一例复杂性皮质发育不良伴脑畸形患儿的临床与KIF2A基因变异分析  

Genetic and clinical analysis of KIF2A gene variant in a Chinese patient with complex cortical dysplasia and other brain malformations

作　　者：程双喜[1] 王清明 洪晓纯[1] 陈霭信 袁海明 Cheng Shuangxi;Wang Qingming;Hong Xiaochun;Chen Aixin;Yuan Haiming(Dongguan Maternal and Child Health Care Hospital,Dongguan,Guangdong 523120,China;Dongguan Institute of Reproductive and Genetic Research,Dongguan,Guangdong 523120,China)

机构地区：[1]东莞市妇幼保健院,523120 [2]东莞市生殖遗传研究所,523120

出　　处：《中华医学遗传学杂志》2022年第3期312-315,共4页Chinese Journal of Medical Genetics

基　　金：东莞市社会科技发展重点项目(202050715007220);东莞市社会科技发展一般项目(202050715007852)。

摘　　要：目的探讨临床1例复杂性皮质发育不良伴脑畸形3型(cortical dysplasia,complex,with other brain malformations 3,CDCBM3)患儿的基因型与表型关系。方法收集先证者及其父母外周血,提取基因组DNA,采用全外显子测序对先证者进行检测,并应用Sanger测序对先证者及父母进行验证。结果先证者为1例1岁2个月男性患儿,表现为运动发育迟缓,巨脑回,严重认知障碍,语言缺失,先天性喉骨软化等多发性先天异常。全外显子测序检测到患儿KIF2A基因发生了c.952G>A(p.Gly318Arg)杂合错义变异(GRCh37/hg19),该变异位于驱动蛋白运动结构域中的ATP核苷酸结合区,高度保守(PM1);在正常人群数据库频率为0(PM2);多种计算机软件预测有害(PP3);该变异在以往的文献中未有报道,Sanger测序验证显示患儿父母均未检测到该变异,因此患儿的变异为新发(PS2)。根据ACMG指南评估为临床可能致病性变异(PS2+PM1+PM2+PP3)。与已报道的CDCBM3患儿的临床表型进行比较,本例患儿的先天性喉骨软化在以往的文献中未见描述。结论本文研究扩展了KIF2A基因变异谱并丰富了CDCBM3临床表型谱。Objective To explore the genetic basis for a child featuring complex cortical dysplasia and other brain malformations(CDCBM3).Methods Genomic DNA was extracted from peripheral blood samples from the patient and his parents.Whole exome sequencing(WES)was carried out for the family trio.Suspected variant was verified by Sanger sequencing.Results The proband,a 1-year-and-2-month old Chinese boy,had presented with motor developmental delay,lissencephaly,severe cognitive impairments,absent speech and congenital laryngomalacia.WES revealed that he has harbored a heterozygous missense variant of the KIF2A gene,namely NM_001098511.2:c.952G>A,p.Gly318Arg(GRCh37/hg19).The highly conserved residue is located around the ATP nucleotide-binding pocket in the kinesin motor domain(PM1).The variant was not found in the Genome Aggregation Database and the 1000 Genomes Project(PM2),and was predicted to be deleterious on the gene product by multiple in silico prediction tools(PP3).This variant was unreported previously and was de novo in origin(PS2).Based on the ACMG guidelines,it was categorized as likely pathogenic(PS2+PM1+PM2+PP3).Furthermore,the congenital laryngomalacia found in our patient was absent in previously reported CDCBM3 cases.Conclusion The novel variant of the KIF2A gene probably underlay the disorders in the proband.Above finding has expanded the phenotypic and mutational spectrum of CDCBM3.

关 键 词：KIF2A基因 复杂性皮质发育不良伴脑畸形3型 巨脑回 认知障碍 发育迟缓 先天性喉骨软化 

分 类 号：R725.9[医药卫生—儿科]