两例Menkes病家系的临床表型及基因突变分析  

Clinical and genetic analysis of two infant with Menkes disease

作　　者：张志丹 段丽芬[2] 叶磊[2] 孙莹[2] 王晓辉[1] 孙浩[1] 褚嘉祐[1] 杨昭庆[1] ZHANG Zhidan;DUAN Lifen;YE Lei;SUNYing;WANG Xiaohui;SUN Hao;CHU Jiayou;YANG Zhaoqing(Institute of Medical Biology,Chinese Academy of Medical Sciences&Peking Union Medical College,Kunming,Yunnan 650118,China;Epilepsy Center,Kunming Childrens Hospital,Kunming,Yunnan 650034,China)

机构地区：[1]中国医学科学院&北京协和医学院医学生物学研究所医学遗传室,云南昆明650118 [2]昆明市儿童医院癫痫中心,云南昆明650034

出　　处：《中国优生与遗传杂志》2022年第1期45-49,共5页Chinese Journal of Birth Health & Heredity

基　　金：云南省高层次卫生健康技术人才培养专项(L-2018003);云南省科技厅昆明医科大学应用基础研究联合专项资金面上项目(202001AY070001-273);昆明市卫生科技人才培养项目暨“十百千”工程培养计划(2021-SW(省)-23);昆明市卫生健康委员会卫生科研课题(2020-06-01-115)。

摘　　要：目的探讨2例Menkes病(Menkes disease,MD)患儿家系的临床表型及致病基因突变,明确病因。方法收集患者临床资料,提取2例家系中患儿及其父母的基因组DNA,并对两家系中先证者进行全外显子组测序(whole exome sequencing,WES),对候选致病突变进行生物信息学分析,并利用Sanger测序对先证者及其父母进行突变位点的验证。结果 2例男性患儿临床表现有癫痫、毛发异常及脑电图异常,均检出X染色体上ATP7A基因(NM_000052)突变,1例为c.2938C>T(p.Arg980Ter)无义突变半合子。另1例为c.4127_4127delT(p.F1377LfsTer24)移码突变半合子,该突变尚未见文献报道,在正常人群数据库中未发现该突变。根据美国医学遗传学与基因组学学会遗传突变分类标准与指南,ATP7A基因c.4127_4127delT新突变被判定为可能的致病突变((PVS1+PM2)。结论 ATP7A基因上的c.2938C>T和c.4127_4127delT突变分别是2例Menkes病患儿的致病原因,新突变的检出丰富了Menkes病的基因突变谱。Objective To explore the genetic basis for two children with Menkes disease.Methods Genomic DNA was extracted from the peripheral blood samples of the family members,whole exome sequencing(WES)was performed on the 2 probands,and the candidate pathogenic mutations were analyzed by bioinformatics,suspected mutations were verified by Sanger sequencing of their family members.Results The clinical manifestations of 2 male children were epilepsy,abnormal hair and abnormal electroencephalogram.Mutations of the ATP7 A gene were detected in all of the two families,including a c.2938 C>T(p.Arg980 Ter)nonsense mutation in family1,and a novel c.4127_4127 delT(p.F1377 LfsTer24)frameshift mutation in family2,and this mutation has not been found in the normal population database.Based on the American College of Medical Genetics and Genomics standards and guidelines,the c.4127_4127 delT was predicted to be likely pathogenic(PVS1+PM2).Conclusion The two pathogenic mutations c.2938 C>T and c.4127_4127 delT in the ATP7 A gene may underlay the Menkes disease in the two children,the detection of new mutations enriched the gene mutation spectrum of Menkes disease.

关 键 词：MENKES病 ATP7A基因 全外显子组测序 基因突变 移码突变 

分 类 号：R725.9[医药卫生—儿科]