摘要目的:分析增强蓝视锥细胞综合征(ESCS)一家系的临床表型及致病基因。方法:采用家系调查研究方法，收集2021年6—9月于河南省立眼科医院就诊的中国汉族疑似ESCS一家系，该家系共3代8人，其中患者1例。对先证者进行全面的眼科检查，包括视力、斜视程度、眼前节和眼底情况、视网膜自发荧光、荧光素眼底血管造影、全视野视网膜电图(ERG)、多焦ERG、光相干断层扫描，以评估表型。收集该家系成员外周血样本，提取DNA，采用全外显子组测序(WES)技术进行测序，筛查致病基因及变异位点。采用Sanger测序验证变异位点是否与临床表型共分离。采用SIFT、Polyphen2、MutationTaster在线工具分析变异位点有害性；采用美国医学遗传学及基因组学会(ACMG)遗传变异分类标准与指南分析变异位点致病性；采用SIFT分析变异位点对应氨基酸序列保守性。结果:该家系符合常染色体隐性遗传方式。先证者自幼夜盲、远视、调节性内斜视、周边视网膜色素样沉积、视网膜劈裂、ERG明视反应以大振幅波为主。WES检测发现1个复合杂合变异 NR2E3 5号外显子c.671C>T：p.S224L和6号外显子c.955G>A：p.E319K，Sanger测序验证结果显示变异位点与临床表型共分离。2个变异位点均为错义变异，在gnomAD数据库东亚人群中变异频率为0；SIFT、Polyphen2、MutationTaster预测基因产物有害；其中c.671C>T变异在疾病数据库ClinVar中有意义不明记录，c.955G>A变异为未报道新位点。ACMG遗传变异分类标准与指南显示2个变异均为临床意义未明变异。2个变异位点对应的氨基酸序列在不同物种中均具有高度保守性。 结论:该家系符合ESCS的临床特征和遗传学诊断。本研究发现了 NR2E3基因2个未报道的变异位点c.671C>T：p.S224L和c.955G>A：p.E319K。

abstractsObjective:To analyze the clinical phenotypes and pathogenic gene of a Han Chinese family with enhanced S-cone syndrome (ESCS).Methods:The method of pedigree investigation was adopted.A suspected ESCS Han Chinese family including 8 members of 3 generations was recruited in Henan Eye Hospital from June to September 2021.There was one patient in the family.A thorough ophthalmic examination of the proband was carried out to evaluate the phenotypes, including visual acuity, degree of strabismus, anterior segment and fundus, autofluorescence imaging, fluorescein fundus angiography, full-field electroretinogram (ERG), multifocal ERG, optical coherence tomography.DNA was extracted from peripheral blood samples from the proband and family members.The pathogenic gene and variation were screened by whole exome sequencing (WES).The variation and co-segregation were verified by Sanger sequencing.The deleteriousness of the variation was analyzed by SIFT, Polyphen2 and MutationTaster.The pathogenicity of the variation was evaluated in accordance with the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines.The analysis of amino acid sequence conservation was performed by SIFT.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Henan Eye Hospital (No.HNEECKY-2017[6]).Written informed consent was obtained from each subject.Results:This pedigree was consistent with autosomal recessive inheritance.The proband had clinical features such as night blindness, hyperopia, accommodative esotropia, peripheral retinal pigmentation, retinoschisis, and photopic ERG responses dominated by large-amplitude waves.Variations including a compound heterozygous variation, c.671C>T: p.S224L on exon 5 and c. 955G>A: p.E319K on exon 6 of NR2E3 were identified by WES.The variations were confirmed to be consistent with co-segregation.The both loci were missense variations, the variation frequency of which was 0 in the East Asian population via the gnomAD database.The variations were predicted to be deleterious by SIFT, Polyphen2 and MutationTaster.The c.671C>T variation was recorded with unknown significance in ClinVar database, and the c.955G>A variation was an unreported new locus.According to the ACMG Standards and Guidelines, the both variations were labeled as with uncertain clinical significance, and the corresponding amino acid sequences were highly conservative across multiple species. Conclusions:This family has the clinical characteristics of ESCS and meets the genetic diagnosis criteria.Two novel variations in NR2E3 gene, c.671C>T: p.S224L and 955G>A: p.E319K, are found.