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      BEST1 novel mutation causes Bestrophinopathies in six families with distinct phenotypic diversity


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          To report novel BEST1 variants in six Chinese families with bestrophinopathies of two different inheritance modes and analyze the intrafamilial phenotypic diversity.


          A total of 25 participants including 13 patients and 12 healthy family members from 6 Chinese families with bestrophinopathies were available for genetic and clinical analysis. All of the patients were subjected to comprehensive ophthalmic evaluations and exome sequencing was performed on the probands to detect the causative variants. The pathogenicity of gene variants was predicted using silico analysis and evaluated according to ACMG guidelines. All (likely) pathogenic variants were determined by Sanger sequencing and co‐segregation analyses were performed on available family members. The relevant original literature previously reported was retrieved to explore the relationship between BEST1‐related gene variants and clinical features.


          In the 6 families, 3 families (10 patients) were assigned as autosomal dominant bestrophinopathies (VMD) and 3 families (3 patients) were assigned as Autosomal recessive Bestrophinopathies (ARB). A total of 9 variants on the BEST1 gene were identified, containing 7 missense variants, 1 nonsense variant, and 1 frameshift variant, respectively, of which 3 variants c.88A > G (p.Lys30Glu), c.764G > A (p.Arg255Gln) and c.233dupT (p.Ser79Phefs*153) were novel variants. Three families with ARB were detected with heterozygous variants on the BEST1 gene.2 families (8 patients) with BVMD showed markedly irregular dominant inheritance, and the severity of macular lesions varies greatly among individuals of the same family. Among them, the probands showed typical vitelliform lesions in the macula, while the other six patients had no visible signs of the disease by fundus photography (ophthalmoscopy) and minor lesions could be detected on OCT in two patients, the continuity of the ellipsoidal band was interrupted with the chimeric band. The phenotypes of the patients in the three ARB families ranged from typical/atypical vitelliform lesions to extensive extramacular deposits (peripheral spots).


          This study provided evidence that the phenotype of BVMD manifested irregular dominant inheritance, with patients carrying a pathogenic heterozygous variant of BEST1 to develop obvious intrafamilial phenotypic diversity, and the patients who harbor two pathogenic alleles showed recessive inheritance bestrophinopathies with distinct phenotypic diversity. Our study also emphasized the importance of comprehensive genetic analysis in patients with bestrophinopathies, and in such challenging families with distinct intrafamilial phenotypic diversity, it shall provide novel insights into phenotypic assessments of bestrophinopathies, and contribute to better diagnosis, prognosis, and treatment for these patients.


          BEST1 novel mutation causes Bestrophinopathies in six families with distinct phenotypic diversity.

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          Most cited references28

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          Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

          The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.
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            Bestrophin 1 and retinal disease.

            Mutations in the gene BEST1 are causally associated with as many as five clinically distinct retinal degenerative diseases, which are collectively referred to as the "bestrophinopathies". These five associated diseases are: Best vitelliform macular dystrophy, autosomal recessive bestrophinopathy, adult-onset vitelliform macular dystrophy, autosomal dominant vitreoretinochoroidopathy, and retinitis pigmentosa. The most common of these is Best vitelliform macular dystrophy. Bestrophin 1 (Best1), the protein encoded by the gene BEST1, has been the subject of a great deal of research since it was first identified nearly two decades ago. Today we know that Best1 functions as both a pentameric anion channel and a regulator of intracellular Ca(2+) signaling. Best1 is an integral membrane protein which, within the eye, is uniquely expressed in the retinal pigment epithelium where it predominantly localizes to the basolateral plasma membrane. Within the brain, Best1 expression has been documented in both glial cells and astrocytes where it functions in both tonic GABA release and glutamate transport. The crystal structure of Best1 has revealed critical information about how Best1 functions as an ion channel and how Ca(2+) regulates that function. Studies using animal models have led to critical insights into the physiological roles of Best1 and advances in stem cell technology have allowed for the development of patient-derived, "disease in a dish" models. In this article we review our knowledge of Best1 and discuss prospects for near-term clinical trials to test therapies for the bestrophinopathies, a currently incurable and untreatable set of diseases.
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              Autosomal recessive bestrophinopathy: differential diagnosis and treatment options.

              To describe the clinical and genetic characteristics of patients with autosomal recessive bestrophinopathy (ARB).

                Author and article information

                Mol Genet Genomic Med
                Mol Genet Genomic Med
                Molecular Genetics & Genomic Medicine
                John Wiley and Sons Inc. (Hoboken )
                15 November 2022
                January 2023
                : 11
                : 1 ( doiID: 10.1002/mgg3.v11.1 )
                : e2095
                [ 1 ] Clinical Medical College Ningxia Medical University Yinchuan China
                [ 2 ] Ningxia Eye Hospital, People's Hospital of Ningxia Hui Autonomous Region Third Clinical Medical College of Ningxia Medical University Yinchuan China
                [ 3 ] Gansu Aier Ophthalmiology and Optometry Hospital Lanzhou City China
                [ 4 ] Aier Eye Hospital Group Hubin Aier Eye Hospital Binzhou City China
                Author notes
                [*] [* ] Correspondence

                Xunlun Sheng, Gansu Aier Ophthalmiology and Optometry Hospital, 1228‐437, Guazhou Road, Qilihe District, Lanzhou City, Gansu, 730050, China.

                Email: shengxunlun@ 123456163.com

                Weining Rong, Ningxia Eye Hospital, People's Hospital of Ningxia Hui Autonomous Region, Third Clinical Medical College of Ningxia Medical University, No. 936, Huang He East Road, Jinfeng District, Yinchuan, 750001, China.

                Email: rongweining426@ 123456126.com

                Author information
                MGG32095 MGG3-2022-05-0724.R2
                © 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                : 24 October 2022
                : 14 May 2022
                : 26 October 2022
                Page count
                Figures: 6, Tables: 5, Pages: 18, Words: 8424
                Funded by: The key research and development project of Ningxi Hui Autonomous Region
                Award ID: 2020BEG03047
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 81760180
                Funded by: The Key R & D Plan Project of Ningxia Hui Autonomous Region
                Award ID: 2021BEG02045
                Funded by: Ningxia Natural Science Foundation Project
                Award ID: 2021AAC03302
                Funded by: The Training Project of the Scientific Innovation Commanding Talented Person in Ningxia Hui Autonomous Region
                Award ID: KJT2020013
                Original Article
                Original Articles
                Custom metadata
                January 2023
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.3 mode:remove_FC converted:11.01.2023

                autosomal recessive bestrophinopathies,best vitelliform macular dystrophy, best1 gene,genotype and phenotype,irregular dominant inheritance


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