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ENGLISH ABSTRACT
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
闫莹玉
贺莉
杨颖
王端
张海清
陈艳妮
作者及单位信息
·
DOI： 10.3760/cma.j.cn511374-20240905-00470
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
Yan Yingyu
He Li
Yang Ying
Wang Duan
Zhang Haiqing
Chen Yanni
Authors Info & Affiliations
Yan Yingyu
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
He Li
Department of Child Health Care, Xi′an Children′s Hospital, Xi′an, Shaanxi 710003, China
Yang Ying
Research Institute of Pediatric Disease of Shaanxi province, Xi′an Children′s Hospital, Xi′an, Shaanxi 710003, China
Wang Duan
Department of Child Health Care, Xi′an Children′s Hospital, Xi′an, Shaanxi 710003, China
Zhang Haiqing
Department of Child Health Care, Xi′an Children′s Hospital, Xi′an, Shaanxi 710003, China
Chen Yanni
Department of Child Health Care, Xi′an Children′s Hospital, Xi′an, Shaanxi 710003, China
·
DOI： 10.3760/cma.j.cn511374-20240905-00470
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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。

Opitz G/BBB综合征; MIDI基因 ;mRNA降解;逃逸;无义变异
ABSTRACT

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).

Results① The 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. ② WES 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.③ Recombinant 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.

Opitz G/BBB syndrome; MID1 gene ;mRNA decay;Escape;Nonsense variant
Chen Yanni, Email: mocdef.3ab61lihcinnaynehc
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引用本文

闫莹玉,贺莉,杨颖,等. 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 [J]. 中华医学遗传学杂志,2025,42(02)：219-225.

DOI:10.3760/cma.j.cn511374-20240905-00470

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Opitz G/BBB综合征(Opitz G/BBB syndrome，OS)是一种罕见的遗传异质性疾病，存在2种遗传方式：由 MID1基因变异导致的X连锁Opitz G/BBB综合征(X-Link Opitz G/BBB syndrome，XLOS)与常染色体显性遗传 [ 1 ]。OS以人体中线发育畸形为主要临床表现，患者发育缺陷主要表现为眼距变宽、尿道下裂以及先天性心脏病，同时合并有泌尿生殖系统缺陷、闭锁或异位结构缺陷等其他临床表现。OS患者通常也存在神经系统症状，如精神运动发育障碍等。男性OS患者的临床表型通常比女性患者更为复杂与严重 [ 2 ]。本研究拟通过对1例罕见的轻度XLOS患儿的临床表型与基因型进行研究，旨在探索该病临床表型多样的原因。现将研究成果报道如下。
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备注信息
A
陈艳妮，Email： mocdef.3ab61lihcinnaynehc
B

闫莹玉：数据采集、实验研究、论文撰写；贺莉：数据采集、论文修改；杨颖：实验数据分析、论文修改；王端：数据采集、数据分析、经费支持；张海清：数据采集、数据分析、经费支持；陈艳妮：实验设计、研究指导、论文修改、经费支持

C
所有作者均声明不存在利益冲突
D
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)
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