目的：明确一个彝族大家系视网膜色素变性(RP)的基因突变位点，分析RHO基因突变位点与临床表型的相关性。

方法：收集一诊断为RP的先证者及其家系成员临床资料并进行详细的眼科检查。采集家系成员外周血，提取基因组DNA，用全外显子组测序(WES)筛选出先证者的潜在致病基因突变位点，用Sanger测序法对变异位点进行验证，随后用遗传学数据库和相关文献等资料对突变位点进行分析，最终确认致病突变位点，并对突变基因型与表型关系进行分析。

结果：该RP家系共5代，共42名成员，其中男19人，女23人； 确诊RP共13例，其中男4例，女9例，符合常染色体显性遗传模式。该家系的临床特点为发病早，病情发展迅速，病情较严重。患者6岁左右即被发现有夜盲，这是目前报道的RP家系中夜盲发生最早的病例； 视网膜表现为进行性的眼底骨细胞样色素沉着，视野缩小，ERG显示a，b波幅明显下降甚至熄灭； WES和Sanger测序结果共同显示先证者存在RHO基因杂合错义变异c.1040C>T：p.P347L，该变异为cDNA第1 040碱基C被T替换，导致第347位密码子由编码脯氨酸变为编码亮氨酸。通过查阅数据库、文献等资料，发现该突变未在中国人群中报道过。

结论：本研究证实了一彝族家系RP的突变基因是RHO(c.1040C>T)。该突变导致第347位密码子由编码脯氨酸变为编码亮氨酸，导致家系成员出现严重的临床表型，该研究为RHO的遗传咨询及基因诊断提供一定的分子临床及遗传基础。

METHODS:A comprehensive clinical evaluation was conducted on the proband diagnosed with RP and other familial members, complemented by a thorough ophthalmic examination. Peripheral blood samples were obtained from the proband and familial members, from which genomic DNA was extracte. Subsequent whole exome sequencing(WES)was employed to identify the variant genes in the proband. The identified variant gene was validated through Sanger sequencing, then an in-depth analysis of the mutation genes was carried out using genetic databases to ascertain the pathogenic mutation sites. Furthermore, an exhaustive analysis was performed to delineate the genotype and phenotype characteristics.

RESULTS:The RP pedigree encompasses 5 generations with 42 members, including 19 males and 23 females. A total of 13 cases of RP were identified, consisting of 4 males and 9 females, which conforms to the autosomal dominant inheritance pattern. The clinical features of this family include an early onset age, rapid progression, and a more severe condition. The patients were found to have night blindness around 6 years old, representing the earliest reported case of night blindness in RP families. The retina was manifested by progressive osteocytoid pigmentation of the fundus, a reduced visual field, and significantly decreased or even vanished a and b amplitudes of ERG. The combined results of WES and Sanger sequencing indicated that the proband had a heterozygous missense mutation of the RHO gene c.1040C>T:p.P347L, where the 1 040 base C of cDNA was replaced by T, causing codon 347 to encode leucine instead of proline. Interestingly, this mutation has not been reported in the Chinese population.

CONCLUSION:This study confirmed that the mutant gene of RP in a Yi nationality pedigree was RHO(c.1040C>T). This variant leads to the change of codon 347 from encoding proline to encoding leucine, resulting in a severe clinical phenotype among family members. This study provides a certain molecular, clinical, and genetic basis for genetic counseling and gene diagnosis of RHO.