CEP290基因新变异相关单纯视锥视杆细胞营养不良基因型与临床表型分析  

Genotypes and phenotypes analysis of a novel complex heterozygous mutation of CEP290 related isolated cone-rod dystrophy

作　　者：郭庆歌 李亚 游雅 刘长庚 李舒茵 雷博 Guo Qingge;Li Ya;You Ya;Liu Changgeng;Li Shuyin;Lei Bo(Henan Eye Hospital,Henan Provincial People's Hospital,People's Hospital of Zhengzhou University,Zhengzhou 450003,China)

机构地区：[1]河南省立眼科医院河南省人民医院郑州大学人民医院,郑州450003

出　　处：《中华眼底病杂志》2022年第8期650-655,共6页Chinese Journal of Ocular Fundus Diseases

基　　金：国家自然科学基金(82071008);河南省科技攻关项目(212102310308)。

摘　　要：目的观察并分析CEP290基因新复合杂合变异导致的单纯视锥视杆细胞营养不良(CORD)的临床表型和致病性。方法回顾性研究。2021年12月于河南省立眼科医院就诊并经基因检测确诊的1个CORD家系中的2例患者及2名家系成员纳入研究。受检者均行最佳矫正视力(BCVA)、彩色眼底照相、自身荧光、扫频源光相干断层扫描(SS-OCT)、自适应光学眼底成像、静态阈值视野、全视野和多焦视网膜电图(ERG)检查,以及全身其他系统检查。采集受检者外周静脉血,提取全基因组DNA。应用遗传性视网膜疾病试剂盒PS400对DNA进行测序,对可疑致病突变位点进行Sanger验证及家系共分离分析。参照美国医学遗传学和基因组学学会(ACMG)指南对突变位点致病性进行分析。通过GERP++、Clustal Omega、Weblogo分析软件明确该基因突变位点在不同物种间的保守性。结果2例患者均为男性,年龄分别为21、29岁。患者右眼和左眼BCVA分别为0.7、0.4和0.3、0.4。全视野、多焦ERG检查,视锥细胞、视杆细胞功能降低,以视锥细胞功能下降更甚。SS-OCT检查,黄斑外核层变薄,椭圆体带及嵌合体带光反射信号减弱。自适应光学眼底成像检查,黄斑中心凹10°视角内视锥细胞排列紊乱、密度降低,部分区域视锥细胞萎缩透见视网膜色素上皮细胞。全身其他系统检查未见明显异常。基因检测结果显示,2例患者均携带CEP290 c.950T>A(p.Leu317*)(M1)、c.4144_4149del(p.Tyr1382_Glu1383del)(M2)复合杂合变异。其父亲、母亲分别携带M2、M1。M1、M2分别为新发现无义突变、新发现缺失突变,在人群基因频率数据库、ExAC数据库、千人基因组计划数据库中未见。M1被Mutation Taster、CADD软件预测为有害,GERP++显示其影响的氨基酸高度保守;根据ACMG指南评为疑似致病性变异。M2为临床意义未明变异。先证者父母临床表型未见明显异常。Sanger测序验证,符合家系共�Objective The clinical phenotypes and pathogenicity of isolated cone-rod dystrophy(CORD)caused by two novel complex heterozygous variants of the CEP290 gene were analyzed using high-resolution multi-mode imaging and gene detection techniques.Methods A retrospective study.Two patients and two family members from a CORD family who were diagnosed by genetic testing at Henan Provincial People's Hospital in December 2021 were included in the study.All subjects underwent best-corrected visual acuity(BCVA),color fundus photography,autofluorescence,swept-source optical coherence tomography(SS-OCT),adaptive optics fundus imaging,static threshold field,full field and multiple electroretinogram(ERG)examination,as well as other systemic examinations throughout the body.The peripheral venous blood of the subjects was collected,and the whole genome DNA was extracted.DNA sequencing was performed using the Inherited Retinal Disease Kit PS400,and Sanger verification and pedigree co-segregation analysis were performed on the suspected pathogenic mutation sites.Validation was performed by Sanger sequencing,pathogenicity analysis was performed in accordance with the American College of Medical Genetics and Genomics(ACMG)guidelines.Conservation of variation among different species was analyzed by GERP++,Clustal Omega and Weblogo.Results Both patients were male,and their ages were 21 and 29 years old,respectively.The right eye and left eye about BCVAs were 0.7,0.4 and 0.3,0.4,respectively.The full field and multiple electroretinogram ERG showed a decreased function of cones and rods,especially cones.SS-OCT showed thinning of the outer nuclear layer of macular,and attenuation of ellipsoid zone reflectivity in B-scan.Adaptive optics fundus imaging examination showed that the arrangement of cone cells in the fovea of the fovea was disordered and the density decreased,and the retinal pigment epithelial cells were seen through the atrophy of cone cells in some areas at 10°visual angle.No obvious abnormality was found in other systemic exa

关 键 词：基因 突变 锥杆细胞营养不良 临床表型 CEP290基因 

分 类 号：R774.5[医药卫生—眼科]