Data_Sheet_2_Genotype–Phenotype Analysis of RPGR Variations: Reporting of 62 Chinese Families and a Literature Review.PDF

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基因是X连锁视网膜色素变性（X-linked retinitis pigmentosa, RP）最常见的致病原因，其女性携带者也常受累。本研究旨在基于本实验室及既往研究的数据，探究RPGR基因的变异谱及其相关表型。
方法：本研究从7092例存在不同眼部疾病的先证者的外显子组测序数据中筛选RPGR基因变异。对这些先证者及其可获取的家族成员进行全面的眼部检查。通过检索PubMed、Web of Science及Google Scholar数据库，从既往发表的文献中收集相似数据。对基因型、表型及其相关性开展系统分析。
结果：本研究的内部队列中，共在62个无亲缘关系的家系中检测到46个可能致病的RPGR基因变异，其中包括9个错义变异、1个位于RCC1样结构域（RCC1-like domain）的框内变异，以及36个截短变异。此外，从已发表文献中共鉴定出585个变异，其中491个（83.9%）为截短变异。对本研究内部数据集、文献数据及gnomAD数据库中的变异进行系统分析后发现，RPGR基因的绝大多数致病变异为截短变异，而致病的错义变异与框内变异则富集于RCC1样结构域。男性患者与女性携带者之间存在表型差异：女性携带者的屈光不正程度更严重，但最佳矫正视力（best corrected visual acuity, BCVA）优于男性患者。男性患者的BCVA随年龄增长显著下降，且携带外显子1-14区域变异的男性患者，其BCVA优于携带ORF15区域变异的患者。女性携带者的BCVA同样随年龄增长出现显著下降，但携带外显子1-14区域变异的女性携带者与携带ORF15区域变异的女性携带者之间，BCVA无显著差异。
结论：RPGR基因的绝大多数致病变异为截短变异。位于RCC1样结构域外的错义变异与框内变异可能为良性变异，对这类变异的致病性判定标准需更为谨慎。男性患者与女性携带者的BCVA及屈光状态存在差异。年龄增长以及变异位于ORF15区域，是导致男性患者BCVA下降的相关因素。本研究结果有助于深入理解RPGR相关疾病的基因型与表型特征。