早期发病的神经发育障碍伴非自主运动患儿1例的遗传学分析及文献复习

Genetic analysis of a child with early onset neurodevelopmental disorder with involuntary movement and a literature review

目的探讨1例早期发病的神经发育障碍伴非自主运动(NEDIM)患儿的临床特征与遗传学病因。方法选取2020年10月8日于湖南省儿童医院神经内科就诊的1例早期发病NEDIM患儿为研究对象。收集患儿的临床资料,抽取患儿及其父母的外周静脉血样,对患儿进行全外显子组测序(WES),用Sanger测序对候选变异进行家系验证,并对其进行生物信息学分析。在中国知网(CNKI)、美国医学文摘数据库(PubMed)及谷歌学术等数据库中检索GNAO1基因c.626G>A变异相关的NEDIM病例报道,对患者的临床表型及GNAO1基因的变异情况进行总结。结果患儿为男性,3岁1月龄,临床表现为四肢不自主抖动、运动与语言发育迟缓。WES检测结果提示其携带GNAO1基因c.626G>A(p.Arg209His)杂合错义变异。经Sanger测序验证,患儿父母GNAO1基因均为野生型,提示患儿为新发变异。GNAO1基因c.626G>A(p.Arg209His)变异在HGMD及ClinVar数据库中已见报道。经dbSNP、ExAC及1000 Genomes等数据库检索,该变异均未见收录。SIFT、PolyPhen-2及Mutation Taster等在线软件预测结果均提示,该变异对编码蛋白产生有害影响。经UniProt数据库分析,该变异编码氨基酸在不同物种间高度保守;Modeller与PyMOL软件预测结果显示,该变异可能影响其编码蛋白Gαo蛋白的功能。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》,该变异被评级为致病性变异(PS2+PS1+PM1+PM2_Supporting+PP3)。结论GNAO1基因c.626G>A(p.Arg209His)变异可能为NEDIM患儿的遗传学病因,进一步丰富了GNAO1基因c.626G>A(p.Arg209His)变异的表型谱,为该病患儿临床诊断与遗传咨询提供参考依据。

Objective To explore the clinical phenotype and genetic basis of a child with early onset neurodevelopmental disorder with involuntary movement(NEDIM).Methods A child who presented at Department of Neurology of Hunan Children′s Hospital on October 8,2020 was selected as the study subject.Clinical data of the child were collected.Genomic DNA was extracted from peripheral blood samples of the child and his parents.Whole exome sequencing(WES)was carried out for the child.Candidate variant was verified by Sanger sequencing and bioinformatic analysis.Relevant literature was searched from the CNKI,PubMed and Google Scholar databases to summarize the clinical phenotypes and genetic variants of the patients.Results This child was a 3-year-and-3-month boy with involuntary trembling of limbs and motor and language delay.WES revealed that the child has harbored a c.626G>A(p.Arg209His)variant of the GNAO1 gene.Sanger sequencing confirmed that neither of his parents has carried the same variant.The variant had been reported in HGMD and ClinVar databases,but not in the dbSNP,ExAC and 1000 Genomes databases.Prediction with SIFT,PolyPhen-2,and Mutation Taster online software suggested that the variant may be deleterious to the protein function.By UniProt database analysis,the encode amino acid is highly conserved among various species.Prediction with Modeller and PyMOL software indicated that the variant may affect the function of GαO protein.Based on the guideline of the American College of Medical Genetics and Genomics(ACMG),the variant was rated as pathogenic.Conclusion The GNAO1 gene c.626G>A(p.Arg209His)variant probably underlay the NEDIM in this child.Above finding has expanded the phenotypic spectrum of GNAO1 gene c.626G>A(p.Arg209His)variant and provided a reference for clinical diagnosis and genetic counseling.