Ocular Phenotype Analysis of a Family With Biallelic Mutations in the BEST1 Gene

Sharon, Dror; Al-Hamdani, Sermed; Engelsberg, Karl; Mizrahi-Meissonnier, Liliana; Obolensky, Alexey; Banin, Eyal; Sander, Birgit; Jensen, Hanne; Larsen, Michael; Schatz, Patrik

doi:10.1016/j.ajo.2013.12.010

Cited by 16 publications

(9 citation statements)

References 31 publications

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“…S1f–i ). The electrophysiologic characteristics were similar to the earlier reported cases of ARB 35 . No ocular abnormalities were observed in the unaffected parents.…”

Section: Resultssupporting

confidence: 86%

“…While the BEST1 p.Thr91Ile mutation identified in family D is suggestive of a dominant mutation, the mild phenotype in the father is indicative of the variable penetrance of this mutation that might be modulated by other background genomic variations. Consistent with this, incomplete penetrance of an autosomal dominant BEST1 mutation has been reported in multiple studies 35 , 47 , 48 . Interestingly, in 23 patients with heterozygous BEST1 mutations, six were found to have no clinically detectable disease related phenotype 49 .…”

Section: Discussionsupporting

confidence: 75%

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Next generation sequencing identifies novel disease-associated BEST1 mutations in Bestrophinopathy patients

Nguyen¹,

Poornachandra

Verma

et al. 2018

Sci Rep

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Bestinopathies are a spectrum of retinal disorders associated with mutations in BEST1 including autosomal recessive bestrophinopathy (ARB) and autosomal dominant Best vitelliform macular dystrophy (BVMD). We applied whole-exome sequencing on four unrelated Indian families comprising eight affected and twelve unaffected individuals. We identified five mutations in BEST1, including p.Tyr131Cys in family A, p.Arg150Pro in family B, p.Arg47His and p.Val216Ile in family C and p.Thr91Ile in family D. Among these, p.Tyr131Cys, p.Arg150Pro and p.Val216Ile have not been previously reported. Further, the inheritance pattern of BEST1 mutations in the families confirmed the diagnosis of ARB in probands in families A, B and C, while the inheritance of heterozygous BEST1 mutation in family D (p.Thr91Ile) was suggestive of BVMD. Interestingly, the ARB families A and B carry homozygous mutations while family C was a compound heterozygote with a mutation in an alternate BEST1 transcript isoform, highlighting a role for alternate BEST1 transcripts in bestrophinopathy. In the BVMD family D, the heterozygous BEST1 mutation found in the proband was also found in the asymptomatic parent, suggesting an incomplete penetrance and/or the presence of additional genetic modifiers. Our report expands the list of pathogenic BEST1 genotypes and the associated clinical diagnosis.

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“…S1f–i ). The electrophysiologic characteristics were similar to the earlier reported cases of ARB 35 . No ocular abnormalities were observed in the unaffected parents.…”

Section: Resultssupporting

confidence: 86%

Section: Discussionsupporting

confidence: 75%

Next generation sequencing identifies novel disease-associated BEST1 mutations in Bestrophinopathy patients

Nguyen¹,

Poornachandra

Verma

et al. 2018

Sci Rep

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“…[8][9][10][11][12][13][24][25][26][27][28][29] An important clinical component of ARB is its autosomal recessive nature with a BEST1-null phenotype, which makes it a potentially attractive candidate for gene replacement therapy. 12 Unlike ARB, most other diseases ascribed to BEST1 mutations are autosomal dominantly inherited.…”

Section: Discussionmentioning

confidence: 99%

A NovelBEST1Mutation in Autosomal Recessive Bestrophinopathy

Lee

Jun

Choi

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Lee CS, Jun I, Choi S, et al. A novel BEST1 mutation in autosomal recessive bestrophinopathy. Invest Ophthalmol Vis Sci. 2015;56:8141-8150. DOI:10.1167/iovs.15-18168 PURPOSE. To describe the clinical characteristics associated with a newly identified mutant of autosomal recessive bestrophinopathy (ARB) and confirm the associated physiological functional defects.METHODS. Two patients with ARB from one family underwent a full ophthalmic examination, including dilated fundus examination, fundus photography, fluorescein angiography, fundus autofluorescence imaging, spectral-domain optical coherence tomography (OCT), electroretinography (ERG), and electrooculography (EOG). Subsequently, genetic analysis for bestrophin-1 (BEST1) mutations was conducted through direct Sanger sequencing. The effect of ARB-associated mutations of BEST1 on the cellular localization was determined by in vitro experiments. Whole-cell patch clamping was conducted to measure the chloride conductance of wild-type BEST1 and the identified BEST1 mutants in transfected HEK293T cells. RESULTS.Two related patients (66-year-old brother and 52-year-old sister) presented with reduced visual acuity and bilateral symmetrical subretinal deposits of hyperautofluorescent materials in the posterior pole. Spectral-domain OCT showed macular thinning with submacular fluid. The female patient had a concomitant macular edema associated with branched retinal vein occlusion in the left eye, which responded well to intravitreal bevacizumab injections. Genetic analysis demonstrated that both patients were compound heterozygous for one novel (Leu40Pro) and one previously identified (Ala195Val) BEST1 variant. HEK293T cells transfected with the identified BEST1 mutant showed significantly small currents compared to those transfected with the wild-type gene, whereas cells cotransfected with mutant and wild-type BEST1 showed good chloride conductance. Cellular localization of BEST1 was well conserved to the plasma membrane in the mutants.CONCLUSIONS. We have identified and described the phenotype and in vitro functional aspects of a new BEST1 mutation causing ARB. Clinically suspected ARB cases warrant genetic confirmation to confirm the diagnosis.

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“…The SD-OCT findings of previous ARB cases included diffuse intraretinal cystic spaces across both the inner and outer plexiform layers, subretinal fluid with shallow serous retinal detachment, and thickening and hyper-reflectivity of the ellipsoid and interdigitation zones which may represent an elongation of the photoreceptors [ 21 , 24 , 25 ]. The Arden ratio of the EOGs of patients with ARB is reported to be low with an absence of the light rise [ 11 , 19 , 23 ]. The imaging and functional findings in our patient are typical of ARB.…”

Section: Discussionmentioning

confidence: 99%

Detailed analysis of family with autosomal recessive bestrophinopathy associated with new BEST1 mutation

et al. 2016

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PurposeTo describe the clinical and genetic findings in a patient with autosomal recessive bestrophinopathy (ARB) and his healthy parents.MethodsThe patient and his healthy non-consanguineous parents underwent detailed ophthalmic evaluations including electro-oculography (EOG), spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) imaging. Mutation analysis of the BEST1 gene was performed by Sanger sequencing.ResultsThe FAF images showed multiple spots of increased autofluorescence, and the sites of these spots corresponded to the yellowish deposits detected by ophthalmoscopy. SD-OCT showed cystoid macular changes and a shallow serous macular detachment. The Arden ratio of the EOG was markedly reduced to 1.1 in both eyes. Genetic analysis of the proband detected two sequence variants of the BEST1 gene in the heterozygous state: a novel variant c.717delG, p.V239VfsX2 and an already described c.763C>T, p.R255W variant associated with Best vitelliform macular dystrophy and ARB. The proband’s father carried the c.717delG, p.V239VfsX2 variant in the heterozygous state, and the mother carried the c.763C>T, p.R255W variant in the heterozygous state. The parents who were heterozygous for the BEST1 variants had normal visual acuity, EOG, SD-OCT, and FAF images.ConclusionsIn a truncating BEST1 mutation, the phenotype associated with ARB is most likely due to a marked decrease in the expression of BEST1 promoted by the nonsense-mediated decay surveillance mechanism, and it may depend on the position of the premature termination of the codon created.

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Ocular Phenotype Analysis of a Family With Biallelic Mutations in the BEST1 Gene

Cited by 16 publications

References 31 publications

Next generation sequencing identifies novel disease-associated BEST1 mutations in Bestrophinopathy patients

Next generation sequencing identifies novel disease-associated BEST1 mutations in Bestrophinopathy patients

A NovelBEST1Mutation in Autosomal Recessive Bestrophinopathy

Detailed analysis of family with autosomal recessive bestrophinopathy associated with new BEST1 mutation

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