Table_4_Genotype–Phenotype Analysis of RPGR Variations: Reporting of 62 Chinese Families and a Literature Review.XLSX

PurposeRPGR is the most common cause of X-linked retinitis pigmentosa (RP), of which female carriers are also frequently affected. The aim of the current study was to explore the RPGR variation spectrum and associated phenotype based on the data from our lab and previous studies.MethodsVariants in RPGR were selected from exome sequencing data of 7,092 probands with different eye conditions. The probands and their available family members underwent comprehensive ocular examinations. Similar data were collected from previous reports through searches in PubMed, Web of Science, and Google Scholar. Systematic analyses of genotypes, phenotypes and their correlations were performed.ResultsA total of 46 likely pathogenic variants, including nine missense and one in-frame variants in RCC1-like domain and 36 truncation variants, in RPGR were detected in 62 unrelated families in our in-house cohort. In addition, a total of 585 variants, including 491 (83.9%) truncation variants, were identified from the literature. Systematic analysis of variants from our in-house dataset, literature, and gnomAD suggested that most of the pathogenic variants of RPGR were truncation variants while pathogenic missense and in-frame variants were enriched in the RCC1-like domain. Phenotypic variations were present between males and female carriers, including more severe refractive error but better best corrected visual acuity (BCVA) in female carriers than those in males. The male patients showed a significant reduction of BCVA with increase of age and males with exon1-14 variants presented a better BCVA than those with ORF15 variants. For female carriers, the BCVA also showed significant reduction with increase of age, but BCVA in females with exon1-14 variants was not significant difference compared with those with ORF15 variants.ConclusionMost pathogenic variants of RPGR are truncations. Missense and in-frame variants located outside of the RCC1-like domain might be benign and the pathogenicity criteria for these variants should be considered with greater caution. The BCVA and refractive error are different between males and female carriers. Increase of age and location of variants in ORF15 contribute to the reduction of BCVA in males. These results are valuable for understanding genotypes and phenotypes of RPGR.

RPGR（视网膜色素变性基因）是X连锁视网膜色素变性（RP）最常见的原因，其中女性携带者也常受影响。本研究旨在基于我实验室及先前研究的数据，探究RPGR的变异谱及其相关表型。方法上，我们从7,092例不同眼病患者的外显子组测序数据中选取了RPGR变异。受试者及其可用的家庭成员接受了全面的眼睛检查。通过PubMed、Web of Science和Google Scholar的搜索，收集了先前报道中的类似数据。对基因型、表型及其相关性进行了系统分析。结果在62个无关家庭中，我们内部队列检测到46个可能的致病变异，包括RCC1样域中的9个错义变异和1个框内变异，以及36个截断变异。此外，从文献中确定了585个变异，包括491个（83.9%）截断变异。对我们内部数据集、文献和gnomAD中的变异的系统分析表明，RPGR的大部分致病变异为截断变异，而致病性错义和框内变异则集中在RCC1样域。在男性和女性携带者之间存在表型变异，女性携带者的最佳矫正视力（BCVA）优于男性，但女性携带者的屈光误差更严重。男性患者的BCVA随着年龄的增长而显著下降，而携带exon1-14变异的男性患者的BCVA优于携带ORF15变异的患者。对于女性携带者，BCVA随着年龄的增长也显著下降，但携带exon1-14变异的女性的BCVA与携带ORF15变异的女性之间没有显著差异。结论RPGR的大部分致病变异为截断型。位于RCC1样域之外的错义和框内变异可能为良性，对这些变异的致病性标准应更加谨慎考虑。男性和女性携带者的BCVA和屈光误差存在差异。年龄的增长和ORF15中变异的位置是男性BCVA下降的原因。这些结果对于理解RPGR的基因型和表型具有重要意义。