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ENGLISH ABSTRACT
伴有早发性高度近视的遗传性眼病基因型与表型研究
芮雪
任英华
杨尚英
程婉玉
容维宁
盛迅伦
作者及单位信息
·
DOI： 10.3760/cma.j.cn115989-20211216-00695
Genotypes and phenotypes of hereditary eye diseases associated with early-onset high myopia
Rui Xue
Ren Yinghua
Yang Shangying
Cheng Wanyu
Rong Weining
Sheng Xunlun
Authors Info & Affiliations
Rui Xue
Gansu Aier Ophthalmology and Optometry Hospital, Lanzhou 730050, China
Ren Yinghua
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
Yang Shangying
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
Cheng Wanyu
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
Rong Weining
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
Sheng Xunlun
Gansu Aier Ophthalmology and Optometry Hospital, Lanzhou 730050, China
·
DOI： 10.3760/cma.j.cn115989-20211216-00695
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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_15insAAGA (p.Asp5fs*)、RPGR基因杂合性移码变异c.2234_2237del (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_1660insACGGTGACC 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_619delTCCACGGCACTCAGGG (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。建议对eoHM患儿进一步行眼科结构和功能的临床评估及遗传筛查。

遗传性眼病;基因突变;早发性高度近视;RetNet
ABSTRACT

ObjectiveTo analyze the genotype of hereditary eye diseases with early-onset high myopia (eoHM) and its relationship with phenotype.

MethodsThe 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).

ResultsA 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) inFZD4 gene, a heterozygous variant c. 14_15insAAGA (p.Asp5fs*) in TSPAN12 gene, a heterozygous frameshift variant c. 2234_2237del (p.Arg745fs) in RPGR gene, a compound heterozygous variant of c. 481C>T (p.Gln161Ter*) and c. 355>T (p.Arg119Cys*) in GPR179 gene, a frameshift variant c. 1659_1660insACGGTGACCCTGGCCGTCCTGG (p.Pro554fs*) in COL2A1 gene, a compound heterozygous variant of c. 1811C>T (p.Thr604Ile*) and c. 967G>A (p.Gly323Ser) inPDE6B gene, a compound heterozygous variant of c. 604_619delTCCACGGCACTCAGGG (p.Ser202fs*) and c. 995G>C (p.Arg332Pro) inGUCY2D gene, a homozygous variant c. 772C>T (p.Pro241Leu) inOAT gene.Seven of them were novel variants.Compared with the previous literature, the clinical and gene phenotypes of the 8 families were analyzed in detail in this study, which provided the basis for the diagnosis of hereditary eye diseases with eoHM.

ConclusionsEoHM is closely related to some hereditary eye diseases, which may be the reason for the early diagnosis of children and an important clue for clinicians to detect potential hereditary eye diseases.Further clinical evaluations of ocular structure and function as well as genetic screening in children with eoHM are recommended.

Hereditary eye diseases;Mutation;Early onset high myopia;RetNet
Sheng Xunlun, Email: mocdef.3ab61nulnuxgnehs
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引用本文

芮雪,任英华,杨尚英,等. 伴有早发性高度近视的遗传性眼病基因型与表型研究[J]. 中华实验眼科杂志,2023,41(07)：662-674.

DOI:10.3760/cma.j.cn115989-20211216-00695

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近视在全球范围内日益流行，特别是在东亚地区[ 1 , 2 , 3 ]。根据世界卫生组织报告，未矫正近视是全球视力损害的主要原因[ 4 ]。屈光度≤－6.00 DS列为高度近视，高度近视多伴有严重的眼部并发症，如黄斑变性、视网膜脱离、白内障和青光眼，是不可逆盲的主要原因[ 1 , 2 , 3 , 4 , 5 ]。高度近视分为发生在学龄前(<7岁)的早发性高度近视(early-onset high myopia，eoHM)和发生在学龄后的迟发性高度近视(late-onset high myopia，loHM)[ 6 ]。虽然近视是环境因素和遗传因素共同作用的结果，但尚无一个理论能完整地阐述近视的病因。eoHM患儿面临的环境压力风险较少，因此，其病因多由遗传倾向引起。eoHM是符合孟德尔遗传规律的单基因遗传病，遗传方式有常染色体显性(autosomal dominant，AD)、常染色体隐性(autosomal recessive，AR)和X染色体连锁(X-linked，XL)[ 7 ]。迄今为止，通过全外显子组测序和单基因连锁分析，共发现10个与eoHM相关的基因突变，其中5个与常染色体显性eoHM相关，3个与常染色体隐性eoHM相关，2个与X-连锁eoHM相关。约10%的eoHM患者(eoHM是唯一的临床特征，无眼部或全身异常)携带这些基因突变。此外，在仅约23.8%的eoHM先证者中可检测到RetNet(https：//sph.uth.edu/retnet/)中列出的基因突变。其余67%~70%eoHM患者的遗传因素尚未明确[ 10 ]。我们在临床工作中发现，一些遗传性视网膜疾病和综合征，如家族性渗出性玻璃体视网膜病变(familial exudative vitreoretinopathy，FEVR)、先天性静止性夜盲(congenital stationary night blindness，CSNB)、全色盲、X-连锁遗传视网膜色素变性(X-linked retinitis pigmentosa，XLRP)、Leber先天性黑矇(Leber congenital amaurosis，LCA)、回旋状脉络膜视网膜萎缩(gyrate atrophy of the choroid and retina，GA)和Stickler综合征等，往往伴有eoHM。由于眼科医生对这一类遗传性眼病的认识与重视程度不够，易导致患者被误诊或漏诊。本研究通过高通量测序技术检测伴有eoHM的遗传性眼病患者的致病基因突变，结合患者临床表现，分析基因型及其与表型的关系，并检索文献回顾分析既往已报道的伴有eoHM的遗传性眼病研究数据，旨在帮助眼科医生更全面地了解eoHM遗传因素及可能存在的潜在疾病，提高临床诊断水平。
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芮雪：参与试验设计、数据分析及文章撰写；任英华、杨尚英、程婉玉：直接参与研究实施、数据采集及分析；盛迅伦、容维宁：对数据分析和论文撰写进行指导

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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)
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