摘要目的:分析常染色体显性遗传性视神经萎缩(ADOA)一家系的临床表型及基因型。方法:采用家系调查研究方法，纳入2023年7—10月在河南省立眼科医院就诊的中国河南地区汉族ADOA一家系2代4名成员，包括2例患者。详细询问患者及其家系成员病史，并进行全面的眼科检查，包括视力、视野、眼底、视网膜电图(ERG)、视觉诱发电位(VEP)、光学相干断层扫描；同时进行听力、肌电图及颅脑磁共振检查以明确是否伴有全身异常。收集该家系4名成员的外周血，对先证者进行全外显子组测序，其他成员采用Sanger测序验证。对新发现的变异位点进行致病性和蛋白结构分析。结果:先证者女，15岁，左眼视力下降4年，双眼视神经萎缩，双眼黄斑区中心凹厚度稍变薄，神经节细胞复合体层厚度局部轻度变薄，VEP各波呈低振幅改变，部分视野缺失；全身检查未见明显听力障碍和肌张力异常。先证者母亲视神经部分区域萎缩，双眼黄斑区中心凹厚度稍变薄，VEP检查未见明显异常，ERG轻度异常。全外显子组测序结果显示，先证者及其母亲 OPA1基因外显子6出现杂合无义变异c.676C>T(p.Gln226Ter)，该变异位点在HGMD数据库未见报道，千人基因组和gnomAD数据库未见收录，其可导致226位谷氨酰胺处发生提前终止。蛋白结构分析显示，OPA1蛋白p.Gln226Ter可造成蛋白与周围残基相结合的氢键改变，进而导致蛋白功能改变。根据ACMG指南，该变异可能致病。 结论:该ADOA家系患者表现为青少年时期发病的双眼视神经萎缩，左眼为主； OPA1基因c.676C>T变异可能为该ADOA家系致病变异位点，该变异位点为首次报道。

abstractsObjective:To analyze the clinical phenotype and the associated pathogenic genes in a family exhibiting autosomal dominant inherited optic atrophy (ADOA).Methods:A pedigree analysis was conducted on a Han Chinese family with ADOA comprising two generations and four individuals from Henan Province.The family with two ADOA patients was recruited at Henan Eye Hospital between July and October 2023.Detailed medical histories were collected for the proband and family members.Comprehensive ophthalmologic evaluations were performed, including assessments of visual acuity, visual field, fundus photography, electroretinogram (ERG), visual evoked potential (VEP), and optical coherence tomography.Additionally, hearing, electromyography, and magnetic resonance imaging were performed on the proband to assess the presence of systemic symptoms.Peripheral blood samples were collected from four family members, and whole exome sequencing (WES) was performed on the proband, with subsequent validation via Sanger sequencing for the other family members.The pathogenicity and protein struture of the novel variant were analyzed.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Henan Eye Hospital (No.HNEECKY-2019[15]).Written informed consent was obtained from each subject.Results:The proband was a 15-year-old female with a 4-year history of vision loss in the left eye and optic atrophy, mild thinning of central macular foveal thickness, locally mild thinning of ganglion cell complex layer thickness, low VEP amplitude, and partial visual field defects in both eyes, and no significant hearing impairment or dystonia on systemic examination.The proband's mother had partial optic nerve atrophy and slightly decreased central macular foveal thickness in both eyes, and mild ERG abnormalities, but no significant VEP abnormalities.WES identified a heterozygous nonsense variant c. 676C>T (p.Gln226Ter) in exon 6 of the OPA1 gene of the proband and her mother.This variant has not been previously reported in the literature, nor is it listed in the Human Gene Mutation Database, the Thousand Genomes Project, or the Genome Aggregation Database, which results in a premature termination codon at glutamine position 226.Protein structure analysis showed that p. Gln226Ter of the OPA1 protein induces alterations in the hydrogen bonding of the protein binding to surrounding residues, which in turn leads to protein function alterations.The variant was classified as potentially pathogenic according to the ACMG standards and guidelines. Conclusions:Patients in this ADOA family present with adolescent-onset optic atrophy in both eyes, with a predominance in the left eye.The c. 676C>T variant in OPA1 gene might be the causative variant in this ADOA family.Notably, this is the first report of this specific variant.