摘要目的:确定并观察一个Leber先天性黑矇（LCA）家系的致病基因变异和临床表型。方法:回顾性临床研究。2024年1月于西安交通大学第一附属医院就诊并经基因检测确诊的LCA7型一家系2例患者和4名家系成员纳入研究。详细询问患者病史、家族史并行最佳矫正视力（BCVA）、眼压、眼底彩色照相、眼底自发荧光（FAF）、闪光视觉诱发电位（F-VEP）、全视野视网膜电图（ff-ERG）及光相干断层扫描（OCT）检查。家系成员行BCVA、眼底彩色照相检查。采集患者及其4名家系成员的外周静脉血5 ml，提取全基因组DNA，高通量测序法筛选致病基因。对筛选出的变异位点通过Sanger进行验证。参考美国医学遗传学和基因组学学会（ACMG）对所有变异位点进行致病等级评估。应用生物信息学软件Mutation Taster、Polyphen-2、 PROVEN、REVEL对变异位点进行致病性分析。结果:先证者（Ⅱ-2），女，14岁。父母为姑表近亲婚配。先证者双眼BCVA 0.1；眼压正常；眼前节未见明显异常。眼底彩色照相检查，双眼视盘蜡黄，视网膜呈"铜钱样"、"椒盐样"改变；FAF检查，视网膜黄斑区大片弱荧光；OCT检查，黄斑中心凹变浅甚至消失，视网膜层次结构不清，椭圆体带消失；F-VEP检查，P2波可引出，峰时未见明显延迟，振幅稍降低；ff-ERG检查，明暗适应a、b波振幅显著降低，甚至无波形。先证者姐姐（Ⅱ-1）双眼BCVA及眼底表现与先证者类似。先证者父母亲（Ⅰ-1、Ⅰ-2）、弟弟（Ⅱ-3）、妹妹（Ⅱ-4）眼部表型未见明显异常。基因检测结果显示，先证者及其姐姐携带 CRX基因c.122G>A:p.Arg41Gln纯合变异。先证者父亲、母亲、弟弟携带 CRX基因c.122G>A:p.Arg41Gln杂合变异；妹妹该位点未见变异。结合临床表现、ff-ERG和基因检测结果，最终诊断LCA7型。依据ACMG指南，c.122G>A为可能致病性变异。Mutation Taster、Polyphen-2软件预测该变异有害；REVEL评分为0.929，为可能致病变异。 结论:CRX基因c.122G>A:p.Arg41Gln纯合变异导致本家系常染色体隐性遗传LCA7型；LCA具有发病年龄小、视功能严重损害等特点。

abstractsObjective:To identify and observe the pathogenic gene variant and clinical phenotype in a family with Leber congenital amaurosis (LCA).Methods:A retrospective clinical study. Two patients and four family members from one LCA family (type 7), diagnosed via genetic testing at the First Affiliated Hospital of Xi'an Jiaotong University in January 2024 were included. Detailed patient and family histories were collected. All patients underwent examinations including best-corrected visual acuity (BCVA), intraocular pressure, color fundus photography, fundus autofluorescence (FAF), flash visual evoked potential (F-VEP), full-field electroretinography (ff-ERG), and optical coherence tomography (OCT). Family members underwent BCVA and color fundus photography examinations. Peripheral venous blood (5 ml) was collected from the patients and the four family members for genomic DNA extraction. High-throughput sequencing was used to screen for pathogenic gene variants. Identified variants were verified by Sanger sequencing. All variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Bioinformatics software including Mutation Taster, Polyphen-2, PROVEAN, and REVEL was used to analyze the pathogenicity of the variants.Results:The proband (Ⅱ-2), a 14-year-old female, was born to consanguineous parents (first cousins). Her BCVA was 0.1 in both eyes; intraocular pressure was normal; the anterior segments showed no significant abnormalities. Color fundus photography showed waxy optic discs and a "coin-shaped," "salt-and-pepper" appearance in the retina. FAF revealed large areas of hypoautofluorescence in the macular region. OCT showed shallowing or disappearance of the foveal, disorganized retinal layers, and absence of the ellipsoid zone. F-VEP showed recordable P2 waves with no significant delay in peak time but slightly reduced amplitude. ff-ERG showed significantly reduced or non-detectable amplitudes of the scotopic and photopic a- and b-waves. The proband's elder sister (Ⅱ-1) had similar BCVA and fundus findings. The proband's parents (Ⅰ-1, Ⅰ-2), younger brother (Ⅱ-3), and younger sister (Ⅱ-4) showed no significant ocular phenotypic abnormalities. Genetic testing revealed that the proband and her elder sister were homozygous for the CRX gene variant c.122G>A:p.Arg41Gln. The proband's father, mother, and younger brother were heterozygous carriers of the same CRX variant; the younger sister showed no variation at this locus. Based on the clinical presentation, ff-ERG, and genetic test results, the final diagnosis was LCA type 7. According to ACMG guidelines, the c.122G>A variant was classified as likely pathogenic. Mutation Taster and Polyphen-2 software predicted the variant to be damaging; the REVEL score was 0.929, indicating a likely pathogenic variant. Conclusions:The homozygous CRX gene variant c.122G>A:p.Arg41Gln causes autosomal recessive LCA type 7 in this family. LCA is characterized by early onset and severe visual impairment.