COL2A1、 COL11A1基因新生变异相关Stickler综合征Ⅰ、Ⅱ型患者基因型表型分析  

Genotype-phenotype analysis of COL2A1 and COL11A1 de novo mutations leading to Stickler syndrome types 1 and 2

作　　者：李佳玙 李春花 孙彩红 方薇 齐小龙 李文静 张少弛[1] 张雯 李瑞 庄文娟[1,2] Li Jiayu;Li Chunhua;Sun Caihong;Fang Wei;Qi Xiaolong;Li Wenjing;Zhang Shaochi;Zhang Wen;Li Rui;Zhuang Wenjuan(Department of Ophthalmology,People's Hospital of Ningxia Hui Autonomous Region(Affiliated Hospital of Ningxia Medical University),Ningxia Medical University,Yinchuan 750011,China;Third Clinical College,Ningxia Medical University,Yinchuan 750041,China)

机构地区：[1]宁夏回族自治区人民医院(宁夏医科大学附属自治区人民医院)眼科,银川750011 [2]宁夏医科大学第三临床学院,银川750041

出　　处：《中华眼底病杂志》2025年第3期186-193,共8页Chinese Journal of Ocular Fundus Diseases

基　　金：国家自然科学基金(82460202);2023年中央引导地方科技发展专项(2023FRD05047);宁夏自然科学基金(2024AAC05081)。

摘　　要：目的观察分析COL2A1、COL11A1基因新生变异(DNM)相关Stickler综合征Ⅰ、Ⅱ型患者的临床表型及遗传特征。方法家系调查研究。2023年12月至2024年11月在宁夏回族自治区人民医院眼科经临床及基因检查确诊的Stickler综合征患者4例(均为先证者)及其父母8名纳入研究。患者来自4个无血缘关系家庭。详细询问患者病史并行最佳矫正视力(BCVA)、屈光度、眼底彩色照相检查。全身检查包括口面部、骨骼、关节以及听力。采集患者及其父母外周静脉血样本并提取基因组DNA,采用全外显子测序技术进行致病基因及其位点筛选,随后通过Sanger测序验证并结合家系共分离分析,最终确定候选基因突变位点。依据美国医学遗传学与基因组学学会(ACMG)相关遗传变异分类标准与指南,对候选变异进行致病性评估;同时,通过跨物种保守性分析确定野生型氨基酸的进化保守性,并运用蛋白质三维建模技术表征变异蛋白质的空间构象变化及其局部氢键网络的改变。结果4例患者中,男性2例,女性2例;年龄3~12岁。Stickler综合征Ⅰ(家系1、2先证者)、Ⅱ(家系3、4先证者)型各2例。屈光度-8.00~-18.00 D。BCVA无光感~0.6-。玻璃体膜状、"串珠状"混浊各2例。双眼视盘旁萎缩弧,视网膜"豹纹状"改变3例;双眼视网膜脱离伴左眼巨大裂孔1例,既往已行玻璃体切割手术治疗。双耳感音神经性耳聋1例。单纯小颌畸形3例;鼻梁低平、短鼻、面中部凹陷、小颌畸形1例。肘关节活动伸展过度2例。4例患者的父母表型均正常。基因检测结果显示,家系1、2先证者分别携带COL2A1基因c.85+1G>C(M1)剪切位点变异、c.3950_3951insA(p.M1317Ifs*48)(M2)移码变异;家系3、4先证者分别携带COL11A1基因(NM_001854.4)c.2549 G>T(p.G850V)(M3)错义变异、c.3816+6T>C(M4)剪切位点变异。其父母亲均未携带相关基因变异。其中,M2、M3、M4为首次报道的DNM。根据ACMG指南均�ObjectiveTo observe and analyze the clinical phenotype and genetic characteristics of COL2A1 and COL11A1 de novo mutation(DNM)related Stickler syndrome typeⅠandⅡpatients.MethodsA family-based cohort study.From December 2023 to November 2024,4 patients(all probands)with Stickler syndrome diagnosed by clinical and genetic testing in Department of Ophthalmology of People's Hospital of Ningxia Hui Autonomous Region and their parents(8 cases)were included in the study.The patients came from 4 unrelated families.A detailed medical history was taken,and the patients underwent best-corrected visual acuity(BCVA),refraction,and fundus color photography examinations.Systemic examinations included the oral and facial regions,skeletal,joints,and hearing.Peripheral venous blood samples were collected from the patients and their parents,and genomic DNA was extracted.Whole-exome sequencing was used to screen for pathogenic genes and their loci,which were then validated by Sanger sequencing and combined with segregation analysis in the families to identify candidate gene mutation sites.The candidate variants were assessed for pathogenicity according to the American College of Medical Genetics and Genomics(ACMG)criteria and guidelines for the classification of genetic variants.Additionally,cross-species conservation analysis was performed to determine the evolutionary conservation of wild-type amino acids,and protein three-dimensional modeling techniques were used to characterize the spatial conformational changes of the variant proteins and the alterations in their local hydrogen bond networks.ResultsAmong the 4 patients,there were 2 males and 2 females;their ages ranged from 3 to 12 years.There were 2 cases of Stickler syndrome typeⅠ(proband of families 1 and 2)and 2 cases of typeⅡ(proband of families 3 and 4).The diopters ranged from-8.00 to-18.00 D.BCVA ranged from no light perception to 0.6-.There were 2 cases each of vitreous membrane-like and"bead-like"opacity.Three cases showed peripapillary atrophy arcs and leopar

关 键 词：Stickler综合征 COL2A1基因 COL11A1基因 新生变异 基因型及表型研究 

分 类 号：R73[医药卫生—肿瘤]