Brittle cornea syndrome

Summary

Brittle cornea syndrome (MONDO:0009242) is a disease with 2 cohort genes and 1 clinical trial. Top therapeutic interventions include riboflavin.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 1
• Phenotypes (HPO): 34
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		65	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0000974	Hyperextensible skin	Very frequent (80-99%)
HP:0000977	Soft skin	Very frequent (80-99%)
HP:0001119	Keratoglobus	Very frequent (80-99%)
HP:0001131	Corneal dystrophy	Very frequent (80-99%)
HP:0011003	High myopia	Very frequent (80-99%)
HP:0100689	Decreased corneal thickness	Very frequent (80-99%)
HP:0000405	Conductive hearing impairment	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000559	Corneal scarring	Frequent (30-79%)
HP:0000572	Visual loss	Frequent (30-79%)
HP:0000592	Blue sclerae	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0003326	Myalgia	Frequent (30-79%)
HP:0009887	Abnormality of hair pigmentation	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000501	Glaucoma	Occasional (5-29%)
HP:0000541	Retinal detachment	Occasional (5-29%)
HP:0001166	Arachnodactyly	Occasional (5-29%)
HP:0001319	Neonatal hypotonia	Occasional (5-29%)
HP:0001385	Hip dysplasia	Occasional (5-29%)
HP:0001634	Mitral valve prolapse	Occasional (5-29%)
HP:0001642	Pulmonic stenosis	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0001822	Hallux valgus	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002659	Increased susceptibility to fractures	Occasional (5-29%)
HP:0005930	Abnormality of epiphysis morphology	Occasional (5-29%)
HP:0012385	Camptodactyly	Occasional (5-29%)
HP:0100790	Hernia	Occasional (5-29%)
HP:0200020	Corneal erosion	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	brittle cornea syndrome
Mondo ID	MONDO:0009242
OMIM	229200
Orphanet	90354
DOID	DOID:14775
SNOMED CT	719096006
GARD	0001019
Is cancer (heuristic)	no

Also known as: BCS1 · brittle cornea syndrome · brittle cornea syndrome 1 · brittle cornea syndrome 2 · brittle cornea syndrome type 1 · EDS VIB (formerly) · Ehlers-Danlos syndrome type 6B (formerly) · kyphoscoliosis type

Data availability: 1 ClinVar variant · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › corneal disorder › brittle cornea syndrome

Related subtypes (23): cornea plana, pseudopterygium, corneal deposit, Bowman’s membrane folds or rupture, corneal degeneration, corneal staphyloma, corneal argyrosis, corneal ectasia, keratopathy, keratitis, corneal edema, megalocornea, X-linked corneal dermoid, Peters anomaly, pellucid marginal degeneration, keratoconus, corneal dystrophy, sclerocornea, cornea neoplasm, Arnold stickler bourne syndrome, limbal stem cell deficiency, thygeson superficial punctate keratopathy, Terrien marginal degeneration

Subtypes (2): brittle cornea syndrome 2, brittle cornea syndrome 1

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

1 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
321026	NM_001367624.2(ZNF469):c.11425G>A (p.Glu3809Lys)	ZNF469	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 2 · 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
PRDM5	Definitive	Autosomal recessive	brittle cornea syndrome 2	8
ZNF469	Definitive	Autosomal recessive	brittle cornea syndrome 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZNF469	Orphanet:90354	Brittle cornea syndrome
PRDM5	Orphanet:90354	Brittle cornea syndrome

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
ZNF469	HGNC:23216	ENSG00000225614	Q96JG9	Zinc finger protein 469	gencc,clinvar
PRDM5	HGNC:9349	ENSG00000138738	Q9NQX1	PR domain zinc finger protein 5	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZNF469	Zinc finger protein 469	May be involved in transcriptional regulation.
PRDM5	PR domain zinc finger protein 5	Sequence-specific DNA-binding transcription factor.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · 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	2	8.3×	0.015

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZNF469	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, ZNF469
PRDM5	Transcription factor	no		SET_dom, Znf_C2H2_type, Znf_PRDM5-like

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
cartilage tissue	1
tibia	1
upper arm skin	1
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZNF469	211	broad	yes	tibia, upper arm skin, cartilage tissue
PRDM5	206	ubiquitous	marker	calcaneal tendon, sural nerve, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRDM5	1,303
ZNF469	954

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRDM5	Q9NQX1	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZNF469	Q96JG9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
regulation of extracellular matrix organization	2	1872.4×	2e-06	ZNF469, PRDM5
negative regulation of transcription by RNA polymerase II	2	17.7×	0.013	ZNF469, PRDM5
methylation	1	85.1×	0.024	PRDM5
cellular response to leukemia inhibitory factor	1	79.5×	0.024	PRDM5
mitotic cell cycle	1	66.9×	0.024	PRDM5
chromatin organization	1	49.6×	0.027	PRDM5
negative regulation of DNA-templated transcription	1	15.8×	0.071	PRDM5
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	PRDM5

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
ZNF469	0	0
PRDM5	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	ZNF469, PRDM5

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)
ZNF469	0	—
PRDM5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01307527	Not specified	UNKNOWN	Riboflavin Corneal Crosslinking for Brittle Cornea Syndrome and Ehlers-Danlos Syndrome Type VI

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RIBOFLAVIN	4	1
CHEMBL511565	0	1
CHEMBL5267279	0	1