Analysis of <i>BEST1</i> gene mutation and clinical phenotype in two families with Best vitelliform macular dystrophy and autosomal recessive bestrophinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Pan Meng , Xie Kunpeng , Du Liping , Zhou Pengyi ,  Jin Xuemin

Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, Zhengzhou 450052, China;

Corresponding author：

Jin Xuemin, Email: 2740913223@qq.com

Keywords：

Vitelliform macular dystrophy; BEST1 gene mutation

DOI：

10.3760/cma.j.cn511434-20210802-00413

Video：

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Objective To report the BEST1 gene mutations and clinical phenotypes in two pedigrees with Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB)．Methods A retrospective clinical study. From November 2019 to March 2021, in the Department of Ophthalmology of The First Affiliated Hospital of Zhengzhou University, the BVMD family (4 patients and 6 family members) and the ARB family (2 patients, 2 family members), a total of 6 patients and 8 normal family members were included in the study. Detailed medical history was obtained; best corrected visual acuity, fundus color photography, electrophysiology, optical coherence tomography and fundus autofluorescence examination were performed. The clinical characteristics for all patients in the two families were analyzed. Three milliliter peripheral venous blood of all participants in the family was collected, and the whole genomic DNA was extracted with gene sequencing using next-generation sequencing technology based on targeted capture. Compared with the database to identify the pathogenicity mutation sites, suspected pathogenic mutation sites were selected, then mutations in other members in the family was assayed by Sanger sequencing. Results In family 1, the proband was demonstrated as typical BVMD, other patients were multifocal vitelliform macular dystrophy. The DNA sequencing result showed that all the 4 patients carried heterozygous missense mutations in exon 3 of BEST1 gene: c.240C>G (p.F80L) (M1) and 2 members carried this mutation, but without clinical phenotype. M1 was a likely-pathogenic mutation reported for the first time. In family 2, the proband and the other patient were diagnosed as ARB. The DNA result showed that the 2 patients carried heterozygous missense mutations in exon 5 and exon 2 of BEST1 gene: c.584C>T (p.A195V) (M2)、c.139C>A (p.R47S) (M3), and a heterozygous frameshift mutation in exon 3 of BEST1 gene: c.235dupT (p.S79Ffs*153) (M4). M2 was a pathogenic mutation reported previously. M3 variant was of undetermined significance. M4 was a first reported pathogenic mutation. Conclusions The BEST1 gene mutation is the main cause of BVMD and ARB. Different mutation sites have different clinical phenotypes. BVMD and ARB have genetic and clinical heterogeneity.

Citation： Pan Meng, Xie Kunpeng, Du Liping, Zhou Pengyi, Jin Xuemin. Analysis of BEST1 gene mutation and clinical phenotype in two families with Best vitelliform macular dystrophy and autosomal recessive bestrophinopathy. Chinese Journal of Ocular Fundus Diseases, 2021, 37(11): 841-847. doi: 10.3760/cma.j.cn511434-20210802-00413 Copy

1.	Guziewicz KE, Sinha D, Gómez NM, et al. Bestrophinopathy: an RPE-photoreceptor interface disease[J]. Prog Retin Eye Res, 2017, 58: 70-88. DOI: 10.1016/j.preteyeres.2017.01.005.
2.	Boon CJ, Klevering BJ, Leroy BP, et al. The spectrum of ocular phenotypes caused by mutations in the BEST1 gene[J]. Prog Retin Eye Res, 2009, 28(3): 187-205. DOI: 10.1016/j.preteyeres.2009.04.002.
3.	Battaglia Parodi M, Iacono P, Romano F, et al. Spectral domain optical coherence tomography features in different stages of Best vitelliform macular dystrophy[J]. Retina, 2018, 38(5): 1041-1046. DOI: 10.1097/iae.0000000000001634.
4.	Casalino G, Khan KN, Armengol M, et al. Autosomal recessive bestrophinopathy: clinical features, natural history, and genetic findings in preparation for clinical trials[J]. Ophthalmology, 2021, 128(5): 706-718. DOI: 10.1016/j.ophtha.2020.10.006.
5.	Johnson AA, Guziewicz KE, Lee CJ, et al. Bestrophin 1 and retinal disease[J]. Prog Retin Eye Res, 2017, 58: 45-69. DOI: 10.1016/j.preteyeres.2017.01.006.
6.	Tian R, Yang G, Wang J, et al. Screening for BEST1 gene mutations in Chinese patients with bestrophinopathy[J]. Mol Vis, 2014, 20: 1594-1604.
7.	Gao FJ, Qi YH, Hu FY, et al. Mutation spectrum of the bestrophin-1 gene in a large Chinese cohort with bestrophinopathy[J]. Br J Ophthalmol, 2020, 104(6): 846-851. DOI: 10.1136/bjophthalmol-2019-314679.
8.	Richards S, Aziz N, Bale S, et al. 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[J]. Genet Med, 2015, 17(5): 405-424. DOI: 10.1038/gim.2015.30.
9.	Milenkovic VM, Röhrl E, Weber BH, et al. Disease-associated missense mutations in bestrophin-1 affect cellular trafficking and anion conductance[J]. J Cell Sci, 2011, 124(Pt 17): 2988-2996. DOI: 10.1242/jcs.085878.
10.	Cordes M, Bucichowski P, Alfaar AS, et al. Inhibition of Ca(2+) channel surface expression by mutant bestrophin-1 in RPE cells[J]. FASEB J, 2020, 34(3): 4055-4071. DOI: 10.1096/fj.201901202RR.
11.	Katagiri S, Hayashi T, Ohkuma Y, et al. Mutation analysis of BEST1 in Japanese patients with Best's vitelliform macular dystrophy[J]. Br J Ophthalmol, 2015, 99(11): 1577-1582. DOI: 10.1136/bjophthalmol-2015-306830.
12.	Hufendiek K, Hufendiek K, Jägle H, et al. Clinical heterogeneity in autosomal recessive bestrophinopathy with biallelic mutations in the Best1 gene[J/OL]. Int J Mol Sci, 2020, 21(24): 9353[2020-12-08].https://pubmed.ncbi.nlm.nih.gov/33302512/. DOI: 10.3390/ijms21249353.
13.	Xuan Y, Zhang Y, Zong Y, et al. The clinical features and genetic spectrum of a large cohort of Chinese patients with vitelliform macular dystrophies[J]. Am J Ophthalmol, 2020, 216: 69-79. DOI: 10.1016/j.ajo.2020.03.047.
14.	Liu J, Taylor RL, Baines RA, et al. Small molecules restore bestrophin 1 expression and function of both dominant and recessive bestrophinopathies in patient-derived retinal pigment epithelium[J/OL]. Invest Ophthalmol Vis Sci, 2020, 61(5): 28[2020-05-11].https://pubmed.ncbi.nlm.nih.gov/32421148/. DOI: 10.1167/iovs.61.5.28.
15.	Burgess R, Millar ID, Leroy BP, et al. Biallelic mutation of BEST1 causes a distinct retinopathy in humans[J]. Am J Hum Genet, 2008, 82(1): 19-31. DOI: 10.1016/j.ajhg.2007.08.004.
16.	Guziewicz KE, Slavik J, Lindauer SJ, et al. Molecular consequences of BEST1 gene mutations in canine multifocal retinopathy predict functional implications for human bestrophinopathies[J]. Invest Ophthalmol Vis Sci, 2011, 52(7): 4497-4505. DOI: 10.1167/iovs.10-6385.
17.	Gao T, Tian C, Xu H, et al. Disease-causing mutations associated with bestrophinopathies promote apoptosis in retinal pigment epithelium cells[J]. Graefe's Arch Clin Exp Ophthalmol, 2020, 258(10): 2251-2261. DOI: 10.1007/s00417-020-04636-5.
18.	Marquardt A, Stöhr H, Passmore LA, et al. Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease)[J]. Hum Mol Genet, 1998, 7(9): 1517-1525. DOI: 10.1093/hmg/7.9.1517.
19.	Tian L, Sun T, Xu K, et al. Screening of BEST1 Gene in a Chinese cohort with best vitelliform macular dystrophy or autosomal recessive bestrophinopathy[J]. Invest Ophthalmol Vis Sci, 2017, 58(9): 3366-3375. DOI: 10.1167/iovs.17-21999.
20.	Chien LT, Hartzell HC. Rescue of volume-regulated anion current by bestrophin mutants with altered charge selectivity[J]. J Gen Physiol, 2008, 132(5): 537-546. DOI: 10.1085/jgp.200810065.
21.	Alapati A, Goetz K, Suk J, et al. Molecular diagnostic testing by eyeGENE: analysis of patients with hereditary retinal dystrophy phenotypes involving central vision loss[J]. Invest Ophthalmol Vis Sci, 2014, 55(9): 5510-5521. DOI: 10.1167/iovs.14-14359.
22.	Nguyen TT, Poornachandra B, Verma A, et al. Next generation sequencing identifies novel disease-associated BEST1 mutations in bestrophinopathy patients[J/OL]. Sci Rep, 2018, 8(1): 10176[2018-07-05].https://pubmed.ncbi.nlm.nih.gov/29976937/. DOI: 10.1038/s41598-018-27951-8.
23.	Wabbels B, Preising MN, Kretschmann U, et al. Genotype-phenotype correlation and longitudinal course in ten families with Best vitelliform macular dystrophy[J]. Graefe's Arch Clin Exp Ophthalmol, 2006, 244(11): 1453-1466. DOI: 10.1007/s00417-006-0286-6.
24.	Querques G, Zerbib J, Santacroce R, et al. Functional and clinical data of Best vitelliform macular dystrophy patients with mutations in the BEST1 gene[J]. Mol Vis, 2009, 15: 2960-2972.
25.	Wong RL, Hou P, Choy KW, et al. Novel and homozygous BEST1 mutations in Chinese patients with Best vitelliform macular dystrophy[J]. Retina, 2010, 30(5): 820-827. DOI: 10.1097/IAE.0b013e3181c700c1.
26.	Lacassagne E, Dhuez A, Rigaudière F, et al. Phenotypic variability in a French family with a novel mutation in the BEST1 gene causing multifocal best vitelliform macular dystrophy[J]. Mol Vis, 2011, 17: 309-322.
27.	Mullins RF, Oh KT, Heffron E, et al. Late development of vitelliform lesions and flecks in a patient with best disease: clinicopathologic correlation[J]. Arch Ophthalmol, 2005, 123(11): 1588-1594. DOI: 10.1001/archopht.123.11.1588.
28.	Schatz P, Bitner H, Sander B, et al. Evaluation of macular structure and function by OCT and electrophysiology in patients with vitelliform macular dystrophy due to mutations in BEST1[J]. Invest Ophthalmol Vis Sci, 2010, 51(9): 4754-4765. DOI: 10.1167/iovs.10-5152.
29.	Mullins RF, Kuehn MH, Faidley EA, et al. Differential macular and peripheral expression of bestrophin in human eyes and its implication for Best disease[J]. Invest Ophthalmol Vis Sci, 2007, 48(7): 3372-3380. DOI: 10.1167/iovs.06-0868.
30.	Shah M, Broadgate S, Shanks M, et al. Association of clinical and genetic heterogeneity with BEST1 sequence variations[J]. JAMA Ophthalmol, 2020, 138(5): 544-551. DOI: 10.1001/jamaophthalmol.2020.0666.

1. Guziewicz KE, Sinha D, Gómez NM, et al. Bestrophinopathy: an RPE-photoreceptor interface disease[J]. Prog Retin Eye Res, 2017, 58: 70-88. DOI: 10.1016/j.preteyeres.2017.01.005.
2. Boon CJ, Klevering BJ, Leroy BP, et al. The spectrum of ocular phenotypes caused by mutations in the BEST1 gene[J]. Prog Retin Eye Res, 2009, 28(3): 187-205. DOI: 10.1016/j.preteyeres.2009.04.002.
3. Battaglia Parodi M, Iacono P, Romano F, et al. Spectral domain optical coherence tomography features in different stages of Best vitelliform macular dystrophy[J]. Retina, 2018, 38(5): 1041-1046. DOI: 10.1097/iae.0000000000001634.
4. Casalino G, Khan KN, Armengol M, et al. Autosomal recessive bestrophinopathy: clinical features, natural history, and genetic findings in preparation for clinical trials[J]. Ophthalmology, 2021, 128(5): 706-718. DOI: 10.1016/j.ophtha.2020.10.006.
5. Johnson AA, Guziewicz KE, Lee CJ, et al. Bestrophin 1 and retinal disease[J]. Prog Retin Eye Res, 2017, 58: 45-69. DOI: 10.1016/j.preteyeres.2017.01.006.
6. Tian R, Yang G, Wang J, et al. Screening for BEST1 gene mutations in Chinese patients with bestrophinopathy[J]. Mol Vis, 2014, 20: 1594-1604.
7. Gao FJ, Qi YH, Hu FY, et al. Mutation spectrum of the bestrophin-1 gene in a large Chinese cohort with bestrophinopathy[J]. Br J Ophthalmol, 2020, 104(6): 846-851. DOI: 10.1136/bjophthalmol-2019-314679.
8. Richards S, Aziz N, Bale S, et al. 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[J]. Genet Med, 2015, 17(5): 405-424. DOI: 10.1038/gim.2015.30.
9. Milenkovic VM, Röhrl E, Weber BH, et al. Disease-associated missense mutations in bestrophin-1 affect cellular trafficking and anion conductance[J]. J Cell Sci, 2011, 124(Pt 17): 2988-2996. DOI: 10.1242/jcs.085878.
10. Cordes M, Bucichowski P, Alfaar AS, et al. Inhibition of Ca(2+) channel surface expression by mutant bestrophin-1 in RPE cells[J]. FASEB J, 2020, 34(3): 4055-4071. DOI: 10.1096/fj.201901202RR.
11. Katagiri S, Hayashi T, Ohkuma Y, et al. Mutation analysis of BEST1 in Japanese patients with Best's vitelliform macular dystrophy[J]. Br J Ophthalmol, 2015, 99(11): 1577-1582. DOI: 10.1136/bjophthalmol-2015-306830.
12. Hufendiek K, Hufendiek K, Jägle H, et al. Clinical heterogeneity in autosomal recessive bestrophinopathy with biallelic mutations in the Best1 gene[J/OL]. Int J Mol Sci, 2020, 21(24): 9353[2020-12-08].https://pubmed.ncbi.nlm.nih.gov/33302512/. DOI: 10.3390/ijms21249353.
13. Xuan Y, Zhang Y, Zong Y, et al. The clinical features and genetic spectrum of a large cohort of Chinese patients with vitelliform macular dystrophies[J]. Am J Ophthalmol, 2020, 216: 69-79. DOI: 10.1016/j.ajo.2020.03.047.
14. Liu J, Taylor RL, Baines RA, et al. Small molecules restore bestrophin 1 expression and function of both dominant and recessive bestrophinopathies in patient-derived retinal pigment epithelium[J/OL]. Invest Ophthalmol Vis Sci, 2020, 61(5): 28[2020-05-11].https://pubmed.ncbi.nlm.nih.gov/32421148/. DOI: 10.1167/iovs.61.5.28.
15. Burgess R, Millar ID, Leroy BP, et al. Biallelic mutation of BEST1 causes a distinct retinopathy in humans[J]. Am J Hum Genet, 2008, 82(1): 19-31. DOI: 10.1016/j.ajhg.2007.08.004.
16. Guziewicz KE, Slavik J, Lindauer SJ, et al. Molecular consequences of BEST1 gene mutations in canine multifocal retinopathy predict functional implications for human bestrophinopathies[J]. Invest Ophthalmol Vis Sci, 2011, 52(7): 4497-4505. DOI: 10.1167/iovs.10-6385.
17. Gao T, Tian C, Xu H, et al. Disease-causing mutations associated with bestrophinopathies promote apoptosis in retinal pigment epithelium cells[J]. Graefe's Arch Clin Exp Ophthalmol, 2020, 258(10): 2251-2261. DOI: 10.1007/s00417-020-04636-5.
18. Marquardt A, Stöhr H, Passmore LA, et al. Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease)[J]. Hum Mol Genet, 1998, 7(9): 1517-1525. DOI: 10.1093/hmg/7.9.1517.
19. Tian L, Sun T, Xu K, et al. Screening of BEST1 Gene in a Chinese cohort with best vitelliform macular dystrophy or autosomal recessive bestrophinopathy[J]. Invest Ophthalmol Vis Sci, 2017, 58(9): 3366-3375. DOI: 10.1167/iovs.17-21999.
20. Chien LT, Hartzell HC. Rescue of volume-regulated anion current by bestrophin mutants with altered charge selectivity[J]. J Gen Physiol, 2008, 132(5): 537-546. DOI: 10.1085/jgp.200810065.
21. Alapati A, Goetz K, Suk J, et al. Molecular diagnostic testing by eyeGENE: analysis of patients with hereditary retinal dystrophy phenotypes involving central vision loss[J]. Invest Ophthalmol Vis Sci, 2014, 55(9): 5510-5521. DOI: 10.1167/iovs.14-14359.
22. Nguyen TT, Poornachandra B, Verma A, et al. Next generation sequencing identifies novel disease-associated BEST1 mutations in bestrophinopathy patients[J/OL]. Sci Rep, 2018, 8(1): 10176[2018-07-05].https://pubmed.ncbi.nlm.nih.gov/29976937/. DOI: 10.1038/s41598-018-27951-8.
23. Wabbels B, Preising MN, Kretschmann U, et al. Genotype-phenotype correlation and longitudinal course in ten families with Best vitelliform macular dystrophy[J]. Graefe's Arch Clin Exp Ophthalmol, 2006, 244(11): 1453-1466. DOI: 10.1007/s00417-006-0286-6.
24. Querques G, Zerbib J, Santacroce R, et al. Functional and clinical data of Best vitelliform macular dystrophy patients with mutations in the BEST1 gene[J]. Mol Vis, 2009, 15: 2960-2972.
25. Wong RL, Hou P, Choy KW, et al. Novel and homozygous BEST1 mutations in Chinese patients with Best vitelliform macular dystrophy[J]. Retina, 2010, 30(5): 820-827. DOI: 10.1097/IAE.0b013e3181c700c1.
26. Lacassagne E, Dhuez A, Rigaudière F, et al. Phenotypic variability in a French family with a novel mutation in the BEST1 gene causing multifocal best vitelliform macular dystrophy[J]. Mol Vis, 2011, 17: 309-322.
27. Mullins RF, Oh KT, Heffron E, et al. Late development of vitelliform lesions and flecks in a patient with best disease: clinicopathologic correlation[J]. Arch Ophthalmol, 2005, 123(11): 1588-1594. DOI: 10.1001/archopht.123.11.1588.
28. Schatz P, Bitner H, Sander B, et al. Evaluation of macular structure and function by OCT and electrophysiology in patients with vitelliform macular dystrophy due to mutations in BEST1[J]. Invest Ophthalmol Vis Sci, 2010, 51(9): 4754-4765. DOI: 10.1167/iovs.10-5152.
29. Mullins RF, Kuehn MH, Faidley EA, et al. Differential macular and peripheral expression of bestrophin in human eyes and its implication for Best disease[J]. Invest Ophthalmol Vis Sci, 2007, 48(7): 3372-3380. DOI: 10.1167/iovs.06-0868.
30. Shah M, Broadgate S, Shanks M, et al. Association of clinical and genetic heterogeneity with BEST1 sequence variations[J]. JAMA Ophthalmol, 2020, 138(5): 544-551. DOI: 10.1001/jamaophthalmol.2020.0666.

Chinese Journal of Ocular Fundus Diseases

Analysis of BEST1 gene mutation and clinical phenotype in two families with Best vitelliform macular dystrophy and autosomal recessive bestrophinopathy

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