Bestrophinopathies are a spectrum of inherited retinal dystrophies caused by pathogenic variants in BEST1, which encodes bestrophin-1, a calcium-activated chloride channel localized to the basolateral membrane of the retinal pigment epithelium (RPE). BEST1 dysfunction disrupts RPE ion transport and fluid homeostasis, leading to subretinal fluid accumulation, vitelliform (egg-yolk) lesions, and progressive macular and retinal degeneration. The spectrum includes autosomal dominant Best vitelliform macular dystrophy (BVMD), autosomal dominant vitreoretinochoroidopathy (ADVIRC), autosomal dominant microcornea rod-cone dystrophy cataract and posterior staphyloma (MRCS), BEST1-associated retinitis pigmentosa, and autosomal recessive bestrophinopathy (ARB). Over 250 BEST1 mutations have been described, with dominant-negative and loss-of-function mechanisms underlying AD and AR forms respectively.
BEST1 bestrophinopathies are a group of autosomal dominant and autosomal recessive inherited retinal diseases (IRDs) caused by pathogenic variants in BEST1, most prominently manifesting as Best vitelliform macular dystrophy (BVMD; “Best disease”) and autosomal recessive bestrophinopathy (ARB), but also including ADVIRC, adult-onset vitelliform phenotypes, and BEST1‑associated retinitis pigmentosa. These conditions share a central theme of retinal pigment epithelium (RPE) dysfunction with characteristic subretinal material (vitelliform deposits and/or fluid) and frequent electro‑oculogram (EOG) abnormalities. (bianco2024multimodalimagingin pages 1-2, amato2023genetherapyin pages 2-3)
Concise overview (current understanding): BEST1 dysfunction perturbs RPE ion/fluid homeostasis and calcium‑regulated physiology; clinically this produces vitelliform lesions, subretinal/intraretinal fluid, abnormal EOG light rise, and progressive macular/retinal degeneration with variable severity and inheritance. (amato2023genetherapyin pages 1-2, khan2018normalelectrooculographyin pages 9-13)
The retrieved evidence explicitly provides the following MIM/OMIM identifiers: - BVMD / Best disease: MIM #153700 (bianco2024multimodalimagingin pages 1-2) - BEST1 gene: MIM #607854 (bianco2024multimodalimagingin pages 1-2) - Autosomal recessive bestrophinopathy (ARB): OMIM 611809 (zhao2024clinicalandgenetic pages 1-2) - ADVIRC: MIM #193220 (bianco2024multimodalimagingin pages 1-2) - BEST1-associated retinitis pigmentosa: MIM #613194 (bianco2024multimodalimagingin pages 1-2) - Adult-onset vitelliform macular degeneration: OMIM 608161 (zhao2024clinicalandgenetic pages 1-2)
MONDO / Orphanet / ICD‑10/ICD‑11 / MeSH: Not available in the retrieved text evidence set; therefore, specific IDs cannot be asserted here without adding new database retrieval. (No relevant evidence found in provided corpus)
Information summarized here is derived from: - Aggregated disease-level resources in the form of cohort studies and reviews (e.g., imaging review, prevalence analysis) (bianco2024multimodalimagingin pages 1-2, beryozkin2024bestdiseaseglobal pages 1-2) - Primary human cohort/case series studies (e.g., ARB cohorts in China; BVMD/ARB clinical series) (zhao2024clinicalandgenetic pages 1-2, shi2023comprehensivegeneticanalysis pages 5-8) - Preclinical animal and in vitro models (canine models; iPSC‑RPE) (amato2023genetherapyin pages 6-7, khan2018normalelectrooculographyin pages 9-13)
Primary cause: Germline pathogenic variants in BEST1. The BEST1 gene encodes bestrophin‑1, a homopentameric Ca2+-activated anion (chloride) channel expressed in RPE, and BEST1 pathogenic variants cause a phenotypic spectrum collectively termed “bestrophinopathies.” (amato2023genetherapyin pages 1-2, amato2023genetherapyin pages 2-3)
The retrieved evidence does not provide robust epidemiologic environmental risk factors (e.g., smoking/diet/exposures). The conditions are primarily genetic with variable expressivity; modifiers are suspected but not quantified here. (khan2018normalelectrooculographyin pages 9-13)
No specific genetic or environmental protective factors were identified in the retrieved evidence corpus.
The retrieved evidence supports the concept that phenotype is variable and may involve modifiers, but does not provide a specific, validated gene–environment interaction. (khan2018normalelectrooculographyin pages 9-13)
Below are common clinical phenotypes across the BEST1 spectrum. HPO term suggestions are provided as likely mappings.
Suggested HPO: Vitelliform macular dystrophy (HP:0007757); Macular lesion (HP:0001103); Retinal flecks (HP:0001086)
Subretinal fluid and intraretinal cystic/schitic spaces (especially ARB)
Suggested HPO: Subretinal fluid (HP:0031889); Cystoid macular edema (HP:0000605); Retinoschisis (HP:0000579)
Abnormal electro‑oculogram (EOG) Arden ratio / reduced light peak
Suggested HPO: Abnormal electrooculogram (HP:0025206) (term may vary by HPO release)
Visual acuity impairment / central vision loss
Suggested HPO: Reduced visual acuity (HP:0007663); Central scotoma (HP:0000603)
Macular neovascularization / choroidal neovascularization (CNV/CNVM)
Suggested HPO: Choroidal neovascularization (HP:0007701)
Angle-closure glaucoma predisposition (especially ARB with short axial length/narrow angles)
The retrieved evidence does not provide formal QoL instrument results (e.g., EQ‑5D, VFQ‑25). However, progressive central vision loss and macular atrophy logically impair reading/driving and daily functioning; this should be confirmed with disease-specific QoL studies not present in the current corpus. (No direct QoL evidence in retrieved texts)
BEST1 pathogenic variants are described in mechanistic categories: - Loss-of-function (LOF) - Dominant-negative (DN) (enabled by pentameric co-assembly, “poisoning” WT complexes) - Gain-of-function (GOF) (less common; may require silencing + augmentation) Gene therapy design implications follow from this classification. (amato2023genetherapyin pages 4-6, amato2023genetherapyin pages 1-2)
No validated modifier genes, epigenetic alterations, or chromosomal abnormalities were identified in the retrieved evidence set.
No clear non-genetic causal environmental exposures were identified in the retrieved evidence. BEST1 bestrophinopathies are primarily genetic. (amato2023genetherapyin pages 2-3)
Upstream trigger: pathogenic BEST1 variant → altered bestrophin‑1 channel quantity/function.
Core molecular role: bestrophin‑1 is a Ca2+-activated anion (Cl−) channel in RPE; its activity contributes to RPE electrophysiology and the EOG light rise. (amato2023genetherapyin pages 2-3, khan2018normalelectrooculographyin pages 9-13)
Proposed downstream steps (integrated from human and iPSC‑RPE evidence): 1. BEST1 dysfunction perturbs RPE chloride conductance and Ca2+-dependent physiology, including ER calcium handling/store-dependent signaling. (khan2018normalelectrooculographyin pages 9-13, amato2023genetherapyin pages 7-8) 2. Altered Ca2+ homeostasis affects multiple RPE processes (reported/implicated): photoreceptor outer segment (POS) phagocytosis, pigment granule migration, and membrane potential dynamics. (khan2018normalelectrooculographyin pages 9-13) 3. RPE support failure contributes to accumulation of subretinal material, fluid dysregulation (subretinal/intraretinal fluid), and progressive outer retinal disruption leading to photoreceptor dysfunction/degeneration and macular atrophy. (boon2009clinicalandmolecular pages 11-13, pfister2021phenotypicandgenetic pages 1-2)
Owji et al. (Nature Communications, Dec 2024) solved ligand-bound bestrophin structures and identified an extracellular positive allosteric site where PABA (4-aminobenzoic acid) binds (same site as GABA in Best2). PABA activates Best1 with EC50 ~192 nM and can rescue currents of multiple patient-derived dominant LOF Best1 mutants (A10T, R218H, L234P, A243T, Q293K, D302A) in co-expression experiments. This provides a mechanistically grounded small-molecule strategy complementary to gene therapy approaches. (owji2024neurotransmitterboundbestrophinchannel pages 5-6, owji2024neurotransmitterboundbestrophinchannel pages 1-2)
GO Biological Process (suggested): - Chloride transmembrane transport (GO:1902476) - Calcium ion homeostasis (GO:0055074) - Phagocytosis (GO:0006909) - Visual perception (GO:0007601)
GO Cellular Component (suggested): - Basolateral plasma membrane (GO:0016323) - Endoplasmic reticulum membrane (GO:0005789)
Cell types (CL terms, suggested): - Retinal pigment epithelial cell (CL:0002584) - Rod photoreceptor cell (CL:0000740) - Cone photoreceptor cell (CL:0000742)
Primary system: Eye / visual system, with disease centered on: - Retina, especially macula (BVMD) and broader posterior pole involvement (ARB). (beryozkin2024bestdiseaseglobal pages 1-2, zhao2024clinicalandgenetic pages 1-2)
Suggested UBERON terms: - Retina (UBERON:0000966) - Macula lutea (UBERON:0001807) - Retinal pigment epithelium (UBERON:0001994) - Anterior chamber of eye (UBERON:0001769) (relevant to ARB angle closure predisposition)
Specific prognostic biomarkers are not established in the retrieved evidence; however, multimodal imaging (OCT staging, ellipsoid zone integrity, neovascularization status) is emphasized for monitoring and prognostication. (bianco2024multimodalimagingin pages 1-2)
No approved disease-modifying pharmacotherapy is established in the retrieved evidence; management focuses on monitoring and treating complications.
Complication-directed care: - Anti-VEGF therapy for CNV/CNVM (e.g., bevacizumab, conbercept) is used when neovascular complications occur. (shakeel2024phenotypeandgenetic pages 2-3, zhao2024clinicalandgenetic pages 2-4) - Angle-closure risk management in ARB: preventive laser peripheral iridotomy and glaucoma surgery (trabeculectomy + iridotomy) were used in a 2024 cohort. (zhao2024clinicalandgenetic pages 1-2, zhao2024clinicalandgenetic pages 2-4)
Suggested MAXO terms (examples): - Anti-VEGF therapy (MAXO:0001298) (term label may vary) - Laser peripheral iridotomy (MAXO term not confirmed in evidence) - Trabeculectomy (MAXO term not confirmed in evidence) - Genetic counseling (MAXO:0000079) (term label may vary)
Preclinical gene augmentation in canine models shows lesion reversal after subretinal AAV delivery with sustained effects up to 245 weeks and no inflammatory response in reported experiments, supporting a translational basis for human trials. (amato2023genetherapyin pages 6-7)
PABA and related small molecules activate Best1 and can rescue currents for multiple dominant LOF mutants in vitro, suggesting a potential pharmacologic approach for dominant LOF bestrophinopathies. (owji2024neurotransmitterboundbestrophinchannel pages 5-6)
Primary prevention is not generally possible for monogenic inherited retinal diseases, but genetic counseling, cascade testing, and reproductive options are key.
Canine multifocal retinopathy (cmr) caused by biallelic BEST1 mutations reproduces clinical/molecular/histologic features and has enabled long-term AAV augmentation studies. (amato2023genetherapyin pages 6-7)
BEST1 knockout mice reportedly show no retinal phenotype, whereas a knock-in model with W93C recapitulates BVMD-like features with dominant inheritance/incomplete penetrance and reduced EOG light peak. (amato2023genetherapyin pages 6-7)
Patient-derived iPSC‑RPE models demonstrate reduced phagocytosis and stress-dependent autofluorescent material accumulation, plus altered ER-dependent Ca2+ currents; these systems have been used to test rescue strategies including augmentation and silencing+augmentation for GOF/DN contexts. (khan2018normalelectrooculographyin pages 9-13, amato2023genetherapyin pages 7-8)
References
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(shi2023comprehensivegeneticanalysis pages 3-5): Jie-Feng Shi, Lu Tian, Tengyang Sun, Xiao Zhang, K. Xu, Yue Xie, Xiaoyan Peng, Xin Tang, Zidan Jin, and Yang Li. Comprehensive genetic analysis unraveled the missing heritability and a founder variant of best1 in a chinese cohort with autosomal recessive bestrophinopathy. Investigative Opthalmology & Visual Science, 64:37, Sep 2023. URL: https://doi.org/10.1167/iovs.64.12.37, doi:10.1167/iovs.64.12.37. This article has 8 citations.
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name: BEST1 Bestrophinopathies
creation_date: '2026-04-04T12:00:00Z'
updated_date: '2026-04-06T23:35:31Z'
description: >-
Bestrophinopathies are a spectrum of inherited retinal dystrophies caused by
pathogenic variants in BEST1, which encodes bestrophin-1, a calcium-activated
chloride channel localized to the basolateral membrane of the retinal pigment
epithelium (RPE). BEST1 dysfunction disrupts RPE ion transport and fluid
homeostasis, leading to subretinal fluid accumulation, vitelliform (egg-yolk)
lesions, and progressive macular and retinal degeneration. The spectrum
includes autosomal dominant Best vitelliform macular dystrophy (BVMD), autosomal
dominant vitreoretinochoroidopathy (ADVIRC), autosomal dominant microcornea
rod-cone dystrophy cataract and posterior staphyloma (MRCS), BEST1-associated
retinitis pigmentosa, and autosomal recessive bestrophinopathy (ARB). Over
250 BEST1 mutations have been described, with dominant-negative and
loss-of-function mechanisms underlying AD and AR forms respectively.
category: Genetic
parents:
- Inherited Retinal Dystrophy
- Macular Dystrophy
disease_term:
preferred_term: BEST1 bestrophinopathy spectrum
term:
id: MONDO:0000390
label: vitelliform macular dystrophy
has_subtypes:
- name: BVMD
display_name: Best Vitelliform Macular Dystrophy (BVMD)
subtype_term:
preferred_term: Best vitelliform macular dystrophy
term:
id: MONDO:0007931
label: vitelliform macular dystrophy 2
description: >
Most common bestrophinopathy. Autosomal dominant with incomplete penetrance
and variable expression. Typically presents in childhood with a central
macular vitelliform (egg-yolk) lesion that progresses through six stages:
previtelliform, vitelliform, vitelliruptive, pseudohypopion, atrophic, and
cicatricial. Visual acuity is initially preserved but declines in later stages.
Full-field ERG is normal; EOG shows reduced Arden ratio (less than 1.5).
Mild hyperopia is common.
evidence:
- reference: PMID:34015078
reference_title: "Phenotypic and Genetic Spectrum of Autosomal Recessive Bestrophinopathy and Best Vitelliform Macular Dystrophy."
supports: SUPPORT
snippet: "The VMD phenotype consists of a prominent raised central macular lesion that undergoes morphological changes classified into six stages: previtelliform, vitelliform, vitelliruptive, pseudohypopion, atrophic, and cicatricial."
explanation: Describes the six classical stages of BVMD macular lesion progression.
- name: ARB
display_name: Autosomal Recessive Bestrophinopathy (ARB)
subtype_term:
preferred_term: autosomal recessive bestrophinopathy
term:
id: MONDO:0012733
label: autosomal recessive bestrophinopathy
description: >
Caused by biallelic (homozygous or compound heterozygous) BEST1 mutations
resulting in absent functional bestrophin-1. Presents with central visual
loss in the first two decades. Features include macular changes resembling
BVMD vitelliruptive/atrophic stages, extramacular punctate deposits,
subretinal and intraretinal fluid, hyperopia, short axial length,
severely reduced EOG Arden ratio (1.0 or less), and reduced full-field ERG.
Angle-closure glaucoma and amblyopia may co-occur.
evidence:
- reference: PMID:30578502
reference_title: "Best Vitelliform Macular Dystrophy."
supports: SUPPORT
snippet: "Autosomal recessive bestrophinopathy (ARB) results from a total absence of functional bestrophin-1 protein owing to two BEST1 mutations, one on each of the chromosomes."
explanation: Confirms ARB results from biallelic BEST1 mutations causing total absence of functional protein.
- reference: PMID:34015078
reference_title: "Phenotypic and Genetic Spectrum of Autosomal Recessive Bestrophinopathy and Best Vitelliform Macular Dystrophy."
supports: SUPPORT
snippet: "ARB displays macular changes resembling the vitelliruptive, atrophic, and cicatricial stages of VMD. The phenotype additionally encompasses extramacular punctate deposits, intraretinal and subretinal fluid (SRF) accumulation, punctate or diffuse fundus hyperautofluorescence, hyperopia, short axial-length, central visual field loss, severely decreased Arden ratio"
explanation: Comprehensive description of ARB phenotype distinguishing it from BVMD.
- name: MRCS
display_name: Microcornea, Rod-Cone Dystrophy, Cataract, and Posterior Staphyloma (MRCS)
subtype_term:
preferred_term: MRCS syndrome
term:
id: MONDO:0033644
label: microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 1
description: >
Rare autosomal dominant condition with anterior segment involvement. Features
include microcornea, rod-cone dystrophy, early-onset cataract, and posterior
staphyloma. Represents the most complex bestrophinopathy phenotype extending
beyond pure macular disease.
- name: BEST1-RP
display_name: BEST1-Associated Retinitis Pigmentosa
subtype_term:
preferred_term: BEST1-associated retinitis pigmentosa
term:
id: MONDO:0019200
label: retinitis pigmentosa
description: >
Rare autosomal dominant form presenting as classical retinitis pigmentosa
with rod-cone dystrophy, nyctalopia, peripheral visual field loss, and
attenuated retinal vessels. Caused by specific BEST1 mutations that
produce a rod-cone dystrophy phenotype rather than typical macular lesions.
pathophysiology:
- name: BEST1 Channel Dysfunction
description: >
Pathogenic variants in BEST1 disrupt the calcium-activated chloride channel
function of bestrophin-1. The channel normally forms a stable homopentamer
in the RPE basolateral membrane, mediating transepithelial ion transport,
regulation of intracellular calcium signaling, and RPE cell volume. Dominant
mutations cause a dominant-negative effect while recessive mutations result
in loss of function.
genes:
- preferred_term: BEST1
term:
id: hgnc:12703
label: BEST1
molecular_functions:
- preferred_term: calcium-activated chloride channel activity
term:
id: GO:0005229
label: intracellularly calcium-gated chloride channel activity
cell_types:
- preferred_term: Retinal Pigment Epithelial Cell
term:
id: CL:0002586
label: retinal pigment epithelial cell
biological_processes:
- preferred_term: Chloride Transport
term:
id: GO:0006821
label: chloride transport
modifier: DECREASED
evidence:
- reference: PMID:34612806
reference_title: "Structure and Function of the Bestrophin family of calcium-activated chloride channels."
supports: SUPPORT
snippet: "Bestrophins are a family of calcium-activated chloride channels (CaCCs) with relevance to human physiology and a myriad of eye diseases termed \"bestrophinopathies\"."
explanation: Confirms bestrophins are CaCCs and their dysfunction causes bestrophinopathies.
- reference: PMID:29507198
reference_title: "BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure."
supports: SUPPORT
snippet: "BEST1 acts as a multifunctional channel protein responsible for mediating transepithelial ion transport, regulation of intracellular calcium signaling and RPE cell volume, and modulation of the homeostatic milieu in the subretinal space"
explanation: Describes the multifunctional role of BEST1 in RPE physiology.
downstream:
- target: RPE-Photoreceptor Interface Disruption
description: Channel dysfunction impairs ion and fluid homeostasis at the RPE-photoreceptor interface.
- name: RPE-Photoreceptor Interface Disruption
description: >
BEST1 dysfunction leads to loss of the native extracellular compartmentalization
of photoreceptor outer segments. RPE apical microvillar ensheathment of
cone outer segments is lost, and the insoluble interphotoreceptor matrix is
compromised. This results in retina-wide microdetachments between RPE and
photoreceptors that are modulated by light exposure.
cell_types:
- preferred_term: Retinal Pigment Epithelial Cell
term:
id: CL:0002586
label: retinal pigment epithelial cell
evidence:
- reference: PMID:29507198
reference_title: "BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure."
supports: SUPPORT
snippet: "Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells."
explanation: Directly states that BEST1 mutations cause retinal detachment and PR degeneration from RPE channelopathy.
- reference: PMID:29507198
reference_title: "BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In vivo imaging demonstrated a retina-wide RPE-PR microdetachment, which contracted with dark adaptation and expanded upon exposure to a moderate intensity of light."
explanation: Canine model demonstrates retina-wide microdetachments modulated by light.
downstream:
- target: Subretinal Fluid Accumulation and Vitelliform Lesions
description: Loss of RPE-PR interface integrity leads to subretinal fluid and lipofuscin accumulation.
- name: Subretinal Fluid Accumulation and Vitelliform Lesions
description: >
Impaired RPE fluid transport and disrupted photoreceptor outer segment
phagocytosis lead to subretinal fluid accumulation and deposits of
lipofuscin and unphagocytosed outer segment material. These form the
characteristic vitelliform (egg-yolk) lesions. In BVMD, lesions are
typically central macular; in ARB, they are more extensive with
extramacular involvement.
cell_types:
- preferred_term: Retinal Pigment Epithelial Cell
term:
id: CL:0002586
label: retinal pigment epithelial cell
evidence:
- reference: PMID:30578502
reference_title: "Best Vitelliform Macular Dystrophy."
supports: SUPPORT
snippet: "The yellowish lesions are larger and more extensive-extending beyond the arcades-than in the typical autosomal dominant Best disease."
explanation: Describes extent of vitelliform lesions in ARB versus BVMD.
downstream:
- target: Progressive Macular and Retinal Degeneration
description: Chronic subretinal fluid and deposits lead to progressive RPE atrophy and photoreceptor loss.
- name: Progressive Macular and Retinal Degeneration
description: >
Chronic disruption of the RPE-photoreceptor interface leads to progressive
RPE atrophy, photoreceptor degeneration, and macular atrophy. In BVMD
this predominantly affects the macula; in ARB the degeneration is more
widespread with panretinal involvement. Late stages may include subretinal
fibrosis and choroidal neovascularization.
evidence:
- reference: PMID:34015078
reference_title: "Phenotypic and Genetic Spectrum of Autosomal Recessive Bestrophinopathy and Best Vitelliform Macular Dystrophy."
supports: SUPPORT
snippet: "This study suggests that arVMD is part of a continuum of autosomal recessive and dominant BEST1-related retinopathies."
explanation: Confirms that AD and AR forms represent a disease continuum of progressive retinal degeneration.
- reference: PMID:30578502
reference_title: "Best Vitelliform Macular Dystrophy."
supports: SUPPORT
snippet: "As panretinal photoreceptor dysfunction progresses with advancing age, full-field (FF) ERG shows delayed rod and cone responses."
explanation: Documents progressive photoreceptor dysfunction over time in bestrophinopathy.
phenotypes:
- name: Vitelliform Macular Lesion
category: Ophthalmological
frequency: VERY_FREQUENT
diagnostic: true
description: >
Characteristic yellow egg-yolk-like subretinal deposit at the macula.
Central and focal in BVMD; more extensive with extramacular involvement in ARB.
phenotype_term:
preferred_term: Vitelliform macular lesion
term:
id: HP:0030500
label: Yellow/white macular lesion
evidence:
- reference: PMID:34015078
reference_title: "Phenotypic and Genetic Spectrum of Autosomal Recessive Bestrophinopathy and Best Vitelliform Macular Dystrophy."
supports: SUPPORT
snippet: "The VMD phenotype consists of a prominent raised central macular lesion that undergoes morphological changes classified into six stages: previtelliform, vitelliform, vitelliruptive, pseudohypopion, atrophic, and cicatricial."
explanation: Describes the hallmark vitelliform macular lesion and its staging.
- name: Reduced Visual Acuity
category: Ophthalmological
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Reduced visual acuity
term:
id: HP:0007663
label: Reduced visual acuity
evidence:
- reference: PMID:34015078
reference_title: "Phenotypic and Genetic Spectrum of Autosomal Recessive Bestrophinopathy and Best Vitelliform Macular Dystrophy."
supports: SUPPORT
snippet: "The best corrected visual acuity (BCVA) is mildly decreased to 20/50 on average (range 20/20 to 20/200), until later stages, where natural progression and complication create a steep decline."
explanation: Documents visual acuity decline particularly in later disease stages.
- name: Abnormal Electrooculogram
category: Ophthalmological
frequency: VERY_FREQUENT
diagnostic: true
description: >
Reduced EOG Arden ratio is a hallmark of bestrophinopathies. In BVMD,
Arden ratio is moderately decreased (less than 1.5). In ARB, it is
severely decreased (1.0 or less).
phenotype_term:
preferred_term: Abnormal electrooculogram
term:
id: HP:0030453
label: Abnormal visual electrophysiology
evidence:
- reference: PMID:34015078
reference_title: "Phenotypic and Genetic Spectrum of Autosomal Recessive Bestrophinopathy and Best Vitelliform Macular Dystrophy."
supports: SUPPORT
snippet: "electrophysiology changes show a moderately decreased electro-oculography (EOG) Arden ratio of less than 1.5 with frequently normal full-field electroretinogram (ffERG)."
explanation: Documents the characteristic EOG abnormality in BVMD with normal ERG.
- name: Macular Dystrophy
category: Ophthalmological
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Macular dystrophy
term:
id: HP:0007754
label: Macular dystrophy
- name: Macular Atrophy
category: Ophthalmological
frequency: FREQUENT
description: >
Late-stage finding with RPE and photoreceptor loss in the macular region.
phenotype_term:
preferred_term: Macular atrophy
term:
id: HP:0007401
label: Macular atrophy
- name: Hypermetropia
category: Ophthalmological
frequency: FREQUENT
subtype: ARB
description: >
Hyperopia and short axial length are associated with ARB.
phenotype_term:
preferred_term: Hypermetropia
term:
id: HP:0000540
label: Hypermetropia
evidence:
- reference: PMID:34015078
reference_title: "Phenotypic and Genetic Spectrum of Autosomal Recessive Bestrophinopathy and Best Vitelliform Macular Dystrophy."
supports: SUPPORT
snippet: "The phenotype additionally encompasses extramacular punctate deposits, intraretinal and subretinal fluid (SRF) accumulation, punctate or diffuse fundus hyperautofluorescence, hyperopia, short axial-length"
explanation: Hyperopia is listed as part of the ARB phenotype.
- name: Retinal Detachment
category: Ophthalmological
frequency: OCCASIONAL
phenotype_term:
preferred_term: Retinal detachment
term:
id: HP:0000541
label: Retinal detachment
evidence:
- reference: PMID:29507198
reference_title: "BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure."
supports: SUPPORT
snippet: "Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells."
explanation: Retinal detachment is a direct consequence of BEST1 mutations.
- name: Microcornea
category: Ophthalmological
frequency: VERY_RARE
subtype: MRCS
phenotype_term:
preferred_term: Microcornea
term:
id: HP:0000482
label: Microcornea
- name: Rod-Cone Dystrophy
category: Ophthalmological
frequency: OCCASIONAL
description: >
Seen in MRCS and BEST1-associated RP subtypes.
phenotype_term:
preferred_term: Rod-cone dystrophy
term:
id: HP:0000510
label: Rod-cone dystrophy
- name: Cataract
category: Ophthalmological
frequency: VERY_RARE
subtype: MRCS
description: >
Early-onset cataract in MRCS subtype.
phenotype_term:
preferred_term: Cataract
term:
id: HP:0000518
label: Cataract
- name: Nyctalopia
category: Ophthalmological
frequency: OCCASIONAL
subtype: BEST1-RP
phenotype_term:
preferred_term: Nyctalopia
term:
id: HP:0000662
label: Nyctalopia
- name: RPE Atrophy
category: Ophthalmological
frequency: FREQUENT
phenotype_term:
preferred_term: Retinal pigment epithelial atrophy
term:
id: HP:0007722
label: Retinal pigment epithelial atrophy
evidence:
- reference: PMID:30578502
reference_title: "Best Vitelliform Macular Dystrophy."
supports: SUPPORT
snippet: "decreased AF reflects RPE atrophy."
explanation: RPE atrophy is documented as a feature on fundus autofluorescence imaging.
- name: Angle-Closure Glaucoma
category: Ophthalmological
frequency: OCCASIONAL
subtype: ARB
phenotype_term:
preferred_term: Glaucoma
term:
id: HP:0000501
label: Glaucoma
evidence:
- reference: PMID:30578502
reference_title: "Best Vitelliform Macular Dystrophy."
supports: SUPPORT
snippet: "Refractive error is hyperopia, predisposing these eyes for acute angle-closure glaucoma."
explanation: Hyperopia in ARB predisposes to angle-closure glaucoma.
genetic:
- name: BEST1
gene_term:
preferred_term: BEST1
term:
id: hgnc:12703
label: BEST1
association: Causative
features: >
Over 250 pathogenic variants described. Dominant mutations (missense) cause
dominant-negative channel dysfunction in BVMD, ADVIRC, MRCS, and RP.
Recessive mutations (missense, nonsense, frameshift) cause loss of function
in ARB. Most mutations cluster in the transmembrane domains and cytoplasmic
N-terminus. The p.Ala243Val mutation is the most common BVMD-associated variant.
variants:
- name: Dominant missense variants
description: >
Cause BVMD, ADVIRC, MRCS, or RP through dominant-negative mechanism.
Heterozygous pathogenic variants sufficient for disease.
- name: Biallelic loss-of-function variants
description: >
Homozygous or compound heterozygous variants causing ARB through
complete loss of functional bestrophin-1 protein.
evidence:
- reference: PMID:34015078
reference_title: "Phenotypic and Genetic Spectrum of Autosomal Recessive Bestrophinopathy and Best Vitelliform Macular Dystrophy."
supports: SUPPORT
snippet: "mutations in the BEST1 protein lead to a collection of retinopathies: Best vitelliform macular dystrophy (VMD) (OMIM-153700), autosomal dominant vitreoretinochoroidopathy (ADVIRC) and microcornea, rod-cone dystrophy, cataract, and posterior staphyloma syndrome (MRCS) (OMIM-193220), retinitis pigmentosa (RP) (OMIM-613914), and autosomal recessive bestrophinopathy (ARB) (OMIM-611809)."
explanation: Enumerates the full spectrum of BEST1-related retinopathies.
- reference: PMID:29507198
reference_title: "BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure."
supports: SUPPORT
snippet: "The most common IRD due to a primary RPE defect is caused by mutations in BEST1"
explanation: Confirms BEST1 mutations as the most common cause of primary RPE-mediated inherited retinal dystrophy.
inheritance:
- name: Autosomal dominant
description: >
BVMD, ADVIRC, MRCS, and BEST1-associated RP are autosomal dominant with
incomplete penetrance and variable expressivity.
inheritance_term:
preferred_term: Autosomal dominant
term:
id: HP:0000006
label: Autosomal dominant inheritance
- name: Autosomal recessive
description: >
ARB is autosomal recessive, caused by biallelic BEST1 loss-of-function mutations.
inheritance_term:
preferred_term: Autosomal recessive
term:
id: HP:0000007
label: Autosomal recessive inheritance
treatments:
- name: Anti-VEGF Therapy
description: >
Intravitreal anti-VEGF injections for choroidal neovascularization
complicating late-stage BVMD or ARB.
treatment_term:
preferred_term: anti-VEGF pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
- name: Low Vision Aids and Rehabilitation
description: >
Visual rehabilitation and low vision aids for patients with progressive
central vision loss.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
- name: Genetic Counseling
description: >
Recommended for all affected families. Important to distinguish AD
versus AR inheritance for recurrence risk counseling.
treatment_term:
preferred_term: genetic counseling
term:
id: MAXO:0000079
label: genetic counseling
- name: Gene Therapy (Investigational)
description: >
Subretinal AAV2-mediated BEST1 gene augmentation therapy has shown
reversal of retinal detachments and correction of RPE-photoreceptor
interface abnormalities in canine models. Phase 1/2 clinical trials
(OPGx-BEST1/BIRD-1) are underway for BVMD and ARB.
treatment_term:
preferred_term: gene therapy
term:
id: MAXO:0001001
label: gene therapy
evidence:
- reference: PMID:29507198
reference_title: "BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Subretinal BEST1 gene augmentation therapy using adeno-associated virus 2 reversed not only clinically detectable subretinal lesions but also the diffuse microdetachments."
explanation: Canine BEST1 gene therapy reverses both macroscopic and microscopic retinal detachments.
- reference: PMID:29507198
reference_title: "BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Human translation of canine BEST1 gene therapy success in reversal of macro- and microdetachments through restoration of cytoarchitecture at the RPE-PR interface has promise to result in improved visual function and prevent disease progression in patients affected with bestrophinopathies."
explanation: Authors state translational promise of canine gene therapy results for human bestrophinopathies.
prevalence:
- population: Global
percentage: Rare
notes: >
BVMD prevalence estimated at 1 in 16,500 to 1 in 21,000 (Olmsted County, Minnesota).
ARB and MRCS are considerably rarer.
notes: >-
The bestrophinopathies represent a disease continuum rather than strictly
distinct clinical entities. Principal component analysis of clinical features
demonstrates that autosomal recessively inherited VMD falls between autosomal
dominant VMD and ARB on the disease spectrum. Tritan-axis color vision deficit
has been reported as an associated finding in ARB.