先天性虹膜缺损合并先天性白内障一家系的PAX6基因新突变  

A novel mutation in PAX6 gene causing congenital iris coloboma with congenital cataract in a pedigree

作　　者：顾静 易浩安 查旭[3] 孔艳波[3] 江伟阳 杨芳[2] 李凡[4] 何永蜀[2] Gu Jing;Yi Haoan;Zha Xu;Kong Yanbo;Jiang Weiyang;Yang Fang;Li Fan;He Yongshu(Department of Ophthalmology,Yunnan Disabled Rehabilitation Center,Kunming 650032,China;Department of Cell Biology and Medical Genetics,Kunming Medical University,Kunming 650500,China;Department of Ophthalmology,the 2nd Afliated Hospital of Kunming Medical University,Kunming 650101,China;Department of Pathology and Pathophysiology,Kunming Medical University,Kunming 650500,China)

机构地区：[1]云南省残疾人康复中心眼科,昆明650032 [2]昆明医科大学细胞生物学与医学遗传学系,昆明650500 [3]昆明医科大学第二附属医院眼科,昆明650101 [4]昆明医科大学病理学与病理生理学系,昆明650500

出　　处：《中华实验眼科杂志》2022年第10期966-971,共6页Chinese Journal Of Experimental Ophthalmology

基　　金：昆明医科大学第二附属医院院内科研项目(2020yk001)。

摘　　要：目的探讨先天性虹膜缺损合并先天性白内障一家系的致病基因及遗传方式。方法采用家系调查研究方法,2020年2月于云南省残疾人康复中心和昆明医科大学第二附属医院眼科收集云南汉族先天性虹膜缺损合并先天性白内障一家系,对先证者及其父母、子女和丈夫进行眼科临床检查及诊断。收集该家系成员全血,提取基因组DNA。对先证者及其丈夫进行全外显子组测序,采用生物信息学分析方法定位可疑致病基因,采用UGENE进行氨基酸保守性分析;采用MutationTaster预测变异对蛋白翻译的影响;参照美国医学遗传学与基因组学学会(ACMG)遗传变异分类标准与指南对变异位点进行致病性评估。对所有收集样本进行Sanger测序验证,确定致病基因及变异位点。结果先证者临床表现为双眼虹膜大部缺损,仅周边部见少量虹膜组织,晶状体皮质及后囊混浊,伴有眼球震颤,眼部检查无其他异常。先证者全外显子组测序结果显示,PAX6基因第8外显子有1个新的杂合移码变异PAX6:c.415dupA(p.R139fs),发生移码突变的位点在各物种间保守。MutationTaster预测结果显示,该变异位点位于PAX6蛋白高度保守区,变异使蛋白质丧失功能。ACMG遗传变异分类标准与指南评分为PVS1+PM2+PP1,为致病性变异。结合该家系疾病临床表型及Sanger测序分析,显示变异与疾病共分离,表明该变异致病。先证者及子女均患该病,先证者父母表型正常,该变异为新发变异,符合常染色体显性遗传。结论PAX6基因杂合移码突变c.415dupA(p.R139fs)是导致该家系出现先天性虹膜缺损合并先天性白内障的原因,该变异位点为首次报道。Objective To identify the pathogenic gene and inheritance pattern in a pedigree of congenital iris coloboma with congenital cataract.Methods The method of pedigree investigation was adopted.A pedigree of congenital iris coloboma with congenital cataract was collected by Yunnan Disabled Rehabilitation Center and the 2nd Afliated Hospital of Kunming Medical University in February 2020.Ophthalmic examinations were carried out on the female proband,her parents,her children and her husband,and the clinical diagnosis was made.Genomic DNA was extracted from peripheral blood samples collected from the family members.The suspected pathogenic gene in the proband and her husband was screened by whole exome sequencing and was identified by bioinformatics analysis.The amino acid conservation was analyzed by UGENE software.The impact of the mutation on protein translation was predicted using MutationTaster software.The pathogenicity of the mutation was assessed according to the American College of Medical Genetics(ACMG)Standards and Guidelines.Pathogenic gene and mutations were verified by Sanger sequencing.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of the 2nd Afliated Hospital of Kunming Medical University(No.PJ-2020-61).Written informed consent was obtained from each subject or custodian.Results The proband showed large iris defects in both eyes with only a small amount of observable iris tissue in the periphery,lens cortical opacity and posterior capsule opacification,accompanied by nystagmus.A novel heterozygous frameshift variation c.415dupA(p.R139fs)was located in exon 8 of PAX6 gene,and the variation was conservative across multiple species.The variation was in the highly conserved region of PAX6 gene and caused the dysfunction of PAX6 protein.The variation was graded as PVS1+PM2+PP1,a pathogenic variation,based on ACMG guidelines.The pedigree was consistent with co-segregation,indicating that the novel variation was pathogenic.The proband and her children w

关 键 词：虹膜疾病 眼组织缺损 白内障 家系 基因检测 PAX6基因 移码突变 新发突变 

分 类 号：R776.1[医药卫生—眼科] R773.1[医药卫生—临床医学]