Clinical and Genetic Findings of Autosomal Recessive Bestrophinopathy (ARB)

Mutations in BEST1 cause several phenotypes including autosomal dominant (AD) Best vitelliform macular dystrophy type 2 (BVMD), AD vitreo-retino-choroidopathy (ADVIRC), and retinitis pigmentosa-50 (RP50). A rare subtype of Bestrophinopathy exists with biallelic mutations in BEST1. Its frequency is estimated to be 1/1,000,000 individuals. Here we report 6 families and searched for a genotype-phenotype correlation. All patients were referred due to reduced best-corrected visual acuity (BCVA), ranging from 0.1/10 to 3/10. They all showed vitelliform lesions located at the macula, sometimes extending into the midperiphery, along the vessels and the optic disc. Onset of the disease varied from the age of 3 to 25 years. Electrooculogram (EOG) revealed reduction in the EOG light rise in all patients. Molecular analysis revealed previously reported mutations p.(E35K);(E35K), p.(L31M);(L31M), p.(R141H);(A195V), p.(R202W);(R202W), and p.(Q220*);(Q220*) in five families. One family showed a novel mutation: p.(E167G);(E167G). All mutations were heterozygous in the parents. In one family, heterozygous children showed various reductions in the EOG light rise and autofluorescent deposits. Autosomal recessive Bestrophinopathy (ARB), although rare, can be recognized by its phenotype and should be validated by molecular analysis. Genotype-phenotype correlations are difficult to establish and will require the analysis of additional cases.

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Clinical Heterogeneity in Autosomal Recessive Bestrophinopathy with Biallelic Mutations in the BEST1 Gene

International Journal of Molecular Sciences ◽

10.3390/ijms21249353 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9353

Author(s):

Karsten Hufendiek ◽

Katerina Hufendiek ◽

Herbert Jägle ◽

Heidi Stöhr ◽

Marius Book ◽

...

Keyword(s):

Autosomal Recessive ◽

Age Of Onset ◽

Fundus Autofluorescence ◽

Serous Retinal Detachment ◽

Fundus Photography ◽

Macular Dystrophy ◽

Ophthalmological Examination ◽

Hyperreflective Foci ◽

Autosomal Recessive Bestrophinopathy ◽

Biallelic Mutations

Autosomal recessive bestrophinopathy (ARB) has been reported as clinically heterogeneous. Eighteen patients (mean age: 22.5 years; 15 unrelated families) underwent ophthalmological examination, fundus photography, fundus autofluorescence, and optical coherence tomography (OCT). Molecular genetic testing of the BEST1 gene was conducted by the chain-terminating dideoxynucleotide Sanger methodology. Onset of symptoms (3 to 50 years of age) and best-corrected visual acuity (0.02–1.0) were highly variable. Ophthalmoscopic and retinal imaging defined five phenotypes. Phenotype I presented with single or confluent yellow lesions at the posterior pole and midperiphery, serous retinal detachment, and intraretinal cystoid spaces. In phenotype II fleck-like lesions were smaller and extended to the far periphery. Phenotype III showed a widespread continuous lesion with sharp peripheral demarcation. Single (phenotype IV) or multifocal (phenotype V) vitelliform macular dystrophy-like lesions were observed as well. Phenotypes varied within families and in two eyes of one patient. In addition, OCT detected hyperreflective foci (13/36 eyes) and choroidal excavation (11/36). Biallelic mutations were identified in each patient, six of which have not been reported so far [c.454C>T/p.(Pro152Ser), c.620T>A/p.(Leu207His), c.287_298del/p.(Gln96_Asn99del), c.199_200del/p.(Leu67Valfs*164), c.524del/p.(Ser175Thrfs*19), c.590_615del/p.(Leu197Profs*26)]. BEST1-associated ARB presents with a variable age of onset and clinical findings, that can be categorized in 5 clinical phenotypes. Hyperreflective foci and choroidal excavation frequently develop as secondary manifestations.

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Clinical & Molecular Analysis of Patients with Type 2 (Qualitative) Hereditary Antithrombin (AT) Deficiency

Blood ◽

10.1182/blood.v116.21.4201.4201 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4201-4201

Author(s):

Mrinal M. Patnaik ◽

Jennifer Guenther ◽

Rajiv Pruthi ◽

John Heit

Keyword(s):

Molecular Analysis ◽

Conflicts Of Interest ◽

Novel Mutation ◽

Adult Life ◽

Obstetric Complications ◽

Molecular Testing ◽

At Deficiency ◽

The Mean

Abstract Abstract 4201 Background: Hereditary AT deficiency is classified as type 1 (quantitative) or type 2 (qualitative). Type 2 deficiency can be further subdivided into type 2a (reactive center loop [RCL]), type 2b (heparin binding domain), and type 2c (pleiotropic) based on functional and molecular AT analysis. Patients with heterozygous type 2b AT deficiency are thought to be at a lower risk for venous thromboembolism (VTE). Objectives: 1) To estimate the frequency of type 2 hereditary AT deficiency. 2) To utilize molecular analysis to accurately sub type patients with type 2 defects. 3) To correlate thrombotic and obstetric complications with AT deficiency sub types. Methods: Apparently unrelated Mayo Clinic AT-deficient patients (n=20) were categorized as type 1 or 2 based on plasma AT activity and antigen, or by molecular analysis for previously reported type 2a-c mutations. Demographic and clinical characteristics were abstracted from patient medical records. The SERPINC1 putative promoter region, all exons (n=7) and splice junctions, and the 3′UTR were PCR amplified from leukocyte genomic DNA, and sequenced with nested forward and reverse primers. For patients without identifiable mutations, multiplex ligand-dependent probe amplification (MLPA) was performed. Results: Out of 20 probands tested 7 (35%) had type 2 AT deficiency. The mean patient age at diagnosis was 36 years (range 18–65) and 5 (69%) were women. There were 2 patients with type 2a, 4 with type 2b (including 1 with a homozygous defect), and 1 with type 2c AT deficiency. The mean plasma AT (range) activity/antigen for these patients were 50% (37-67%)/93% (78-103%) [AT activity & antigen normal range=80-130%]. 6 patients had a previously described mutation, whereas 1 had a novel mutation [S380R] affecting the RCL (Table1). All patients with type 2a and type 2c AT deficiency had unprovoked VTE occurring at a young age. All 3 patients with heterozygous type 2b AT deficiency had no VTE or obstetric complications. One patient with a homozygous type 2b defect (AT Vienna) presented with an unprovoked DVT at age 15. One family with AT Toyama (type 2b AT deficiency) had 5 asymptomatic adult family members with the mutation. Background: Molecular testing is important for an accurate subtyping of patients with type 2 AT deficiency. Type 2 defects have a diverse clinical spectrum. Patients with heterozygous type 2b AT deficiency have a low rate of VTE and obstetric complications. Homozygous type 2b AT deficiency can be compatible with adult life. Disclosures: No relevant conflicts of interest to declare.

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Phenotypic and Genetic Spectrum of Autosomal Recessive Bestrophinopathy and Best Vitelliform Macular Dystrophy

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.62.6.22 ◽

2021 ◽

Vol 62 (6) ◽

pp. 22

Author(s):

Tyler A. Pfister ◽

Wadih M. Zein ◽

Catherine A. Cukras ◽

Hatice N. Sen ◽

Ramiro S. Maldonado ◽

...

Keyword(s):

Autosomal Recessive ◽

Macular Dystrophy ◽

Vitelliform Macular Dystrophy ◽

Best Vitelliform Macular Dystrophy ◽

Autosomal Recessive Bestrophinopathy

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Phenotypic and genetic differences of autosomal recessive bestrophinopathy and Best vitelliform macular dystrophy

Journal of American Association for Pediatric Ophthalmology and Strabismus ◽

10.1016/j.jaapos.2021.08.102 ◽

2021 ◽

Vol 25 (4) ◽

pp. e26

Author(s):

Tyler Pfister ◽

Wadih Zein ◽

Hatice Sen ◽

Ramiro Maldonado ◽

Laryssa Huryn ◽

...

Keyword(s):

Autosomal Recessive ◽

Genetic Differences ◽

Macular Dystrophy ◽

Vitelliform Macular Dystrophy ◽

Best Vitelliform Macular Dystrophy ◽

Autosomal Recessive Bestrophinopathy

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Novel BEST1 mutations and clinical characteristics of autosomal recessive bestrophinopathy in a Spanish patient

European Journal of Ophthalmology ◽

10.1177/11206721211010615 ◽

2021 ◽

pp. 112067212110106

Author(s):

Marina Soto-Sierra ◽

María José Morillo-Sánchez ◽

Marta Martín-Sánchez ◽

Manuel Ramos-Jiménez ◽

Mireia López-Domínguez ◽

...

Keyword(s):

Fluorescein Angiography ◽

Autosomal Recessive ◽

Novel Mutation ◽

Fundus Autofluorescence ◽

Index Patient ◽

Ophthalmological Examination ◽

Genetic Characteristics ◽

Spanish Patient ◽

Autosomal Recessive Bestrophinopathy ◽

The Right

Purpose: To describe the clinical and genetic characteristics (novel mutation in BEST1 gene) of a Spanish patient with autosomal recessive bestrophinopathy (ARB). Methods: The detailed ophthalmological examination included best corrected visual acuity (BCVA), color and autofluorescence photography, fluorescein angiography, optical coherence tomography, and electrophysiology tests. A next-generation sequencing (NGS) strategy was applied to the index patient, and then sequenced in an Illumina NextSeq500 system. Results: A 55-year-old male presented with a BCVA of 20/25 in the right eye and 20/20 in the left eye. Fundoscopy revealed perifoveal yellow flecked-like lesions. Fluorescein angiography and fundus autofluorescence results were consistent with pattern dystrophy. A homozygous frameshift mutation in BEST1 (c.341_342del; p.(Leu114Glnfs*57)) was identified as the cause of the disease. Conclusion: ARB is a genetic disease that leads to irreversible visual loss. In this report we found a novel mutation responsible for this disease.

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Screening of BEST1 Gene in a Chinese Cohort With Best Vitelliform Macular Dystrophy or Autosomal Recessive Bestrophinopathy

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.17-21999 ◽

2017 ◽

Vol 58 (9) ◽

pp. 3366 ◽

Cited By ~ 15

Author(s):

Lu Tian ◽

Tengyang Sun ◽

Ke Xu ◽

Xiaohui Zhang ◽

Xiaoyan Peng ◽

...

Keyword(s):

Autosomal Recessive ◽

Macular Dystrophy ◽

Vitelliform Macular Dystrophy ◽

Best Vitelliform Macular Dystrophy ◽

Chinese Cohort ◽

Autosomal Recessive Bestrophinopathy

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Clinical and Mutation Analysis of Patients with Best Vitelliform Macular Dystrophy or Autosomal Recessive Bestrophinopathy in Chinese Population

BioMed Research International ◽

10.1155/2018/4582816 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Tingting Gao ◽

Chengqiang Tian ◽

Qinrui Hu ◽

Zhiming Liu ◽

Jimei Zou ◽

...

Keyword(s):

Clinical Diagnosis ◽

Autosomal Recessive ◽

Phenotypic Variability ◽

Macular Dystrophy ◽

Compound Heterozygous ◽

Serious Adverse Events ◽

Vitelliform Macular Dystrophy ◽

Best Vitelliform Macular Dystrophy ◽

Autosomal Recessive Bestrophinopathy ◽

Compound Heterozygous Mutations

Mutations in the gene BEST1 usually cause bestrophinopathies, such as the rare progressive diseases Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB). This study aimed to investigate the clinical characteristics of patients with BVMD or ARB carrying BEST1 mutations. A total of 12 probands including 9 patients with a clinical diagnosis of BVMD and 3 patients with a clinical diagnosis of ARB were recruited for genetics analysis. All patients underwent detailed ophthalmic examination. All coding exons of the BEST1 gene were screened by PCR-based DNA sequencing. Programs of PolyPhen-2, SIFT, and MutationTaster were used to analyze the potential pathogenicity of the mutations in BEST1. In the 9 unrelated patients with BVMD, one heterozygous BEST1 mutation was revealed in 8 patients and two compound heterozygous mutations in 1 patient. In the 3 unrelated patients with ARB, two compound heterozygous mutations were revealed in 2 patients and three compound heterozygous mutations in 1 patient. Molecular analyses identified a total of 15 mutations, including 3 novel mutations (c.424A>G p.S142G, c.436G>A p.A146T, and c.155T>C p.L52P). Antivascular endothelial growth factor (VEGF) drugs were given to two affected eyes, especially those also exhibiting choroidal neovascularization (CNV), and no serious adverse events occurred. Our study indicates that there is wide genotypic and phenotypic variability in patients with BVMD or ARB in China. The screening of BEST1 gene is significant for the precise diagnosis of BVMD and ARB.

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