伴有早发性高度近视的遗传性眼病基因型与表型研究  

Genotypes and phenotypes of hereditary eye diseases associated with early-onset high myopia

作　　者：芮雪 任英华[2] 杨尚英 程婉玉 容维宁[2] 盛迅伦 Rui Xue;Ren Yinghua;Yang Shangying;Cheng Wanyu;Rong Weining;Sheng Xunlun(Gansu Aier Ophthalmology and Optometry Hospital,Lanzhou 730050,China;Department of Ophthalmology,People's Hospital of Ningxia Hui Autonomous Region,Ningxia Eye Hospital,Ningxia Blindness Eye Disease Clinical Medical Research Center,Yinchuan 750002,China)

机构地区：[1]甘肃爱尔眼视光医院,兰州730050 [2]宁夏回族自治区人民医院眼科,宁夏眼科医院,宁夏致盲性眼病临床医学研究中心,银川750002

出　　处：《中华实验眼科杂志》2023年第7期662-674,共13页Chinese Journal Of Experimental Ophthalmology

基　　金：国家自然科学基金项目(81760180);宁夏回族自治区东西科技合作项目(2017BY086);宁夏回族自治区重点研发项目(2020BEG03047)。

摘　　要：目的分析伴有早发性高度近视(eoHM)的遗传性眼病基因型及其与表型的关系。方法收集2019年1月至2020年6月于宁夏眼科医院就诊的伴有eoHM家系,详细询问并记录先证者及其家庭成员的病例资料,完善相关眼科检查。抽取患者及家属外周静脉血,提取全基因组DNA,应用目标序列捕获测序技术对先证者进行致病基因突变筛查,对检测到的可疑致病位点进行Sanger验证及家系共分离分析。根据ACMG指南对新发现基因变异进行致病性评估。检索既往已报道的伴有eoHM的遗传性眼病原始文献。分析突变基因及临床表型的关系。结果共收集到伴有eoHM家系20个,其中8个家系检测到与遗传性眼病相关的致病性基因变异,8个先证者中诊断为家族性渗出性玻璃体视网膜病变2个,X-连锁隐性遗传视网膜色素变性、先天性静止性夜盲、Stickler综合征、全色盲、Leber先天性黑矇和回旋状脉络膜视网膜萎缩(GA)各1个。8个家系的先证者首诊年龄4~7岁,均诊断为高度近视,屈光度均≤-6.00 DS。基因检测8个家系的先证者分别携带FZD4基因杂合性变异c.313A>G(p.Met105Val)、TSPAN12基因变异c.14_(1)5insAAGA (p.Asp5fs*)、RPGR基因杂合性移码变异c.2234_(2)237del (p.Arg745fs*)、GPR179基因复合杂合性变异c.481C>T (p.Gln161Ter*)和c.355>T (p.Arg119Cys*)、COL2A1基因移码变异c.1659_(1)660insACGGTGACC CTGGCCGTCCTGG (p.Pro554fs*)、PDE6B复合杂合性变异c.1811C>T(p.Thr604Ile*)和c.967G>A (p.Gly323Ser)、GUCY2D基因复合杂合性变异c.604_(6)19delTCCACGGCACTCAGGG (p.Ser202fs*)和c.995G>C (p.Arg332P)、OAT基因纯合性变异c.772C>T (p.Pro241Leu),其中7个为新发现的突变位点。与既往文献相比,本研究详细分析了8个家系的临床及基因表型,为伴有eoHM的遗传性眼病的诊断提供依据。结论 eoHM与一些遗传性眼病密切相关,可能是儿童最早就诊的原因,也是临床医生发现潜在的遗传性眼部疾病的重要线索�Objective To analyze the genotype of hereditary eye diseases with early-onset high myopia(eoHM)and its relationship with phenotype.Methods The families with eoHM were collected in Ningxia Eye Hospital from January 2019 to June 2020.The medical records of the probands and their family members were inquired and recorded in detail,and the relevant ocular examinations were performed.Peripheral venous blood samples were collected from patients and their family members,and whole-genome DNA was extracted.Sequence capture sequencing technology was applied to screen for disease-causing gene mutations in probands.The detected suspected pathogenic variants were verified by Sanger sequencing and were analyzed by family cosegregation analysis.According to ACMG guidelines,the pathogenicity of novel variants was evaluated.The original literature about hereditary eye diseases with eoHM was searched to analyze the relationship between mutated genes and clinical phenotype.This study protocol adhered to the Declaration of Helsinki.All subjects or their guardians were informed of the purpose and procedure of the study and signed the informed consent form.The study protocol was approved by the Ethics Committee of the People's Hospital of Ningxia Hui Autonomous Region(No.2016018).Results A total of 20 eoHM families were collected,among which pathogenic variants associated with inherited eye diseases were detected in 8 families.Of the 8 probands,two were diagnosed with familial exudative vitreoretinopathy,one with X-linked retinitis pigmentosa,one with congenital stationary nightblindness,one with Stickler syndrome,one with achromatopsia,one with Leber congenital amaurosis,and one with gyrate atrophy of the choroid and retina.The first diagnosis age of the 8 probands was 4-7 years old,and they were all diagnosed as high myopia,with a refractive status≤-6.00 DS.Genetic tests showed that the 8 probands carried a heterozygous variant c.313A>G(p.M105Val)in FZD4 gene,a heterozygous variant c.14_15insAAGA(p.Asp5fs*)in TSPAN12 gene,a hetero

关 键 词：遗传性眼病 基因突变 早发性高度近视 RetNet 

分 类 号：R778.11[医药卫生—眼科]