目的:位于X染色体上的n OPN1LW基因变异通常导致蓝色单色视。n OPN1LW基因变异多发生在外显子区域，内含子区域的变异少见。本研究分析n OPN1LW基因内含子新的剪切变异相关的X染色体连锁遗传性视杆视锥细胞营养不良合并近视家系的临床表型及基因突变特点。n 方法:采用家系调查研究方法，收集2020年1月9日于河南省人民医院临床诊断为视杆视锥细胞营养不良合并近视1家系3代7名成员。对部分家系成员进行眼科检查，采集受试者静脉血并提取DNA，用河南省眼科疾病临床研究中心自主研发的眼后段疾病靶向捕获基因检测试剂盒PS400和全外显子测序法筛选致病基因。用一代Sanger测序和家系共分离法对筛选的靶基因进行验证，参照美国医学遗传学协会(ACMG)指南和在线工具SIFT、Polyphen2、Mutation Taster对新发现的变异位点进行致病性分析。结果:先证者5岁，男，临床表现为双眼视力不佳，红绿色盲和眼球震颤。双眼眼前节检查未见明显异常。眼底可见视盘边界清、色淡，黄斑中心凹反光可见。光相干断层扫描(OCT)示双眼黄斑区部分椭圆体带反射模糊，呈颗粒样。全视野ERG显示，双眼暗视0.01 ERG波形记录不到，暗视、明视3.0 ERG a、b波振幅明显降低。先证者舅舅有相似的临床表型，但症状更严重。广角眼底照相示双眼高度近视眼底改变，周边视网膜萎缩并伴有散发黑色圆点病灶；自发荧光示周边视网膜呈弱荧光，中周部未见明显异常。2种二代测序结果均显示n OPN1LW基因内含子1个新的半合子剪切变异c.112＋2T>G和n SEMA4A基因1个新的杂合变异c.1913A>C(p.Y638S)。n OPN1LW基因c.112＋2T>G变异进一步导致1号内含子经典的剪切体供体序列改变。根据ACMG指南分析显示，c.112＋2T>G致病性评分为PVS1＋PM2＋PP1，为致病性变异。n 结论:本研究首次报道了与n OPN1LW基因变异相关的X染色体连锁遗传性视杆视锥细胞营养不良合并近视家系的致病突变，且该新的致病变异位于基因内含子区域。这个结果与以往n OPN1LW基因变异主要发生于外显子的认识不同，因此本研究扩大了n OPN1LW基因致病突变谱和临床表现谱。n ","Objective:Mutations in the n OPN1LW gene located in X chromosome usually lead to blue cone monochromacy.Variations in n OPN1LW gene usually occur in the exon region, but was rare in the intron region.This study was to report a Chinese family with X-linked rod-cone dystrophy associated with a novel n OPN1LW gene hemizygotic splicing variation and analyze the clinical phenotype and gene mutation characteristicsn Methods:A pedigree investigation was performed.The family members clinically diagnosed as rod-cone dystrophy with myopia were enrolled in Henan Provincial Peoples Hospital on January 9, 2020.Detailed ophthalmological examination was carried out, and the periphery venous blood was collected for DNA extraction.The target gene sequencing panel PS400 developed by Henan Clinical Research Center for Eye Diseases and whole exon sequencing were used to detect pathogenic mutations.Sanger sequencing and pedigree co-segregation were used to verify variations.The pathogenicity of the novel variation was analyzed based on American College of Medical Genetics (ACMG) Guidelines and online tools SIFT, Polyphen2, Mutation Taster.This study adhered to the Declaration of Helsinki, and the study protocol was approved by the Medical Ethics Committee of Henan Eye Hospital (HNEECKY-2019 [15]). Written informed consent was obtained from each family member before any medical examination.Results:The proband was a 5-year-old boy with poor vision, red-green blindness and nystagmus in both eyes.No obvious abnormality in ocular anterior segment was found.The boundary of optic disc was clear and the color was reddish, and the reflection of macular fovea was clearly visible.OCT image showed indistinct reflection of some ellipsoids in macular area of both eyes.The amplitudes of a and b waves of full-field ERG were not recorded in scotopic 0.01 scale and significantly reduced in scotopic 3.0 and photopic 3.0 ERG.The uncle of the proband had a more severe clinical phenotype.Wide-angle fundus photography showed high myopia findings, peripheral retinal atrophy and sporadic black lesions, and autofluorescence examination showed attenuated fluorescence in peripheral retina.No obvious abnormality was found in the middle-peripheral retinal region.The results of two kinds next generation sequencing showed a novel hemizygotic splicing variation c. 112+ 2T>G in the intron ofn OPN1LW gene and an unreported heterozygous variation c. 1913A>C (p.Y638S) in then SEMA4A gene.The c. 112+ 2T>G mutation further leaded to the sequence change of classic splice donor of intron 1.According to the ACMG guidelines, the pathogenicity score was PVS1+ PM2+ PP1, which was considered as a pathogenic level.n Conclusions:This is the first report of X-linked rod-cone dystrophy associated with n OPN1LW gene variation, and this novel variant c. 112+ 2T>G locates in the intron region.This result is different from past knowledge that variations ofn OPN1LW gene primarily occur in exon.This study expands the mutational spectrum of n OPN1LW gene inducing retinal degeneration and the spectrum of clinical phenotype.n