眼白化病与眼皮肤白化病患者的基因型与临床特征分析  

Genotype and clinical characteristics of ocular albinism and oculocutaneous albinism in China

作　　者：李妮蒽 仲俊维 由冰 许可 张晓慧 闫玮玉 谢玥 张昕 李杨 Li Nien;Zhong Junwei;You Bing;Xu Ke;Zhang Xiaohui;Yan Weiyu;Xie Yue;Zhang Xin;Li Yang(Beijing Institute of Ophthalmology,Beijing Tongren Eye Center,Beijing Tongren Hospital,Capital Medical University,Beijing Key Laboratory of Ophthalmology and Visual Sciences,Beijing 100730,China)

机构地区：[1]首都医科大学附属北京同仁医院,北京同仁眼科中心,北京市眼科研究所,眼科学与视觉科学北京市重点实验室,100730

出　　处：《眼科》2023年第3期182-191,共10页Ophthalmology in China

摘　　要：目的 分析中国人携带白化病相关致病基因变异患者的基因变异特点和临床特征,比较眼白化病(ocular albinism 1,OA1)和眼皮肤白化病(oculocutaneous albinism,OCA)患者的临床表现。设计回顾性病例系列。研究对象北京同仁医院携带白化病相关基因致病变异的白化病患者32例(来自28个家系)。方法对患者进行详细眼科检查,包括最佳矫正视力(best-corrected visual acuity,BCVA)、眼前节照相、彩色眼底照相及相干光断层扫描(optical coherence tomography,OCT),并记录患者皮肤和毛发色素情况。采集先证者、直系亲属及家系患病成员外周静脉血,提取DNA,通过一代测序、目标区域捕获测序、实时定量PCR确定致病基因变异,多种生物信息学分析软件预测变异致病性,并进行家系共分离验证。主要指标致病基因变异、BCVA、眼球震颤、黄斑中心凹发育不全(foveal hypoplasia,FH)等级、眼部和皮肤毛发色素情况。结果32例患者中,共检出7个基因(GPR143、OCA2、TYR、LRMDA、HPS1、HPS6和SLC45A2)的33种变异,其中8种为新变异。携带GPR143基因变异OA1患者18例,携带其他6个基因变异OCA患者14例。这些患者均有不同程度视力下降、眼底色素减退和FH。除2例患者其余均有先天性眼球震颤。OA1患者虹膜颜色偏深,眼底色素减退以1~2级为主,均无皮肤毛发色素减退;OCA患者虹膜和眼底色素表现多样,大部分有不同程度的皮肤毛发色素减退,综合征型OCA患者还伴有血液或免疫系统异常。2例无眼球震颤的患者视力损伤及FH均较轻。OA1患者与OCA患者间虹膜和眼底色素存在显著差异。结论本研究初步描述了中国白化病患者的致病基因构成并拓展了各致病基因变异谱,发现OA1患者虹膜色素减退程度轻,OCA患者眼部和全身色素表现变异大,无明显基因型表型关系,基因检测对于不典型患者的明确诊断至关重要。Objective To analyze the genetic and clinical characteristics of Chinese patients with albinism-related gene variants,and to compare the clinical manifestations between ocular albinism(0A1) and oculocutaneous albinism(OCA).Design Retrospective case series.Participants 32 patients(from 28 families) with pathogenic variants in albinism-related genes collected from Beijing Tongren Hospital.Methods All patients underwent detailed ophthalmic examinations,including best-corrected visual acuity(BCVA),anterior segment photography,color fundus photography and optical coherence tomography(OCT).The pigmentation of skin and hair was also recorded.Genomic DNA was extracted from peripheral venous blood samples of the proband,his immediate family members and affected family members.Sanger sequencing,targeted exome sequencing(TES) and real-time quantitative polymerase chain reaction(PCR)was used to identify pathogenic variants.Multiple bioinformatics analysis software was used to predict the pathogenicity of the variants and co-segregation verification was performed.Main Outcome Measures Pathogenic variants,BCVA,nystagmus,foveal hypoplasia(FH) grade,pigmentation of eye,skin and hair.Results A total of 33 pathogenic variants in 7 genes(GPR143,OCA2,TYR,LRMDA,HPS1,HPS6 and SLC45A2) were detected in 32 patients,of which 8 were novel variants.There were 18 OA1 patients with GPR143gene variants and 14 OCA patients with the other 6 genes variants.These patients all had varying degrees of vision loss,fundus hypopigmentation and FH.All but two patients had congenital nystagmus.The iris color of OA1 patients was darker,the FH grade was mainly 1-2,and no skin or hair hypopigmentation was found.OCA patients had diverse iris and fundus pigmentation,and most of them had varying degrees of skin and hair hypopigmentation.Patients with syndromic OCA were also associated with blood or immune system abnormalities.The two patients without nystagmus had mild visual impairment and FH.There were significant differences in iris and fundus pigmentation

关 键 词：眼白化病 眼皮肤白化病 基因变异 

分 类 号：R596[医药卫生—内科学]