State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China.
Exp Eye Res. 2021 Feb;203:108405. doi: 10.1016/j.exer.2020.108405. Epub 2020 Dec 18.
Mutations in RHO are the most common cause of autosomal dominant retinitis pigmentosa. However, the pathogenicity of many RHO variants is questionable. This study was designed to investigate the genotype-phenotype correlation for RHO variants. These RHO variants were collected from the in-house exome sequencing data of 7092 probands suffering from different types of eye conditions. The variants were classified using bioinformatics tools, family segregation, and clinical phenotypes. The RHO variants were assessed using multiple online tools and a genotype-phenotype analysis based on the data collected from of ours, gnomAD, and published literature. Totally, 52 heterozygous variants of RHO were detected in the 7092 probands. Of these 52, 17 were potentially pathogenic, were present in 35 families, and comprised 15 missense variants, one inframe deletion and one nonsense variant. All the 15 missense variants were predicted to be damaging by five different online tools. The analysis of the clinical data of the patients from the 35 families revealed certain common features, of an early damage to both the rods and the cones, relatively preserved visual acuity in adulthood, and mid-peripheral tapetoretinal degeneration with pigmentation or RPE atrophy. Our data, the data from gnomAD, and the systematic review of the 246 previously reported variants suggest that approximately two-thirds of the rare missense variants and most of the truncated variants involving upstream of K296 are likely benign. This study provides a brief summary of the characteristics of the pathogenic RHO variants. It emphasizes that the systematic evaluation of these variants at the individual-gene level is crucial in the current era of clinical genetic testing even for a well-known gene such as RHO.
RHO 基因突变是常染色体显性遗传视网膜色素变性的最常见原因。然而，许多 RHO 变体的致病性存在疑问。本研究旨在探讨 RHO 变体的基因型-表型相关性。这些 RHO 变体是从 7092 名患有不同类型眼病的患者的内部外显子组测序数据中收集的。使用生物信息学工具、家族分离和临床表型对变体进行分类。使用多种在线工具和基于我们、gnomAD 和已发表文献收集的数据的基因型-表型分析来评估 RHO 变体。在 7092 名患者中总共检测到 52 个 RHO 杂合变体。其中 17 个为潜在致病性变体，存在于 35 个家庭中，包括 15 个错义变体、1 个框内缺失和 1 个无义变体。所有 15 个错义变体均被 5 种不同的在线工具预测为有害。对 35 个家庭患者的临床数据分析揭示了某些共同特征，即视杆和视锥均早期受损，成年期视力相对保留，中周边毯层视网膜变性伴色素沉着或 RPE 萎缩。我们的数据、gnomAD 中的数据以及对之前报道的 246 个变体的系统回顾表明，大约三分之二的罕见错义变体和大多数涉及 K296 上游的截断变体很可能是良性的。本研究简要总结了致病性 RHO 变体的特征。它强调了即使对于 RHO 等知名基因，在当前临床基因检测时代，对这些变体进行个体基因水平的系统评估至关重要。
