基于全外显子组测序探寻Möbius综合征发病机制的遗传学研究  

Genetic analysis on the pathogenesis of Möbius syndrome based on whole exome sequencing

作　　者：贾红艳[1] 王丹[1] 张冉冉 马茜 焦永红[1] Jia Hongyan;Wang Dan;Zhang Ranran;Ma Qian;Jiao Yonghong(Bejing Tongren Eye Center,Beijing Tongren Hospital,Capital Medical University,Beijing Ophthalmology and Visual Sciences Key Laboratory,Bejing 100730,China;Xi'an People's Hospital(Xi'an Fourth Hospital),Shaanxi Eye Hospital,Affiliated People's Hospital of Northwest University,Xi'an 710004,China)

机构地区：[1]首都医科大学附属北京同仁医院、北京同仁眼科中心、眼科学与视觉科学北京市重点实验室,100730 [2]西安市人民医院(西安市第四医院)眼科、陕西省眼科医院西北大学附属人民医院,710004

出　　处：《中华眼科医学杂志（电子版）》2024年第3期146-154,共9页Chinese Journal of Ophthalmologic Medicine(Electronic Edition)

基　　金：国家自然科学基金面上项目(82070999);国家自然科学基金面上项目(82371085)。

摘　　要：目的:探讨Möbius综合征(MBS)患者的临床特征及可能的遗传发病机制。方法:收集2013年3月至2024年4月首都医科大学附属北京同仁医院眼科中心的14例(28只眼)散发MBS患者的病例资料。其中,男性5例(10只眼),女性9例(18只眼);年龄1~9岁,平均年龄(4.0±0.7)岁。询问或检查并记录患者的性别、年龄、最佳矫正视力、眼球运动、眼前节和眼底、体格发育及颅神经眼眶磁共振成像(MRI)的情况。采集患者及核心家系成员外周静脉血、提取基因组脱氧核糖核酸(DNA)并在illumina平台行全外显子组测序。使用SAMtools和ANNOVAR软件对变异进行识别和注释,对频率数据库中频率低于1%的变异进行过滤。在此基础上,筛选新生突变基因以及≥2个以上患者共有的突变基因。使用R包的maftools和GenVisR软件包分别行共有基因突变特征分析并绘制景观图。年龄、最小分辨角对数(logMAR)视力以及每个样本携带的共有基因突变数量经Shapiro-Wilk检验符合正态分布,以±s表示。性别、单侧或双侧受累、全身发育异常、突变分类、突变类型、突变频谱及共有基因突变频率采用频数和百分比描述。使用R语言ClusterProfiler中的超几何检验进行基因本体(GO)富集分析,使用Benjamini-Hochberg方法进行多重假设检验校正并筛选显著富集的条目。结果:本研究9例(18只眼)患者的logMAR视力为0.56±0.12。双眼外转受限者有10例(20只眼),占71.43%(10/14);单眼外转受限者有4例(4只眼),占28.57%(4/14)。双侧面瘫者有5例,占35.7%(5/14);单侧面瘫者有9例,占64.3%(9/14)。伴其他全身发育异常的患者有9例,占64.29%(9/14)。双侧外展神经(CN6)发育不良者有11例,占78.57%(11/14);单侧CN6发育不良者有3例,占21.43%(3/14)。双侧面神经(CN7)发育不良者有9例,占64.3%(9/14),单侧CN7发育不良者有5例,占35.71%(5/14)。2例MBS患者发现致病候选基因丛状蛋白D1(PLXND1)新变异2个,分别为杂�Objective:To explore the clinical features and possible genetic pathogenesis of patients with Möbius syndrome(MBS).Methods:A total of 14 patients(28 eyes)with sporadic MBs were collected from the Eye Center of Beijing Tongren Hospital affiliated to Capital Medical University from March 2013 to April 2024.There were 5 males(10 eyes)and 9 females(18 eyes)with the average age of(4.0±0.7)years(ranging from 1 to 9 years).The patient′s gender,age,best corrected visual acuity,eye movement,anterior segment and fundus,physical development and cranial nerve orbital magnetic resonance imaging(MRI)were asked or examined and recorded.Peripheral venous blood samples of patients and core family members were collected,genomic DNA was extracted,and full exome sequencing was performed on Illumina platform.SAMtools and ANOVA software were used to identify and annotate the variation,and the variation with frequency less than 1%in the frequency database was filtered.On this basis,newborn mutant genes and mutant genes shared by more than 2 patients were screened.The common gene mutation characteristics were analyzed and the landscape map was drawn using the R package maftools and GenVisR software.Age,logarithm of minimum resolution angle(logMAR)vision and the number of common gene mutations carried by each sample conformed to the normal distribution by Shapiro-Wilk test,which was expressed as±s.Gender,unilateral or bilateral involvement,systemic dysplasia,mutation classification,mutation type,mutation frequency spectrum and common gene mutation frequency were described by frequency and percentage.The hypergeometric test in the R language ClusterProfiler was used for gene ontology(GO)enrichment analysis,and the Benjamini-Hochberg method was used for multiple hypothesis test correction and screening the items with significant enrichment.Results:The logMAR visual acuity of 9 patients(18 eyes)was 0.56±0.12.There were 10 cases(20 eyes)with limited binocular exotropia,accounting for 71.43%(10/14).There were 4 cases(4 eyes)with limited

关 键 词：MOBIUS综合征 全外显子组测序 生物信息学分析 遗传发病机制 

分 类 号：R77[医药卫生—眼科]