IQSEC2无义变异所致X连锁精神发育迟缓患儿的基因分析

Identification of a novel nonsense IQSEC2 variant in a child with X-linked intellectual disability

目的:报道1例由IQSEC2基因变异所致的X连锁精神发育迟缓患儿,并分析IQSEC2基因的致病变异。方法:先证者为男性,1岁6月龄,以"精神发育迟缓伴双眼内斜视"为主要表现。提取患儿及其双亲外周血DNA物,应用全外显子基因组测序法检测相关基因变异,并通过Sanger测序法验证。对可疑变异进行生物信息学预测。结果:经全外显子基因组测序分析发现,患儿IQSEC2基因第12外显子存在一个c.3163C>T(p.Arg1055*)杂合无义变异,该变异为国内未见报道的新发变异。c.3163C>T(p.Arg1055*)变异经Mutation Taster、PROVEAN、SIFT等变异预测软件预测,结果均提示为有害变异,并经HomoloGene及BLAST系统分析IQSEC2基因编码蛋白第1055位Arg在哺乳动物及无脊椎动物中均高度保守,该氨基酸的提前终止编码可严重影响PH结构域(951-1085)的形成进而导致IQSEC2蛋白完整性严重破坏。同时经UCSF chimera软件对蛋白3D结构建模分析发现,该氨基酸的提前终止编码可导致编码蛋白结构中α螺旋、β折叠及无规卷曲等蛋白二级结构丧失,空间结构严重变形,原有功能丧失。结论:IQSEC2基因c.3163C>T(p.Arg1055*)变异可能为该患儿罹患X连锁精神发育迟缓的致病原因。

Objective To explore the genetic basis for a child featuring X-linked intellectual disability.Methods The 1-year-and-6-month-old child presented with growth retardation,intellectual disability and bilateral alternating squint.With DNA extracted from the child and his parents’peripheral venous blood samples,whole exome sequencing was carried out to identify potential variants that can explain his condition.Suspected variants were validated by Sanger sequencing.The impact of variants was predicted by bioinformatic tools.Results The child was found to harbor a de novo nonsense c.3163C>T(p.Arg1055*)variant of the IQSEC2 gene.The variant,unreported previously,was predicted to be pathogenic based on MutationTaster,PROVEAN and SIFT.Analysis using a HomoloGene system suggested Arg1055 in IQSEC2 residues to be highly conserved evolutionarily,and that replacement of Arg1055 may cause destroy of the PH domain(AA 951-1085)and serious damage to the function of IQSEC2 protein.Analysis with UCSF chimera software suggested that the c.3163C>T(p.Arg1055*)variant can induce serious damages to the secondary structures of IQSEC2 protein,causing loss of its function.Conclusion The patient’s condition may be attributed to the de novo nonsense variant c.3163C>T(p.Arg1055*)of the IQSEC2 gene.