摘要目的:探讨6个Stargardt病(STGD)患者家系的基因检测结果，明确其临床表现与基因变异的关系。方法:选取2021年6月至2023年6月于山西省眼科医院就诊6个 ABCA4基因变异呈阳性的STGD家系(家系1～6)中共计7例患者(患者1～7)为研究对象。采用回顾性研究方法，收集家系1～6中共计7例患者的临床及家族史资料。采集7例受检者外周肘静脉血各5 mL，提取基因组DNA，进行3人家系全外显子组测序(trio-WES)，采用Sanger测序对候选 ABCA4基因变异进行家系验证。根据美国医学遗传学与基因组学学会(ACMG)制定的《遗传变异分类标准与指南》(以下简称为"ACMG指南")，对检出的 ABCA4基因变异位点进行致病性评级。本研究遵循的研究程序通过山西省眼科医院医学伦理委员会审查(批准号：SXYYLL-20200620)。 结果:患者1～7就诊时年龄为7～53岁，均于6～15岁时发病。患者1～7表现为中至重度视力损害伴黄斑萎缩，除家系5中患者Ⅱ 2外，均存在黄白色斑点。光学相干断层成像(OCT)结果显示，患者1～7的黄斑中心凹变薄伴IS/OS带，或椭圆体带消失，自发荧光显示黄斑低荧光伴周边点状荧光异常。根据视网膜电流图(ERG)进行分组显示，3个家系为第3组，2个家系为第1组，1个家系为第2组。遗传模式分析结果显示，6个家系均为常染色体隐性遗传，家系1、2、3、4、6为 ABCA4基因复合杂合变异，家系5为纯合变异。本研究共检出 ABCA4基因的11个致病性变异位点，其中p.Glu1704Gly、p.Gly1965Glu、p.Ser1531Phe为首次报道，携带无义变异或移码变异的患者包含患者1(家系1的Ⅱ 1)、患者2(家系1的Ⅱ 2患者)、患者4(家系3的Ⅱ 1患者)、患者6(家系5的Ⅱ 2)和患者7(家系6的Ⅱ 1)，其临床表现较携带错义变异的患者3(家系2的Ⅱ 2)和患者5(家系4的Ⅱ 1)的左、右眼最佳矫正视力(BCVA)受损更为严重。 结论:ABCA4基因变异可能为该研究STGD家系的遗传学病因， ABCA4基因位点p.Glu1704Gly，p.Gly1965Glu，p.Ser1531Phe的发现丰富了STGD病基因变异谱。

abstractsObjective:To explore the correlation between the clinical manifestations and genetic variations in six Chinese Stargardt disease pedigrees.Methods:Six Stargardt disease pedigrees due to ABCA4 gene variants that visited Shanxi Eye Hospital from June 2021 June 2023 were selected as the study subjects. A retrospective study method was used to collect the clinical and family history data of all members of these pedigrees. Peripheral venous blood samples of the examinees were collected, and genomic DNA was extracted for trio-WES. Candidate variants the ABCA4 gene were verified by Sanger sequencing. According to the " Standards and Guidelines for the Classification of Sequence Variants" (hereinafter referred to as the " ACMG Guidelines" ) formulated by American College of Medical Genetics and Genomics (ACMG), the variant sites of the ABCA4 gene were classified for pathogenicity. This study has been approved by the Medical Ethics Committee of Shanxi Eye Hospital (Ethics No. SXYYLL-20200620). Results:From June 2021 to June 2023, 7 patients from families with Stargardt disease with ABCA4 variants were selected as the study subjects. The age of the patients was between 7 to 53 years old, and the age of onset was between 6 to 15 years old. All patients exhibited moderate-to-severe visual impairment with macular atrophy, and yellow white spots were seen in all patients except patient Ⅱ 2 in family 5. Optical coherence tomography (OCT) results showed that the in all patients the macular fovea was significantly thinner, and IS/OS or ellipsoid zone had disappeared. Autofluorescence showed low autofluorescence in the macula, with abnormal dot autofluorescence in the paramacular and periphery retina. ERG grouping classified three pedigrees as Group 3, two as Group 1, and one as Group 2. Pedigree analysis showed that all six pedigrees had autosomal recessive inheritance, family 1, 2, 3, 4, 6 had compound heterozygous variants of the ABCA4, and family 5 had homozygous variants. A total of 11 pathogenic mutations were detected in the ABCA4 gene, of which 3 were found for the first time, including p. Glu1704Gly, p. Gly1965Glu and p. Ser1531Phe. Those carrying nonsense or frameshift mutations include patient 1 (family 1, Ⅱ 1), patient 2 (family 1, Ⅱ 2), patient 4 (family 3, Ⅱ 1), patient 6 (family 5, Ⅱ 2), and patient 7 (family 6, Ⅱ 1), whose clinical manifestations were more severe than those of patient 3 (family 2, Ⅱ 2) and patient 5 (family 4, Ⅱ 1) carrying missense mutations in terms of best corrected visual acuity(BCVA) damage. Conclusion:The ABCA4 gene variation may be the genetic cause of the Stargardt disease in this study, and the discovery of the ABCA4 gene disease variants p. Glu1704Gly, p. Gly1965Glu, p. Ser1531Phe has enriched the mutational spectrum of of Stargardt disease.