摘要目的:探索中国回族一真性小眼球家系的临床表型特征及其遗传学病因。方法:采用家系调查研究方法，收集2005年10月初诊于北京同仁眼科中心并持续随访至2023年10月的中国回族一真性小眼球家系4代共25名成员，其中患者3例。对家系中患者进行病史采集，并进行全面眼科检查，包括视力、眼压、裂隙灯显微镜、IOLMaster、超声生物显微镜、彩色眼底照相、眼部B型超声及视野检查等。采集该家系中3例患者及3名眼部表型正常的家系成员外周静脉血标本并提取DNA，应用全外显子测序筛选致病基因，针对候选变异位点进行生物信息学分析及致病性预测，并进行Sanger测序验证和家系共分离分析。结果:该家系符合常染色体隐性遗传方式。先证者及其2位胞姐均呈现真性小眼球特征性表型，包括视力低下、高度远视、眼轴短、前房浅、房角窄、眼压高、视盘拥挤、视网膜血管扩张迂曲等，并伴有闭角型青光眼、渗出性视网膜脱离、葡萄膜渗漏等并发症。在3例患者 MFRP基因检测到复合杂合变异c.1010_1021del (p.His337_Glu340del)和c.1486G>A (p.Glu496Lys)，其中位点c.1010_1021del为首次报道。这2个变异位点在健康人群中频率低，在本家系中符合家系共分离，经生物信息学蛋白功能预测软件评估该变异为有害性变异。经美国医学遗传及基因组学会的致病性分级指南分析，认为该复合杂合变异具有较强的致病性，是本研究中真性小眼球家系表型的分子病因。 结论:本研究发现真性小眼球新的致病性变异位点c.1010_1021del。

abstractsObjective:To explore the clinical characteristics and genetic etiology of a Chinese Hui family with nanophthalmos.Methods:A pedigree investigation was performed.The clinical features and genetic etiology analysis were conducted in this Chinese family with nanophthalmos who first visited Beijing Tongren Eye Center in October 2005 and were followed up until October 2023.This family included 25 individuals of 4 generations, among which there were 3 patients.All the patients underwent medical history collection and comprehensive ophthalmological examinations, including visual acuity, intraocular pressure, slit-lamp microscope, IOLMaster, ultrasound biomicroscopy, color fundus photography, B-scan ultrasonography, visual field, etc.Genomic DNA was extracted from the 3 patients and 3 phenotypically normal individuals.Disease-causing genes were screened by whole-exome sequencing.Bioinformatic analysis and prediction of pathogenicity of candidate variants were conducted, followed by further validation by Sanger sequencing and co-segregation analysis.All the included subjects were informed of the purpose and methods of the study and signed an informed consent form.The study protocol was reviewed and approved by the Ethics Committee of Beijing Tongren Hospital, Capital Medical University (No.TRECKY2021-241).Results:Nanophthalmos in this family was inherited in an autosomal recessive manner.The proband and his two sisters were diagnosed with nanophthalmos based on clinical evaluation of typical phenotypes including the reduction of visual acuity, hyperpresbyopia, short ocular axis, shallow anterior chamber, narrow anterior chamber angle, high intraocular pressure, crowded optic disc, tortuous retinal vessel, etc.companied by angle-closure glaucoma, exudative retinal detachment and uveal effusion and other common complications.Compound heterozygous variants c. 1010_1021del (p.His337_Glu340del) and c. 1486G>A (p.Glu496Lys) were detected in MFRP gene in all three patients, and c. 1010_1021del, one of the biallelic variants was first reported.Both variants were rare in healthy populations and were co-segregated within this pedigree.According to the standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, the variants were predicted to have strong pathogenicity and were the genetic cause of the nanophthalmos in this pedigree. Conclusions:This study finds a novel pathogenic variant c.1010_1021del in a nanophthalmos pedigree.