Autosomal recessive bestrophinopathy

Summary

Autosomal recessive bestrophinopathy (MONDO:0012733) is a disease caused by BEST1 (GenCC Definitive), with 4 cohort genes and 3 clinical trials. Top therapeutic interventions include amantadine and terfenadine.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: BEST1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 69
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive bestrophinopathy
Mondo ID	MONDO:0012733
MeSH	C567518
OMIM	611809
Orphanet	139455
DOID	DOID:0050662
SNOMED CT	723828008
UMLS	C3888198
MedGen	854806
GARD	0010301
Is cancer (heuristic)	no

Also known as: ARB · bestrophinopathy, autosomal recessive · retinopathy, Burgess-Black type

Data availability: 69 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › macular degeneration › autosomal recessive bestrophinopathy

Related subtypes (8): vitelliform macular dystrophy, degeneration of macula and posterior pole, macular retinal edema, occult macular dystrophy, macular degeneration, early-onset, Stargardt disease, patterned macular dystrophy, isolated macular 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

69 retrieved; paginated sample, class counts are floors:

24 pathogenic/likely pathogenic, 12 pathogenic, 9 likely pathogenic, 9 conflicting classifications of pathogenicity, 6 uncertain significance, 6 benign, 2 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1004951	NM_004183.4(BEST1):c.638A>G (p.Glu213Gly)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1297719	NM_004183.4(BEST1):c.1403C>T (p.Pro468Leu)	BEST1	Pathogenic	criteria provided, multiple submitters, no conflicts
143127	NM_004183.4(BEST1):c.763C>T (p.Arg255Trp)	BEST1	Pathogenic	criteria provided, multiple submitters, no conflicts
1483189	NM_004183.4(BEST1):c.313C>A (p.Arg105Ser)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2039113	NM_004183.4(BEST1):c.508C>T (p.Gln170Ter)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265462	NM_004183.4(BEST1):c.604C>T (p.Arg202Trp)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265463	NM_004183.4(BEST1):c.636+1G>A	BEST1	Pathogenic	criteria provided, multiple submitters, no conflicts
2738	NM_004183.4(BEST1):c.140G>A (p.Arg47His)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2739	NM_004183.4(BEST1):c.1470_1471del (p.His490fs)	BEST1	Pathogenic	criteria provided, multiple submitters, no conflicts
2740	NM_004183.4(BEST1):c.422G>A (p.Arg141His)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2741	NM_004183.4(BEST1):c.598C>T (p.Arg200Ter)	BEST1	Pathogenic	criteria provided, multiple submitters, no conflicts
2742	NM_004183.4(BEST1):c.949G>A (p.Val317Met)	BEST1	Pathogenic	no assertion criteria provided
2743	NM_004183.4(BEST1):c.122T>C (p.Leu41Pro)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279702	NM_004183.4(BEST1):c.103G>A (p.Glu35Lys)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3007895	NM_004183.4(BEST1):c.454C>T (p.Pro152Ser)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3061944	NM_004183.4(BEST1):c.1242G>A (p.Trp414Ter)	BEST1	Pathogenic	criteria provided, single submitter
3359098	NM_004183.4(BEST1):c.551_552delinsT (p.Pro184fs)	BEST1	Pathogenic	criteria provided, single submitter
3776134	NM_004183.4(BEST1):c.948+1del	BEST1	Pathogenic	criteria provided, single submitter
422323	NM_004183.4(BEST1):c.658C>T (p.Gln220Ter)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
427886	NM_004183.4(BEST1):c.400C>G (p.Leu134Val)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4292577	NM_004183.4(BEST1):c.481+1G>T	BEST1	Pathogenic	criteria provided, single submitter
505511	NM_004183.4(BEST1):c.1514_1515del (p.Val505fs)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522511	NM_004183.4(BEST1):c.1370C>G (p.Pro457Arg)	BEST1	Pathogenic	no assertion criteria provided
632163	NM_004183.4(BEST1):c.1415del (p.Leu472fs)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
829895	NM_004183.4(BEST1):c.424_426dup (p.Ser142_Val143insSer)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
877528	NM_004183.4(BEST1):c.302C>T (p.Pro101Leu)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
962776	NM_004183.4(BEST1):c.388C>A (p.Arg130Ser)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
99695	NM_004183.4(BEST1):c.240C>A (p.Phe80Leu)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
99717	NM_004183.4(BEST1):c.38G>A (p.Arg13His)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
99725	NM_004183.4(BEST1):c.584C>T (p.Ala195Val)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 21 · 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
BEST1	Definitive	Autosomal recessive	autosomal recessive bestrophinopathy	22

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BEST1	Orphanet:1243	Best vitelliform macular dystrophy
BEST1	Orphanet:139455	Autosomal recessive bestrophinopathy
BEST1	Orphanet:263347	MRCS syndrome
BEST1	Orphanet:3086	Autosomal dominant vitreoretinochoroidopathy
BEST1	Orphanet:35612	Nanophthalmos
BEST1	Orphanet:791	Retinitis pigmentosa
BEST1	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy
CRB1	Orphanet:251295	Pigmented paravenous retinochoroidal atrophy
CRB1	Orphanet:35612	Nanophthalmos
CRB1	Orphanet:65	Leber congenital amaurosis
CRB1	Orphanet:791	Retinitis pigmentosa
FTH1	Orphanet:247790	FTH1-related iron overload
PRPH2	Orphanet:1872	Cone rod dystrophy
PRPH2	Orphanet:227796	Fundus albipunctatus
PRPH2	Orphanet:52427	Retinitis punctata albescens
PRPH2	Orphanet:75377	Central areolar choroidal dystrophy
PRPH2	Orphanet:791	Retinitis pigmentosa
PRPH2	Orphanet:827	Stargardt disease
PRPH2	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy
PRPH2	Orphanet:99001	Butterfly-shaped pigment dystrophy
PRPH2	Orphanet:99003	Multifocal pattern dystrophy simulating fundus flavimaculatus

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BEST1	HGNC:12703	ENSG00000167995	O76090	Bestrophin-1	gencc,clinvar
CRB1	HGNC:2343	ENSG00000134376	P82279	Protein crumbs homolog 1	clinvar
FTH1	HGNC:3976	ENSG00000167996	P02794	Ferritin heavy chain	clinvar
PRPH2	HGNC:9942	ENSG00000112619	P23942	Peripherin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BEST1	Bestrophin-1	Ligand-gated anion channel that allows the movement of anions across cell membranes when activated by calcium (Ca2+).
CRB1	Protein crumbs homolog 1	Plays a role in photoreceptor morphogenesis in the retina.
FTH1	Ferritin heavy chain	Stores iron in a soluble, non-toxic, readily available form.
PRPH2	Peripherin-2	Essential for retina photoreceptor outer segment disk morphogenesis, may also play a role with ROM1 in the maintenance of outer segment disk structure.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
Enzyme (other)	1	3.0×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BEST1	Other/Unknown	no		Bestrophin, Bestrophin-like
CRB1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G
FTH1	Enzyme (other)	yes	1.16.3.1	Ferritin, Ferritin_DPS_dom, Ferritin-like_diiron
PRPH2	Other/Unknown	no		Peripherin/rom-1, Tetraspanin_EC2_sf, Peripherin/rom-1_CS

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
inferior olivary complex	1
lateral globus pallidus	1
pigmented layer of retina	1
endothelial cell	1
ganglionic eminence	1
ventricular zone	1
nerve	1
stromal cell of endometrium	1
upper lobe of left lung	1
hindlimb stylopod muscle	1
quadriceps femoris	1
vastus lateralis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BEST1	209	ubiquitous	marker	pigmented layer of retina, lateral globus pallidus, inferior olivary complex
CRB1	163	broad	marker	ganglionic eminence, ventricular zone, endothelial cell
FTH1	292	ubiquitous	marker	stromal cell of endometrium, upper lobe of left lung, nerve
PRPH2	176	tissue_specific	marker	quadriceps femoris, vastus lateralis, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FTH1	2,729
PRPH2	1,234
CRB1	1,075
BEST1	959

Intra-cohort edges

A	B	Sources
BEST1	PRPH2	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FTH1	P02794	147
BEST1	O76090	19
CRB1	P82279	1
PRPH2	P23942	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 4 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
Scavenging by Class A Receptors	1	300.5×	0.020	FTH1
Iron uptake and transport	1	173.0×	0.020	FTH1
Golgi Associated Vesicle Biogenesis	1	100.2×	0.023	FTH1
Stimuli-sensing channels	1	68.0×	0.026	BEST1
Ion channel transport	1	48.0×	0.029	BEST1
Transport of small molecules	1	12.6×	0.085	BEST1
Neutrophil degranulation	1	11.5×	0.085	FTH1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
detection of light stimulus involved in visual perception	3	486.1×	5e-07	BEST1, CRB1, PRPH2
photoreceptor cell outer segment organization	2	526.6×	1e-04	CRB1, PRPH2
response to low light intensity stimulus	1	4213.0×	0.002	PRPH2
camera-type eye photoreceptor cell development	1	4213.0×	0.002	CRB1
post-embryonic retina morphogenesis in camera-type eye	1	2106.5×	0.003	CRB1
gamma-aminobutyric acid secretion, neurotransmission	1	2106.5×	0.003	BEST1
establishment of bipolar cell polarity involved in cell morphogenesis	1	1404.3×	0.004	CRB1
visual perception	2	39.8×	0.005	BEST1, PRPH2
transepithelial chloride transport	1	468.1×	0.009	BEST1
glutamate secretion	1	421.3×	0.009	BEST1
protein heterooligomerization	1	263.3×	0.012	PRPH2
cellular response to light stimulus	1	263.3×	0.012	CRB1
iron ion transport	1	221.7×	0.012	FTH1
plasma membrane organization	1	221.7×	0.012	CRB1
glial cell differentiation	1	221.7×	0.012	CRB1
regulation of calcium ion transport	1	200.6×	0.012	BEST1
negative regulation of ferroptosis	1	200.6×	0.012	FTH1
protein complex oligomerization	1	168.5×	0.013	BEST1
retina layer formation	1	162.0×	0.013	CRB1
establishment or maintenance of epithelial cell apical/basal polarity	1	145.3×	0.014	CRB1
negative regulation of fibroblast proliferation	1	123.9×	0.015	FTH1
chloride transport	1	113.9×	0.016	BEST1
establishment or maintenance of cell polarity	1	100.3×	0.017	CRB1
blood vessel remodeling	1	95.8×	0.017	CRB1
photoreceptor cell maintenance	1	89.6×	0.018	CRB1
heterophilic cell-cell adhesion	1	84.3×	0.018	CRB1
regulation of synaptic plasticity	1	64.8×	0.022	BEST1
retina development in camera-type eye	1	63.8×	0.022	PRPH2
intracellular iron ion homeostasis	1	61.1×	0.022	FTH1
chloride transmembrane transport	1	59.3×	0.022	BEST1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BEST1	0	0
CRB1	0	0
FTH1	0	0
PRPH2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
FTH1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FTH1	1.16.3.1	ferroxidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	FTH1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	BEST1, CRB1, PRPH2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BEST1	0	—
CRB1	0	—
FTH1	2	—
PRPH2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07185256	PHASE1/PHASE2	RECRUITING	Safety and Tolerability of Subretinally Injected OPGx-BEST1 in Patients With Best Vitelliform Macular Dystrophy (BVMD) or Autosomal-Recessive Bestrophinopathy (ARB)
NCT04367883	Not specified	RECRUITING	Influenza Vaccination, ACEI and ARB in the Evolution of SARS-CoV2 Infection
NCT04899206	Not specified	WITHDRAWN	ANGIOTENSIN AGENTS AND REDUCTION OF THE PRESCRIPTION OF ANTIDEPRESSANT DRUGS: A RETROSPECTIVE COHORT STUDY USING REAL-WORLD DATA

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AMANTADINE	4	1
TERFENADINE	4	1