癫痫伴全面性发育迟缓患儿1例的临床特征及PAK1基因变异分析  

Analysis of clinical features and PAK1 gene variant in a child with epilepsy and global developmental delay

作　　者：袁梦 张佳 李杨 罗欢 张金秀 甘靖 Yuan Meng;Zhang Jia;Li Yang;Luo Huan;Zhang Jinxiu;Gan Jing(Department of Pediatrics,Key Laboratory of Birth Defects and Related Disease of Women and Children(Sichuan University),Ministry of Education,West China Second University Hospital,Sichuan University,Chengdu,Sichuan 610041,China;Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province,Chengdu,Sichuan 610041,China)

机构地区：[1]四川大学华西第二医院儿科·出生缺陷与相关妇儿疾病教育部重点实验室,成都610041 [2]四川大学华西第二医院发育与妇儿疾病四川省重点实验室,成都610041

出　　处：《中华医学遗传学杂志》2023年第5期552-557,共6页Chinese Journal of Medical Genetics

基　　金：国家自然科学基金(82071686);四川省科技厅重点研发项目(2021YFS0093);四川大学华西第二医院临床科研基金(KL115、KL072)。

摘　　要：目的探讨1例癫痫伴全面性发育迟缓患儿的临床特征与遗传学病因。方法选取2021年4月1日于四川大学华西第二医院小儿神经科就诊的1例癫痫伴全面性发育迟缓患儿为研究对象。收集患儿临床资料,抽取患儿及其父母外周静脉血样,应用全外显子组测序(WES)对患儿进行基因检测,采用Sanger测序进行家系验证,并对候选变异进行生物信息学分析。设定检索年限为2000年1月1日至2021年5月31日,在万方数据知识服务平台、中国知网、PubMed、ClinVar、Embase等数据库中,检索PAK1基因变异相关性癫痫病例报道,对该病患儿临床表型及PAK1基因变异情况进行总结。结果患儿为男性,2岁2个月,临床表现为癫痫、全面运动发育迟缓与大头畸形。WES检测结果提示,患儿携带PAK1基因c.1427T>C变异。经Sanger测序验证,患儿父母PAK1基因均为野生型,提示患儿为新发变异。生物信息学分析:PAK1基因c.1427T>C变异在dbSNP、OMIM、HGMD及ClinVar等数据库中,仅见1篇文献报道。在ExAC、1000 Genomes及gnomAD等数据库中,亚洲正常人群该变异未见携带频率。IFT、PolyPhen-2、LRT、Mutation Taster及FATHMM等在线软件预测结果均提示该变异对编码蛋白功能影响可能有害。根据美国医学遗传学与基因组学学会(ACMG)制订的《序列变异解释的标准和指南》,该变异评级为可能致病性变异。结论PAK1基因c.1427T>C变异可能为该癫痫伴全面性发育迟缓患儿的遗传学病因。本研究为该病患儿临床诊断与遗传咨询提供了参考依据。Objective To investigate the clinical phenotype and genetic basis of a child with epilepsy and global developmental delay.Methods A child with epilepsy and global developmental delay who had visited West China Second University Hospital,Sichuan University on April 1,2021 was selected as the study subject.Clinical data of the child were reviewed.Genomic DNA was extracted from peripheral blood samples of the child and his parents.Whole exome sequencing(WES)was carried out for the child,and candidate variant was verified by Sanger sequencing and bioinformatic analysis.A literature review was also carried out by searching databases such as Wanfang data knowledge service platform,China National Knowledge Infrastructure,PubMed,ClinVar and Embase to summarize the clinical phenotypes and genotypes of the affected children.Results The child was a 2-year-and-2-month-old male with epilepsy,global developmental delay and macrocephaly.Results of WES showed that the child has harbored a c.1427T>C variant of the PAK1 gene.Sanger sequencing confirmed that neither of his parents has carried the same variant.Only one similar case had been recorded by the dbSNP,OMIM,HGMD,and ClinVar databases.No frequency for this variant among Asian population was available in the ExAC,1000 Genomes,and gnomAD databases.Prediction with IFT,PolyPhen-2,LRT,Mutation Taster,and FATHMM online software suggested that this variant is deleterious to the function of encoded protein.Based on the Standards and Guidelines for the Interpretation of Sequence Variants:A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics(ACMG),the PAK1 gene c.1427T>C variant was determined to be likely pathogenic.Conclusion The PAK1 gene c.1427T>C variant probably underlay the epilepsy and global developmental delay in this child,which has provided a reference for the clinical diagnosis and genetic counseling in children with similar disorders.

关 键 词：癫痫 全面性发育迟缓 大头畸形 PAK1基因 全外显子组测序 儿童 

分 类 号：R742.1[医药卫生—神经病学与精神病学]