Bietti crystalline corneoretinal dystrophy

Summary

Bietti crystalline corneoretinal dystrophy (MONDO:0008865) is a disease caused by CYP4V2 (GenCC Definitive), with 3 cohort genes and 2 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: CYP4V2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 180
• Phenotypes (HPO): 19
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000654	Decreased light- and dark-adapted electroretinogram amplitude	Frequent (30-79%)
HP:0000662	Nyctalopia	Frequent (30-79%)
HP:0001133	Constriction of peripheral visual field	Frequent (30-79%)
HP:0007722	Retinal pigment epithelial atrophy	Frequent (30-79%)
HP:0007760	Crystalline corneal dystrophy	Frequent (30-79%)
HP:0030491	Choriocapillaris atrophy	Frequent (30-79%)
HP:0031528	Subretinal deposits	Frequent (30-79%)
HP:0200065	Chorioretinal degeneration	Frequent (30-79%)
HP:0000551	Color vision defect	Occasional (5-29%)
HP:0000580	Pigmentary retinopathy	Occasional (5-29%)
HP:0000603	Central scotoma	Occasional (5-29%)
HP:0000618	Blindness	Occasional (5-29%)
HP:0001129	Large central visual field defect	Occasional (5-29%)
HP:0001141	Severely reduced visual acuity	Occasional (5-29%)
HP:0007814	Retinal pigment epithelial mottling	Occasional (5-29%)
HP:0011505	Cystoid macular edema	Occasional (5-29%)
HP:0030329	Retinal thinning	Occasional (5-29%)
HP:0030528	Paracentral scotoma	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Bietti crystalline corneoretinal dystrophy
Mondo ID	MONDO:0008865
MeSH	C535440
OMIM	210370
Orphanet	41751
DOID	DOID:0050664
NCIT	C179299
SNOMED CT	312927001
UMLS	C1859486
MedGen	347895
GARD	0010050
Is cancer (heuristic)	no

Also known as: BCD · Bietti crystalline corneoretinal dystrophy · Bietti crystalline retinopathy

Data availability: 180 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › inherited retinal dystrophy › hereditary macular dystrophy › familial flecked retinopathy › Bietti crystalline corneoretinal dystrophy

Related subtypes (4): Doyne honeycomb retinal dystrophy, fundus albipunctatus, Kandori fleck retina, Stargardt disease

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

180 retrieved; paginated sample, class counts are floors:

87 uncertain significance, 29 pathogenic, 23 conflicting classifications of pathogenicity, 16 benign, 9 pathogenic/likely pathogenic, 9 benign/likely benign, 7 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
372290	NM_000350.3(ABCA4):c.3210_3211dup (p.Ser1071fs)	ABCA4	Pathogenic	reviewed by expert panel
1075096	NM_207352.4(CYP4V2):c.1168C>T (p.Arg390Cys)	CYP4V2	Pathogenic	criteria provided, multiple submitters, no conflicts
1322187	NM_207352.4(CYP4V2):c.267del (p.Leu89_Leu90insTer)	CYP4V2	Pathogenic	criteria provided, single submitter
1335569	NM_207352.4(CYP4V2):c.414-1G>A	CYP4V2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1697294	NM_207352.4(CYP4V2):c.801+1G>A	CYP4V2	Pathogenic	criteria provided, multiple submitters, no conflicts
1698830	NM_207352.4(CYP4V2):c.1219G>T (p.Glu407Ter)	CYP4V2	Pathogenic	criteria provided, single submitter
209986	NM_207352.4(CYP4V2):c.1396A>G (p.Asn466Asp)	CYP4V2	Pathogenic	no assertion criteria provided
2188	NM_207352.4(CYP4V2):c.332T>C (p.Ile111Thr)	CYP4V2	Pathogenic	criteria provided, multiple submitters, no conflicts
2190	NM_207352.4(CYP4V2):c.181G>A (p.Gly61Ser)	CYP4V2	Pathogenic	no assertion criteria provided
2191	NM_207352.4(CYP4V2):c.1091-2A>G	CYP4V2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39248	NM_207352.4(CYP4V2):c.1020G>A (p.Trp340Ter)	CYP4V2	Pathogenic	criteria provided, multiple submitters, no conflicts
39249	NM_207352.4(CYP4V2):c.1021T>C (p.Ser341Pro)	CYP4V2	Pathogenic	no assertion criteria provided
39250	NM_207352.4(CYP4V2):c.1157A>C (p.Lys386Thr)	CYP4V2	Pathogenic	no assertion criteria provided
39251	NM_207352.4(CYP4V2):c.1169G>A (p.Arg390His)	CYP4V2	Pathogenic	criteria provided, multiple submitters, no conflicts
39252	NM_207352.4(CYP4V2):c.1187C>T (p.Pro396Leu)	CYP4V2	Pathogenic	criteria provided, single submitter
39254	NM_207352.4(CYP4V2):c.1199G>A (p.Arg400His)	CYP4V2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39255	NM_207352.4(CYP4V2):c.1226-6_1235del	CYP4V2	Pathogenic	no assertion criteria provided
39256	NM_207352.4(CYP4V2):c.1348C>T (p.Gln450Ter)	CYP4V2	Pathogenic	criteria provided, multiple submitters, no conflicts
39257	NM_207352.4(CYP4V2):c.1445C>A (p.Ser482Ter)	CYP4V2	Pathogenic	no assertion criteria provided
39260	NM_207352.4(CYP4V2):c.253C>T (p.Arg85Cys)	CYP4V2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39261	NM_207352.4(CYP4V2):c.283G>A (p.Gly95Arg)	CYP4V2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39262	NM_207352.4(CYP4V2):c.327+1G>A	CYP4V2	Pathogenic	criteria provided, single submitter
39263	NM_207352.4(CYP4V2):c.335T>G (p.Leu112Ter)	CYP4V2	Pathogenic	no assertion criteria provided
39265	NM_207352.4(CYP4V2):c.400G>T (p.Gly134Ter)	CYP4V2	Pathogenic	criteria provided, multiple submitters, no conflicts
39266	NM_207352.4(CYP4V2):c.518T>G (p.Leu173Trp)	CYP4V2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39268	NM_207352.4(CYP4V2):c.655T>C (p.Tyr219His)	CYP4V2	Pathogenic	no assertion criteria provided
39269	NM_207352.4(CYP4V2):c.759dup (p.His254fs)	CYP4V2	Pathogenic	no assertion criteria provided
39271	NM_207352.4(CYP4V2):c.802-8_810delinsGC	CYP4V2	Pathogenic	criteria provided, multiple submitters, no conflicts
39272	NM_207352.4(CYP4V2):c.958C>T (p.Arg320Ter)	CYP4V2	Pathogenic	no assertion criteria provided
39273	NM_207352.4(CYP4V2):c.971A>T (p.Asp324Val)	CYP4V2	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · 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
CYP4V2	Definitive	Autosomal recessive	Bietti crystalline corneoretinal dystrophy	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP4V2	Orphanet:41751	Bietti crystalline dystrophy
ABCA4	Orphanet:1872	Cone rod dystrophy
ABCA4	Orphanet:791	Retinitis pigmentosa
ABCA4	Orphanet:827	Stargardt disease
KLKB1	Orphanet:749	Congenital prekallikrein deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYP4V2	HGNC:23198	ENSG00000145476	Q6ZWL3	Cytochrome P450 4V2	gencc,clinvar
ABCA4	HGNC:34	ENSG00000198691	P78363	Retinal-specific phospholipid-transporting ATPase ABCA4	clinvar
KLKB1	HGNC:6371	ENSG00000164344	P03952	Plasma kallikrein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYP4V2	Cytochrome P450 4V2	A cytochrome P450 monooxygenase involved in fatty acid metabolism in the eye.
ABCA4	Retinal-specific phospholipid-transporting ATPase ABCA4	Flippase that catalyzes in an ATP-dependent manner the transport of retinal-phosphatidylethanolamine conjugates like 11-cis and all-trans isomers of N-retinylidene-phosphatidylethanolamine (N-Ret-PE) from the lumen to the cytoplasmic leafl…
KLKB1	Plasma kallikrein	Participates in the surface-dependent activation of blood coagulation.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Transporter	1	25.9×	0.114
Protease	1	12.2×	0.120
Enzyme (other)	1	4.0×	0.230

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYP4V2	Enzyme (other)	yes	1.14.14.79	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS
ABCA4	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABCA4/ABCR
KLKB1	Protease	yes	3.4.21.34	Apple, Trypsin_dom, Peptidase_S1A

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	2
primordial germ cell in gonad	2
ileal mucosa	1
kidney epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
pigmented layer of retina	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYP4V2	254	ubiquitous	marker	kidney epithelium, ileal mucosa, liver
ABCA4	164	tissue_specific	marker	pigmented layer of retina, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
KLKB1	196	tissue_specific	yes	right lobe of liver, liver, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYP4V2	1,867
KLKB1	1,537
ABCA4	1,532

Intra-cohort edges

A	B	Sources
ABCA4	CYP4V2	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KLKB1	P03952	22
ABCA4	P78363	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYP4V2	Q6ZWL3	91.05

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
The canonical retinoid cycle in rods (twilight vision)	2	346.1×	3e-04	CYP4V2, ABCA4
Defective visual phototransduction due to ABCA4 loss of function	1	3806.7×	0.003	ABCA4
R-HSA-9651496	1	1268.9×	0.003	KLKB1
Retinoid cycle disease events	1	951.7×	0.003	ABCA4
Diseases associated with visual transduction	1	951.7×	0.003	ABCA4
Defective factor XII causes hereditary angioedema	1	951.7×	0.003	KLKB1
Defective SERPING1 causes hereditary angioedema	1	951.7×	0.003	KLKB1
Diseases of hemostasis	1	951.7×	0.003	KLKB1
Diseases of the neuronal system	1	951.7×	0.003	ABCA4
R-HSA-140837	1	475.8×	0.005	KLKB1
Regulation of FXIIa and plasma kallikrein activity	1	380.7×	0.005	KLKB1
FXIIa, PKa-dependent activation of coagulation pathway	1	380.7×	0.005	KLKB1
R-HSA-140877	1	317.2×	0.006	KLKB1
Endogenous sterols	1	131.3×	0.013	CYP4V2
Activation of Matrix Metalloproteinases	1	102.9×	0.016	KLKB1
Visual phototransduction	1	86.5×	0.017	ABCA4
FXIIa activates plasma kallikrein-kinin system	1	57.7×	0.023	KLKB1
Disease	2	8.7×	0.023	ABCA4, KLKB1
ABC-family protein mediated transport	1	40.5×	0.030	ABCA4
Degradation of the extracellular matrix	1	39.2×	0.030	KLKB1
Sensory Perception	1	31.7×	0.036	ABCA4
Extracellular matrix organization	1	21.0×	0.051	KLKB1
Hemostasis	1	12.0×	0.085	KLKB1
Transport of small molecules	1	8.4×	0.115	ABCA4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
retinoid metabolic process	2	330.4×	2e-04	CYP4V2, ABCA4
Factor XII activation	1	1872.4×	0.002	KLKB1
phospholipid transfer to membrane	1	1872.4×	0.002	ABCA4
visual perception	2	53.0×	0.002	CYP4V2, ABCA4
positive regulation of fibrinolysis	1	1123.5×	0.003	KLKB1
fatty acid omega-oxidation	1	936.2×	0.003	CYP4V2
phototransduction, visible light	1	432.1×	0.005	ABCA4
plasminogen activation	1	432.1×	0.005	KLKB1
retinal metabolic process	1	312.1×	0.006	ABCA4
sterol metabolic process	1	280.9×	0.006	CYP4V2
fibrinolysis	1	280.9×	0.006	KLKB1
zymogen activation	1	224.7×	0.007	KLKB1
phospholipid translocation	1	208.1×	0.007	ABCA4
photoreceptor cell maintenance	1	119.5×	0.011	ABCA4
lipid transport	1	87.8×	0.014	ABCA4
blood coagulation	1	57.9×	0.019	KLKB1
transmembrane transport	1	56.2×	0.019	ABCA4
proteolysis	1	11.4×	0.085	KLKB1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
KLKB1	BEROTRALSTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KLKB1	10	4
CYP4V2	0	0
ABCA4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEROTRALSTAT	4	KLKB1
DAREXABAN	3	KLKB1
MILVEXIAN	3	KLKB1
AVORALSTAT	3	KLKB1
SEBETRALSTAT	3	KLKB1
GABEXATE	3	KLKB1
LETAXABAN	2	KLKB1
GW813893	2	KLKB1
FENIRALSTAT	2	KLKB1
BMS-962212	1	KLKB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
KLKB1	300	Binding:283, ADMET:17

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP4V2	1.14.14.79	docosahexaenoic acid omega-hydroxylase
KLKB1	3.4.21.34	plasma kallikrein

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
KLKB1	300

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

10 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.

Compound	Max phase	Cohort target (bioactivity)
BEROTRALSTAT	4	KLKB1
DAREXABAN	3	KLKB1
MILVEXIAN	3	KLKB1
AVORALSTAT	3	KLKB1
SEBETRALSTAT	3	KLKB1
GABEXATE	3	KLKB1
LETAXABAN	2	KLKB1
GW813893	2	KLKB1
FENIRALSTAT	2	KLKB1
BMS-962212	1	KLKB1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KLKB1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ABCA4
D	Druggable family + AlphaFold only, no drug	1	CYP4V2
E	Difficult family or no structure, no drug	0

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)
CYP4V2	0	—
ABCA4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06743646	PHASE3	RECRUITING	Efficacy and Safety of ZVS101e in Patients With Bietti ’s Crystalline Dystrophy
NCT06706427	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety and Efficacy Study of NGGT001 in Bietti Crystalline Corneoretinal Dystrophy Subjects