MID1基因无义变异介导的mRNA降解逃逸所致X连锁Opitz G/BBB综合征1例患儿的临床特征与遗传学分析  

Clinical feature and genetic analysis of a child with X-linked Opitz G/BBB syndrome caused by nonsense variant in the MID1 gene mediated by mRNA degradation escape

作　　者：闫莹玉 贺莉[1] 杨颖[3] 王端 张海清 陈艳妮[1] Yan Yingyu;He Li;Yang Ying;Wang Duan;Zhang Haiqing;Chen Yanni(Department of Child Health Care,Xi′an Children′s Hospital,Xi′an,Shaanxi 710003,China;Department of Child Health Care,Xi′an Maternity and Children Healthcare Hospital,Xi′an,Shaanxi 710002,China;Research Institute of Pediatric Disease of Shaanxi province,Xi′an Children′s Hospital,Xi′an,Shaanxi 710003,China)

机构地区：[1]西安市儿童医院儿童保健科,西安710003 [2]西安市妇幼保健院儿童保健科,西安710002 [3]西安市儿童医院陕西省儿科疾病研究所,西安710003

出　　处：《中华医学遗传学杂志》2025年第2期219-225,共7页Chinese Journal of Medical Genetics

基　　金：陕西省重点产业创新链(群)(2024SF-ZDCYL-01-02);陕西省自然科学基础研究计划(2022JQ-979);西安市科技计划项目(22YXYJ0025)。

摘　　要：目的探讨1例轻度临床表型的Opitz G/BBB综合征(OS)患儿的基因型与表型之间的关系。方法选取2021年6月10日西安市儿童医院收治的1例以运动发育迟缓为首发症状的患儿为研究对象。采集患儿临床资料,抽取患儿及其母亲外周血样,采用全外显子组测序(WES)对患儿进行基因检测,对筛选出的候选变异进行Sanger测序家系验证与致病性判定。构建体外重组表达质粒,采用实时荧光定量PCR(RT-qPCR)与蛋白质免疫印迹(WB)分别检测候选变异对mRNA与蛋白表达的影响。本研究已通过西安市儿童医院医学伦理委员会的审查(批准号:20240045)。结果①患儿为9月7 d龄男性,不能独坐,伴有眼距增宽、鼻梁低平的特殊面容,心脏超声提示房间隔缺损。②WES检测结果提示患儿携带MIDI基因c.1483C>T(p.R495X)纯合变异,Sanger测序验证该变异遗传自患儿母亲。③体外重组表达质粒构建成功,RT-qPCR检测结果提示该变异可抑制MIDI基因mRNA表达;WB检测结果提示该变异可导致产生截短蛋白。结论MIDI基因c.1483C>T(p.R495X)无义变异引发的mRNA降解逃逸机制可能是上述OS患儿轻度临床表型的遗传学病因,为该家系的诊疗提供参考依据。ObjectiveTo explore the genotype-phenotype relationship in a child with Opitz G/BBB syndrome(OS)with mild clinical phenotype.MethodsA child with motor developmental delay as the initial symptom admitted to Xi′an Children′s Hospital on June 10,2021 was selected for this study.Clinical data were collected,and peripheral blood samples were obtained from the child and his mother.Whole exome sequencing(WES)was performed to identify genetic variant in the child.Candidate variant were verified by Sanger sequencing to assess inheritance patterns and pathogenicity.Real-time fluorescence quantitative PCR(RT-qPCR)and Western blot(WB)analyses were conducted to evaluate the effects of the variant on mRNA and protein expression,respectively,using recombinant expression plasmids generated in vitro.This study was approved by the Medical Ethics Committee of Xi′an Children′s Hospital(Ethics No.20240045).Results①The child,a 9-month-and-7-day-old boy,presented with a low nasal bridge,hypertelorism,and difficulty sitting independently.Echocardiography revealed an atrial septal defect.②WES identified a homozygous variant in the MIDI gene,c.1483C>T(p.R495X),which was confirmed by Sanger sequencing and found to be inherited from the mother.③Recombinant expression plasmids were successfully constructed.RT-qPCR analysis showed that the variant significantly reduced MIDI gene mRNA expression,while WB results indicated that the variant led to the production of a truncated protein.ConclusionThe mild clinical phenotype of OS in this child may be attributed to the mRNA degradation escape mechanism induced by the nonsense variant c.1483C>T(p.R495X)in the MIDI gene.These findings provide valuable diagnostic insights for this pedigree and contribute to the understanding of the genotype-phenotype correlation in OS.

关 键 词：Opitz G/BBB综合征 MIDI基因 MRNA降解 逃逸 无义变异 

分 类 号：R725.9[医药卫生—儿科]