.*749C>T	VSX1	Uncertain significance	criteria provided, single submitter
337953	NM_014588.6(VSX1):c.*159G>A	VSX1	Uncertain significance	criteria provided, single submitter
337954	NM_014588.6(VSX1):c.*89T>C	VSX1	Uncertain significance	criteria provided, single submitter
337955	NM_014588.6(VSX1):c.*88C>G	VSX1	Uncertain significance	criteria provided, single submitter
337968	NM_014588.6(VSX1):c.281C>A (p.Ala94Glu)	VSX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
337972	NM_014588.5(VSX1):c.-61C>G	VSX1	Uncertain significance	criteria provided, single submitter
337973	NM_014588.5(VSX1):c.-175C>G	VSX1	Uncertain significance	criteria provided, single submitter
337976	NM_014588.5(VSX1):c.-244G>T	VSX1	Uncertain significance	criteria provided, single submitter
337979	NM_014588.5(VSX1):c.-271G>T	VSX1	Uncertain significance	criteria provided, single submitter
488734	NM_014588.6(VSX1):c.165C>A (p.Cys55Ter)	VSX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
5247	NM_014588.6(VSX1):c.496C>T (p.Arg166Trp)	VSX1	Uncertain significance	criteria provided, single submitter
895532	NM_014588.6(VSX1):c.*64G>T	VSX1	Uncertain significance	criteria provided, single submitter
895533	NM_014588.6(VSX1):c.871C>T (p.Leu291Phe)	VSX1	Uncertain significance	criteria provided, single submitter
895534	NM_014588.6(VSX1):c.768C>T (p.Ala256=)	VSX1	Uncertain significance	criteria provided, single submitter
895607	NM_014588.6(VSX1):c.83C>T (p.Pro28Leu)	VSX1	Uncertain significance	criteria provided, single submitter
896936	NM_014588.6(VSX1):c.578C>T (p.Ala193Val)	VSX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
896937	NM_014588.6(VSX1):c.557C>T (p.Ala186Val)	VSX1	Uncertain significance	criteria provided, single submitter
897367	NM_014588.6(VSX1):c.*610G>A	VSX1	Uncertain significance	criteria provided, single submitter
897431	NM_014588.6(VSX1):c.485G>A (p.Arg162Lys)	VSX1	Uncertain significance	criteria provided, single submitter
898522	NM_014588.6(VSX1):c.*416T>C	VSX1	Uncertain significance	criteria provided, single submitter
898523	NM_014588.6(VSX1):c.*396T>G	VSX1	Uncertain significance	criteria provided, single submitter
898524	NM_014588.6(VSX1):c.*169G>A	VSX1	Uncertain significance	criteria provided, single submitter
898525	NM_014588.6(VSX1):c.*112A>G	VSX1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 40 · Orphanet: 9 · 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
OVOL2	Definitive	Autosomal dominant	posterior polymorphous corneal dystrophy 1	6
ZEB1	Definitive	Autosomal dominant	posterior polymorphous corneal dystrophy 3	8
COL8A2	Strong	Autosomal dominant	posterior polymorphous corneal dystrophy 2	4
GRHL2	Strong	Autosomal dominant	corneal dystrophy, posterior polymorphous, 4	14
VSX1	Supportive	Autosomal dominant	posterior polymorphous corneal dystrophy	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZEB1	Orphanet:98973	Posterior polymorphous corneal dystrophy
ZEB1	Orphanet:98974	Fuchs endothelial corneal dystrophy
VSX1	Orphanet:98973	Posterior polymorphous corneal dystrophy
OVOL2	Orphanet:98973	Posterior polymorphous corneal dystrophy
COL8A2	Orphanet:98973	Posterior polymorphous corneal dystrophy
COL8A2	Orphanet:98974	Fuchs endothelial corneal dystrophy
GRHL2	Orphanet:423454	Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome
GRHL2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GRHL2	Orphanet:98973	Posterior polymorphous corneal dystrophy

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ZEB1	HGNC:11642	ENSG00000148516	P37275	Zinc finger E-box-binding homeobox 1	gencc,clinvar
VSX1	HGNC:12723	ENSG00000100987	Q9NZR4	Visual system homeobox 1	gencc,clinvar
OVOL2	HGNC:15804	ENSG00000125850	Q9BRP0	Transcription factor Ovo-like 2	gencc
COL8A2	HGNC:2216	ENSG00000171812	P25067	Collagen alpha-2(VIII) chain	gencc
GRHL2	HGNC:2799	ENSG00000083307	Q6ISB3	Grainyhead-like protein 2 homolog	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZEB1	Zinc finger E-box-binding homeobox 1	Acts as a transcriptional repressor.
VSX1	Visual system homeobox 1	Binds to the 37-bp core of the locus control region (LCR) of the red/green visual pigment gene cluster.
OVOL2	Transcription factor Ovo-like 2	Zinc-finger transcription repressor factor.
COL8A2	Collagen alpha-2(VIII) chain	Macromolecular component of the subendothelium.
GRHL2	Grainyhead-like protein 2 homolog	Transcription factor playing an important role in primary neurulation and in epithelial development.

Protein-family classification

Druggable: 0 · Difficult: 4 · Unknown: 1 · 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
Transcription factor	4	6.6×	0.002
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZEB1	Transcription factor	no		HD, Di19_Zn-bd, Homeodomain-like_sf
VSX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
OVOL2	Transcription factor	no		Znf_C2H2_type, Ovo-like, Znf_C2H2_sf
COL8A2	Other/Unknown	no		C1q_dom, Collagen, Tumour_necrosis_fac-like_dom
GRHL2	Transcription factor	no		CP2, TF_CP2-like, GRHL1/CP2_C

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
colonic epithelium	1
tendon	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
mucosa of transverse colon	1
olfactory segment of nasal mucosa	1
pancreatic ductal cell	1
ascending aorta	1
periodontal ligament	1
tendon of biceps brachii	1
buccal mucosa cell	1
cervix squamous epithelium	1
oviduct epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZEB1	287	ubiquitous	marker	calcaneal tendon, colonic epithelium, tendon
VSX1	110	tissue_specific	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
OVOL2	190	broad	yes	pancreatic ductal cell, mucosa of transverse colon, olfactory segment of nasal mucosa
COL8A2	230	broad	marker	periodontal ligament, tendon of biceps brachii, ascending aorta
GRHL2	200	broad	marker	buccal mucosa cell, oviduct epithelium, cervix squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZEB1	4,171
COL8A2	1,544
GRHL2	1,365
VSX1	1,133
OVOL2	860

Intra-cohort edges

A	B	Sources
COL8A2	VSX1	string_interaction
COL8A2	ZEB1	string_interaction
GRHL2	OVOL2	string_interaction
GRHL2	ZEB1	string_interaction
OVOL2	ZEB1	string_interaction
VSX1	ZEB1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ZEB1	P37275	1
GRHL2	Q6ISB3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VSX1	Q9NZR4	61.61
OVOL2	Q9BRP0	61.52
COL8A2	P25067	58.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 5 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	439.2×	0.018	ZEB1
Collagen chain trimerization	1	129.8×	0.019	COL8A2
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.019	COL8A2
Collagen degradation	1	87.8×	0.019	COL8A2
Collagen biosynthesis and modifying enzymes	1	85.2×	0.019	COL8A2
Integrin cell surface interactions	1	67.2×	0.019	COL8A2
Negative Regulation of CDH1 Gene Transcription	1	60.1×	0.019	ZEB1
Interleukin-4 and Interleukin-13 signaling	1	51.4×	0.019	ZEB1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of mesenchymal cell proliferation	1	3370.4×	0.007	ZEB1
negative regulation of white fat cell proliferation	1	3370.4×	0.007	OVOL2
epithelium migration	1	3370.4×	0.007	GRHL2
epithelial cell morphogenesis involved in placental branching	1	1123.5×	0.011	GRHL2
neural fold formation	1	842.6×	0.011	OVOL2
endocardium formation	1	842.6×	0.011	OVOL2
anterior neural tube closure	1	842.6×	0.011	GRHL2
negative regulation of endothelial cell differentiation	1	674.1×	0.011	ZEB1
regulation of smooth muscle cell differentiation	1	674.1×	0.011	ZEB1
retinal bipolar neuron differentiation	1	561.7×	0.011	VSX1
regulation of T cell differentiation in thymus	1	481.5×	0.011	ZEB1
semicircular canal morphogenesis	1	481.5×	0.011	ZEB1
lung lobe morphogenesis	1	421.3×	0.011	GRHL2
cardiac ventricle morphogenesis	1	374.5×	0.011	GRHL2
lung epithelial cell differentiation	1	374.5×	0.011	GRHL2
basement membrane assembly	1	374.5×	0.011	COL8A2
epidermal cell differentiation	1	337.0×	0.011	OVOL2
cell junction assembly	1	337.0×	0.011	GRHL2
negative regulation of keratinocyte differentiation	1	337.0×	0.011	OVOL2
angiogenesis	2	25.0×	0.011	OVOL2, COL8A2
regulation of keratinocyte proliferation	1	306.4×	0.011	OVOL2
obsolete negative regulation of transcription by competitive promoter binding	1	259.3×	0.013	OVOL2
embryonic camera-type eye morphogenesis	1	224.7×	0.014	ZEB1
heart trabecula formation	1	224.7×	0.014	OVOL2
epithelial cell morphogenesis	1	187.2×	0.014	GRHL2
embryonic digestive tract morphogenesis	1	187.2×	0.014	OVOL2
negative regulation of stem cell proliferation	1	168.5×	0.014	OVOL2
regulation of transforming growth factor beta receptor signaling pathway	1	160.5×	0.014	ZEB1
neuron maturation	1	160.5×	0.014	VSX1
positive regulation of keratinocyte differentiation	1	160.5×	0.014	OVOL2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 0 of 5 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
ZEB1	0	0
VSX1	0	0
OVOL2	0	0
COL8A2	0	0
GRHL2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	5	ZEB1, VSX1, OVOL2, COL8A2, GRHL2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ZEB1	0	—
VSX1	0	—
OVOL2	0	—
COL8A2	0	—
GRHL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00800111	Not specified	COMPLETED	Study of Endothelial Keratoplasty Outcomes
NCT02020044	Not specified	UNKNOWN	Outcome After Descemet Membrane Endothelial Keratoplasty (DMEK) and Ultra-thin Descemet Stripping Automated Endothelial Keratoplasty (DSAEK)
NCT04387331	Not specified	UNKNOWN	The Postoperative Head Position as a Predictor of the Surgical Outcome After DMEK