State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China.
Exp Eye Res. 2022 Oct;223:109217. doi: 10.1016/j.exer.2022.109217. Epub 2022 Aug 13.
Variants in BEST1 are one of the most common cause of retinopathy mainly involving the retinal pigment epithelium with both dominant and recessive traits. This study aimed to describe the characteristics of potential pathogenic variants (PPVs) in BEST1 and their associated clinical features. Variants in BEST1 were collected from our in-house exome sequencing data and systematically evaluated by in silico prediction tools as well as genotype-phenotype analysis. The pathogenicity features of the BEST1 variants were further assessed through database comparison among the in-house data, Genome Aggregation Database from the general population, and all previously published literature. The clinical information of the in-house patients was summarized. The PPVs in BEST1 were identified in 66 patients from 59 families, including 32 families with Best vitelliform macular dystrophy (BVMD) and 27 families with autosomal recessive bestrophinopathy (ARB). These PPVs included 31 missense variants, seven truncation variants, one in-frame deletion, and a known 3-untranslated region variant. All the truncations detected in our study were exclusively involved in ARB but not BVMD. Among the 31 missense variants, 18 missenses associated with BVMD in the dominant trait were clustered in four hotspot regions with statistically significant differences from the recessive missenses. Except for distinct macular changes, there were no statistically significant differences among the other associated clinical features between BVMD and ARB, including peripheral retinopathy, high hyperopia, and angle-closure glaucoma. In conclusion, BEST1-associated dominant retinopathy was preferentially caused by missense variants located in important functional regions. Truncations were most likely benign in heterozygous status. Future studies are expected to elucidate the mystery of the same missense variants contributing to both BVMD and ARB.
BEST1 中的变异是导致视网膜病变的最常见原因之一，主要涉及视网膜色素上皮，具有显性和隐性特征。本研究旨在描述 BEST1 中潜在致病变异（PPV）的特征及其相关临床特征。从我们的内部外显子组测序数据中收集了 BEST1 中的变异，并通过计算机预测工具以及基因型-表型分析进行了系统评估。通过与内部数据、一般人群的基因组聚合数据库以及所有已发表文献进行数据库比较，进一步评估了 BEST1 变异的致病性特征。总结了内部患者的临床信息。从 59 个家系的 66 名患者中鉴定出 BEST1 的 PPV，包括 32 个 Best 卵黄样黄斑营养不良（BVMD）家系和 27 个常染色体隐性贝斯特氏症（ARB）家系。这些 PPV 包括 31 个错义变异、7 个截断变异、1 个框内缺失和 1 个已知的 3'非翻译区变异。我们研究中检测到的所有截断都仅涉及 ARB，而不涉及 BVMD。在 31 个错义变异中，18 个与显性性状的 BVMD 相关的错义突变聚集在四个热点区域，与隐性错义突变有统计学上的显著差异。除了明显的黄斑变化外，BVMD 和 ARB 之间的其他相关临床特征之间没有统计学上的显著差异，包括周边视网膜病变、高度远视和闭角型青光眼。总之，BEST1 相关的显性视网膜病变主要由位于重要功能区域的错义变异引起。在杂合状态下，截断变异很可能是良性的。未来的研究有望阐明导致 BVMD 和 ARB 的相同错义变异的神秘之处。
