无脉络膜症三个家系的基因诊断  

Genetic diagnosis of 3 families with choroideremia

作　　者：白周现 孔祥东[1] Bai Zhouxian;Kong Xiangdong(Genetic and Prenatal Diagnosis Center,the First Affiliated Hospital of Zhengzhou University,Zhengzhou,Henan 450000,China)

机构地区：[1]郑州大学第一附属医院遗传与产前诊断中心,450000

出　　处：《中华医学遗传学杂志》2022年第5期474-478,共5页Chinese Journal of Medical Genetics

基　　金：国家重点研发计划子课题(2018YFC1002206-2);郑州大学第一附属医院院内青年创新基金项目(YNQN2017008)。

摘　　要：目的分析无脉络膜症患者的基因变异,明确其可能的致病原因,为临床诊断和遗传咨询提供依据。方法收集3个家系患者的临床表型资料,采集患者及家系受试者外周血提取基因组DNA。应用全外显子组靶向测序筛查可疑基因变异,对候选变异进一步通过Sanger测序及定量PCR法验证并调查家系其他成员变异携带情况。通过HGMD和PubMed数据库检索基因变异的致病性报道情况,依据根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)变异指南判断候选变异的致病性。结果3个家系均检测到CHM基因致病变异,家系1先证者(Ⅱ1)为c.1584_1587del(p.Val529Hisfs*6)变异半合子,其女儿(Ⅲ_(2))携带c.1584_1587del(p.Val529Hisfs*6)杂合变异;家系2先证者(Ⅱ2)为第10至15外显子缺失(E10-15del)半合子,其母亲(Ⅰ2)和妹妹(Ⅱ3)携带E10-15del杂合变异;家系3先证者(Ⅱ2)为c.544delT(p.Cys182Valfs*14)变异半合子,母亲携带c.544delT(p.Cys182Valfs*14)杂合变异,父亲未检测到该变异。其中2个为已知致病性变异、1个为本研究发现的新变异CHM基因c.544delT(p.C182Vfs*14)。CHM基因c.544delT移码变异可导致翻译过程提前终止、产生无功能的产物蛋白,为致病性变异。结论本研究的发现扩展了无脉络膜症的基因变异谱。Objective To analyze the clinical manifestations and causative gene variants of the choroideremia patients,and to help the patients bedifferential diagnosed by whole exome sequencing and provide theoretical basis for their genetic counseling.Methods Clinical data of 3 families were collected and genomic DNA was extracted respectively from peripheral blood of patients and related subjects.Exome targeted sequencing was used to screen suspicious gene mutations.Sanger sequencing and quantitative PCR were used to verify the candidate mutations and investigate the mutation carrying status of other members of the family.The candidate mutations were searched through HGMD and PubMed databases for the pathogenicity reports,and the pathogenicity of candidate mutations was judged according to a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Results The proband of family 1 is c.1584_1587del(p.Val529Hisfs*6)variant hemizygote,whose daughter carries c.1584_1587del(p.Val529Hisfs*6)heterozygous variation.The proband of family 2 is a hemizygote with deletion of exons 10 to 15(E10-15del),and her mother and sister carry the E10-15del heterozygous variation.In family 3,the proband is c.544delT(p.Cys182Valfs*14)variant hemizygote,and his mother is c.544delT(p.Cys182Valfs*14)heterozygote,but the father do not detect this variant.All the 3 families were detected pathogenic gene variations of CHM,two of which were known pathogenic variation and one of which was novel CHM gene c.544delT(p.C182Vfs*14)in this study.The c.544delT frameshift mutation of CHM gene can lead to the premature termination of the product protein translation and nonfunctioning protein.It is a pathogenic mutation according to ACMG guidelines.Conclusion The findings of this study expand the gene variation spectrum of choroideremia.

关 键 词：无脉络膜症 夜盲 视野缺损 DNA测序 CHM基因 

分 类 号：R773.4[医药卫生—眼科]