Brittle cornea syndrome 1

Summary

Brittle cornea syndrome 1 (MONDO:0024543) is a disease caused by ZNF469 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ZNF469 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 326

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	brittle cornea syndrome 1
Mondo ID	MONDO:0024543
MeSH	C536192
OMIM	229200
SNOMED CT	31798004
UMLS	C0268344
MedGen	78661
GARD	0025424
Is cancer (heuristic)	no

Also known as: BCS1 · brittle cornea syndrome 1 · brittle cornea syndrome caused by mutation in ZNF469 · ZNF469 brittle cornea syndrome

Data availability: 326 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 › brittle cornea syndrome › brittle cornea syndrome 1

Related subtypes (1): brittle cornea syndrome 2

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

326 retrieved; paginated sample, class counts are floors:

98 conflicting classifications of pathogenicity, 88 benign/likely benign, 69 uncertain significance, 19 benign, 18 likely pathogenic, 15 pathogenic, 8 pathogenic/likely pathogenic, 6 likely benign, 5 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
30942	NM_001367624.2(ZNF469):c.10100G>A (p.Cys3367Tyr)	LOC130059719	Pathogenic	no assertion criteria provided
1363096	NM_001367624.2(ZNF469):c.8350C>T (p.Arg2784Ter)	ZNF469	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1364049	NM_001367624.2(ZNF469):c.5661_5668del (p.His1888fs)	ZNF469	Pathogenic	criteria provided, multiple submitters, no conflicts
1683288	NM_001367624.2(ZNF469):c.8428del (p.Ala2810fs)	ZNF469	Pathogenic	criteria provided, multiple submitters, no conflicts
195115	NM_001367624.2(ZNF469):c.9268C>T (p.Arg3090Ter)	ZNF469	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2018583	NM_001367624.2(ZNF469):c.10324_10325del (p.Arg3442fs)	ZNF469	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2429181	NM_001367624.2(ZNF469):c.4112dup (p.Pro1373fs)	ZNF469	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2847327	NM_001367624.2(ZNF469):c.1171_1175del (p.Leu391fs)	ZNF469	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
291239	NM_001367624.2(ZNF469):c.6444del (p.Gln2149fs)	ZNF469	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30943	NM_001367624.2(ZNF469):c.4258G>T (p.Glu1420Ter)	ZNF469	Pathogenic	no assertion criteria provided
3376971	NM_001367624.2(ZNF469):c.612_619dup (p.Ala207fs)	ZNF469	Pathogenic	criteria provided, single submitter
3377486	NM_001367624.2(ZNF469):c.3491del (p.Gly1164fs)	ZNF469	Pathogenic	criteria provided, single submitter
3629492	NM_001367624.2(ZNF469):c.628_629delinsA (p.Pro210fs)	ZNF469	Pathogenic	criteria provided, single submitter
3821087	NM_001367624.2(ZNF469):c.9915del (p.Arg3306fs)	ZNF469	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3907483	NM_001367624.2(ZNF469):c.5281dup (p.Ser1761fs)	ZNF469	Pathogenic	criteria provided, single submitter
453086	NM_001127464.2(ZNF469):c.3034delG (p.Val1012Serfs)	ZNF469	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4531624	NM_001367624.2(ZNF469):c.6593_6596dup (p.Leu2199fs)	ZNF469	Pathogenic	criteria provided, single submitter
4535533	NC_000016.9:g.(88491280_88493752)(88507162?)del	ZNF469	Pathogenic	criteria provided, single submitter
4847422	NM_001367624.2(ZNF469):c.6749dup (p.Leu2250fs)	ZNF469	Pathogenic	criteria provided, single submitter
730	NM_001367624.2(ZNF469):c.6027del (p.Gly2011fs)	ZNF469	Pathogenic	no assertion criteria provided
731	NM_001367624.2(ZNF469):c.9615del (p.Gln3206fs)	ZNF469	Pathogenic	no assertion criteria provided
981037	NM_001367624.2(ZNF469):c.1444del (p.Leu482fs)	ZNF469	Pathogenic	criteria provided, single submitter
981041	NM_001367624.2(ZNF469):c.3307C>T (p.Gln1103Ter)	ZNF469	Pathogenic	criteria provided, single submitter
4082192	Single allele		Likely pathogenic	criteria provided, single submitter
4082193	Single allele		Likely pathogenic	criteria provided, single submitter
3581324	NM_001367624.2(ZNF469):c.3276C>G (p.Tyr1092Ter)	LOC130059718	Likely pathogenic	criteria provided, single submitter
1175895	NM_001367624.2(ZNF469):c.3754dup (p.Cys1252fs)	ZNF469	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1331466	NM_001367624.2(ZNF469):c.10707C>A (p.Cys3569Ter)	ZNF469	Likely pathogenic	criteria provided, single submitter
2429180	NM_001367624.2(ZNF469):c.5402del (p.Val1801fs)	ZNF469	Likely pathogenic	criteria provided, single submitter
2501120	NM_001367624.2(ZNF469):c.7874_7877dup (p.His2626fs)	ZNF469	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ZNF469	HGNC:23216	ENSG00000225614	Q96JG9	Zinc finger protein 469	gencc,clinvar

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.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZNF469	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, ZNF469

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	1
tibia	1
upper arm skin	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZNF469	954

Structural data

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

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 1 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 1 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	1	1872.4×	0.001	ZNF469
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	ZNF469

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	ZNF469

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ZNF469	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.