摘要
目的观察并分析早发型高度近视(eoHM)伴遗传性眼病患者基因型与表型的关系。方法家系调查研究。2022年1月至2023年6月于宁夏回族自治区人民医院眼科诊断为eoHM的30个家系中伴遗传性眼病的7个家系(23.3%,7/30)7例患者(均为先证者)及其父母14名纳入研究。患者来自7个无血缘关系家庭。详细收集患者病史、家族史;患者以及父母均行最佳矫正视力、色觉、眼底彩色照相、光相干断层扫描、荧光素眼底血管造影、眼底自发荧光检查;行全视野视网膜电图检查4例。采集患者及其父母外周静脉血,提取全基因组DNA行全基因组外显子测序,筛选潜在致病位点,进行致病性分析和Sanger测序验证。依据美国医学遗传学与基因组学学会(ACMG)发布的相关遗传变异分类标准与指南,对新发现基因变异进行致病性评估。检索既往已报道的eoHM伴遗传性眼病相关文献,分析变异基因与临床表型的关系。结果7个家系中,X连锁、常染色体隐性、常染色体显性遗传分别为3、2、2个家系。7例患者均为男性;分别确诊为先天性静止性夜盲(CSNB)、博恩霍尔姆眼病、X连锁-色素性视网膜炎(XL-RP)、视锥视杆细胞营养不良、Knobloch综合征、家族性渗出性玻璃体视网膜病变(FEVR)、Stickler综合征综合征。基因检测结果显示,所有患者均检测到与表型高度相关的9个基因变异,包括NYX基因c.647A>T(p.N216I)半合子错义变异(M1)、OPN1LW基因LIAVA单倍体变异(M2)、RPGR基因c.3096_3097del(p.E1033RfsTer45)半合子移码变异(M3)、TTLL5基因c.1588_1589del(p.L531EfsTer24)和c.850G>C(p.D284H)复合杂合变异(M4、M5)、COL18A1基因c.2118dup(p.G707RfsTer23)和c.3523_3524del(p.L1175VfsTer72)复合杂合变异(M6、M7)、FZD4基因c.1499C>T(p.T500I)杂合错义突变(M8)、COL11A2基因c.966dup(p.T323HfsTer19)杂合移码变异(M9)。其中,M2、M4、M5、M8、M9为新发现变异位点,M1、M3、M6、M7为已知变异位点。根据ACMG发布的遗传变异分类标准与指南,M2、M3、M4、M6、M7、M9被判定为致病性变异,M1、M5、M8属于临床意义未明的变异。通过文献复习发现,CSNB、Stickler综合征、FEVR、XL-RP等4类遗传性视网膜疾病的临床表型中,eoHM更为常见。结论eoHM与遗传性眼病密切相关,或许是此类遗传性眼病最早出现的特征。
ObjectiveTo investigate and analyze the relationship between genotype and phenotype in patients with early-onset high myopia(eoHM)associated with hereditary eye diseases.MethodsA family-based study was conducted among 30 families diagnosed with eoHM at Department of Ophthalmology of People's Hospital of Ningxia Hui Autonomous Region from January 2022 to June 2023.Seven families(23.3%,7/30),all probands,and their 14 parents were included.These seven families were unrelated.Detailed patient and family histories were collected.All participants underwent comprehensive ophthalmic examinations,including best-corrected visual acuity,color vision testing,fundus color photography,optical coherence tomography,fluorescein fundus angiography,and fundus autofluorescence imaging.Full-field electroretinography was performed in four cases.Peripheral venous blood samples were collected from patients and their parents for whole-genome DNA extraction and whole-exome sequencing.Potential pathogenic variants were identified,and their pathogenicity was analyzed and confirmed by Sanger sequencing.The pathogenicity of newly discovered gene variants was evaluated according to the guidelines of the American College of Medical Genetics and Genomics(ACMG).Literature on previously reported eoHM associated with hereditary eye diseases was reviewed to analyze the relationship between variant genes and clinical phenotypes.ResultsAmong the seven families,three exhibited X-linked inheritance,two showed autosomal recessive inheritance,and two demonstrated autosomal dominant inheritance.All the patients were male.Among the seven patients,one case each was identified with congenital stationary night blindness(CSNB),Bornholm eye disease,X-linked retinitis pigmentosa(XL-RP),cone-rod dystrophy,Knobloch syndrome,familial exudative vitreoretinopathy(FEVR),and Stickler syndrome.Genetic testing revealed nine gene variants highly correlated with the observed phenotypes.The genetic testing results revealed that all patients were found to carry nine gene variants highly associated with the phenotype,including:a hemizygous missense variant NYX c.647A>T(p.N216I)(M1),an OPN1LW LIAVA haplotype variant(M2),a hemizygous frameshift variant RPGR c.3096_3097del(p.E1033RfsTer45)(M3),compound heterozygous variants TTLL5 c.1588_1589del(p.L531EfsTer24)and c.850G>C(p.D284H)(M4,M5),compound heterozygous variants COL18A1 c.2118dup(p.G707RfsTer23)and c.3523_3524del(p.L1175VfsTer72)(M6,M7),a heterozygous missense mutation FZD4 c.1499C>T(p.T500I)(M8),and a heterozygous frameshift variant COL11A2 c.966dup(p.T323HfsTer19)(M9).Among them,M2,M4,M5,M8 and M9 were newly discovered mutation sites,and M1,M3,M6 and M7 were known mutation sites.According to the classification standards and guidelines of genetic variation issued by ACMG,M2,M3,M4,M6,M7,and M9 were judged to be pathogenic variants,while M1,M5,and M8 were of unknown clinical significance.Through literature review,it was found that eoHM was more common among the clinical phenotypes of 4 types of hereditary retinal diseases,including CSNB,Stickler syndrome,FEVR and XL-RP.ConclusioneoHM is intricately associated with inherited eye diseases and may serve as the earliest indicator of such conditions.
作者
李文静
齐小龙
史宝玉
崔茜玮
王政来
李瑞
刘科言
张少弛
庄文娟
Li Wenjing;Qi Xiaolong;Shi Baoyu;Cui Qianwei;Wang Zhenglai;Li Rui;Liu Keyan;Zhang Shaochi;Zhuang Wenjuan(The Third Clinical School of Medicine,Ningxia Medical University,Yinchuan 750004,China;Department of Ophthalmology,Ningxia Eye Hospital,People's Hospital of Ningxia Hui Autonomous Region,Yinchuan 750002,China)
出处
《中华眼底病杂志》
北大核心
2025年第3期200-212,共13页
Chinese Journal of Ocular Fundus Diseases
基金
中央引导地方科技发展专项项目(2023FRD05047)
宁夏回族自治区重点研发项目(2024BEG02016)。
