目的研究先天性视网膜劈裂症(XLRS)一家系的临床表型及分子遗传学特点，并确定相关基因突变。
方法采用家系调查研究，收集2021年8月在厦门大学附属厦门眼科中心就诊的汉族XLRS一家系，对其临床特征及系谱进行分析。所有患者及变异位点携带者均接受全面的病史采集和眼科常规检查，包括视力、非接触式眼压计、裂隙灯显微镜、直接检眼镜及光学相干断层扫描检查；先证者和部分患者接受医学验光、眼底照相或广角眼底照相、视网膜电图检查。采集该家系成员外周静脉血标本，并对先证者样本行全外显子组测序(WES)分析。针对WES筛选突变位点，通过Sanger测序对家系成员的其他患者及正常人进行扩大验证。采用CADD、FATHMM等生物信息学工具分析变异位点致病性。
结果该XLRS家系共3代8人，符合XLRS临床诊断者共3例，均为男性，先证者母亲为相关基因携带者，表型正常者5人。家系中无近亲结婚史，且为隔代发病，符合X连锁隐性遗传方式。所有患者均无全身病史和其他异常表现，眼部病变共同特征为自幼双眼视力差，先证者及其胞弟表现为黄斑区劈裂呈轮辐状，先证者外公表现为视网膜神经纤维层萎缩。遗传学分析发现，该家系中所有患者均存在已知的 RS1基因上的1个半合子变异c.214G>C：p.Glu72Gln，先证者母亲在该位点为杂合变异，其余表型正常成员在该位点为野生型。经生物信息学分析，预测该位点为有害变异，很可能致病。
结论 RS1基因c.214G>C：p.Glu72Gln半合子变异，可能为该XLRS家系所有患者的致病变异，均表现为轻型XLRS。
ObjectiveTo study the clinical phenotype and molecular genetic characteristics of a Chinese Han family with X-linked retinoschisis (XLRS), and to determine the associated gene variations.
MethodsA pedigree investigation was performed.The clinical characteristics and pedigree analysis of a Han Chinese family line with XLRS was conducted in August 2021 at the Xiamen Eye Center Affiliated to Xiamen University.All patients and the carriers underwent comprehensive medical history collection and routine ophthalmological examinations, including visual acuity, non-contact tonometer, slit lamp microscope, direct ophthalmoscope, and optical coherence tomography.The proband and some patients underwent medical optometry, fundus photography or wide-angle fundus photography, and electroretinogram examination.Peripheral venous blood samples were collected from the family members, and whole exome sequencing (WES) analysis was performed on the proband samples.For variants screened by WES, the expanded verification in other patients and normal persons in the family was carried out by Sanger sequencing.Multiple bioinformatic tools were used to analyze the pathogenicity of variants.This study protocol was approved by the Ethics Committee of Xiamen Eye Center of Xiamen University (No.XMYKZX-KY-2021-012). Written informed consent forms were obtained from each subject or guardian of minors.CADD, FATHMM and other bioinformatics tools were used to analyze the pathogenicity of the variation sites.
ResultsThe Han XLRS pedigree consisted of 8 individuals in 3 generations.Out of the 3 cases diagnosed with XLRS based on clinical evaluation, all were male.The mother of the proband was a carrier of related genes.There were 5 persons with normal phenotypes.There was no history of consanguineous marriages within the family, and the disease was shown to be intergenerational, which is consistent with the recessive inheritance of the X chromosome.None of the patients had a history of systemic disease or any other abnormal manifestations.The prevailing feature of ophthalmopathy was poor binocular vision since childhood.The proband and his younger brother had spoke split in the macula, and their grandfather showed atrophy of retinal nerve fibers.Genetic analysis revealed a hemizygous variation c. 214G>C: p.Glu72Gln in the RS1 gene in all the patients in this family.The proband's mother was heterozygous at this site, and all other phenotypically normal family members exhibited wild type at this site.This variant was predicted to be a deleterious variation and likely to cause disease based on bioinformatics analysis.
ConclusionsThe proband and patients in this Han Chinese family have the known c. 214G>C: p.Glu72Gln hemizygous variation of the RS1 gene and exhibit mild XLRS, which was consistent with the recessive inheritance of X chromosome.
王婷婷,朱益华,范梦杰,等. 中国汉族先天性视网膜劈裂症一家系临床及分子遗传学分析[J]. 中华实验眼科杂志,2023,41(09)：864-870.
DOI:10.3760/cma.j.cn115989-20210922-00523版权归中华医学会所有。
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王婷婷：参与数据收集和分析、论文撰写及修改；刘旭阳、丁小燕：参与研究设计、论文修改和定稿；朱益华、范梦杰、罗小玲、张林燕、张达人：参与数据收集和分析、临床与遗传学研究
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