Genetic and clinical features of BEST1-associated retinopathy based on 59 Chinese families and database comparisons
Genetic and clinical features of BEST1-associated retinopathy based on 59 Chinese families and database comparisons
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DOI：
10.1016/j.exer.2022.109217
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发表时间：
2022-08-18
影响因子：
3.4
通讯作者：
Zhang, Qingjiong
中科院分区：
文献类型：
--
作者：
Wang, Yingwei;Jiang, Yi;Zhang, Qingjiong
BEST1的变异是视网膜病变最常见的原因之一，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潜在致病变异（PPVs）的特征及其相关的临床特征。BEST1的变异是从我们内部的外显子组测序数据中收集的，并通过计算机预测工具和基因型-表型分析进行系统评估。通过内部数据、普通人群基因组聚集数据库和所有已发表文献的数据库比较，进一步评估BEST1变异的致病性特征。总结住院患者的临床资料。本研究在59个家族的66例患者中发现了BEST1中的ppv，其中32例为Best黄斑营养不良（BVMD）家族，27例为常染色体隐性Best strophinopathy （ARB）家族。这些ppv包括31个错义变体，7个截断变体，1个帧内缺失变体和一个已知的3-未翻译区域变体。在我们的研究中检测到的所有截断都只与ARB有关，而与BVMD无关。在31个错义变异中，18个与显性性状BVMD相关的错义聚集在4个热点区域，与隐性错义相比差异有统计学意义。除了明显的黄斑改变外，BVMD和ARB之间的其他相关临床特征，包括周围性视网膜病变、高度远视和闭角型青光眼，均无统计学差异。综上所述，best1相关的显性视网膜病变优先由位于重要功能区域的错义变异引起。在杂合状态下，截断极有可能是良性的。未来的研究有望阐明导致BVMD和ARB的相同错义变异体的奥秘。
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.