ABCA4基因相关视网膜变性类疾病的临床和基因研究

发布时间：2018-08-22 10:38

【摘要】：目的:对ABCA4基因相关视网膜变性类疾病的临床表现进行归纳,并通过分子遗传学研究检测致病突变,总结基因型特点,探讨表型与基因型的联系。方法:收集2010年—2016年于北京协和医院眼科就诊并诊断为视网膜变性的患者,进行临床和遗传学研究。①临床研究方法:询问患者病史及家族史,对患者进行视力、眼前节、散瞳眼底、眼底照相、视野、视网膜电图(ERG)、相干光断层扫描(OCT)及眼底自发荧光(FAF)检查并记录结果。②遗传学研究方法:抽取患者及家庭成员静脉血,提取基因组DNA。应用二代测序(NGS)技术检测其致病突变,筛选所有携带ABCA4致病突变的患者并总结其分子遗传学特征。结果:共纳入来自57个家系的64例患者,其中男性35例,女性29例,年龄6岁～67岁,中位年龄21岁。1.临床结果:该64例患者中临床诊断STGD为49例,CRD6例,RP9例。STGD患者表现为不同程度的黄斑萎缩,部分患者存在眼底黄色斑点或周边部色素沉着;自发荧光表现多样。全视野ERG检查多表现为不同程度的视网膜功能下降,且视锥细胞功能下降较视杆细胞严重。CRD患者表现为轻度的眼底改变合并显著的以视锥功能下降为主的ERG改变。RP患者表现为视网膜广泛萎缩及骨细胞样色素沉着,伴ERG平波或表现为以视杆功能下降为主的ERG改变。本组患者中尚存在4例晚发型STGD病例,5个家系存在连续两代患者或隔代患者。2.分子遗传学结果:57个先证者均携带ABCA4致病突变,c.2424CG:p.Y808X突变出现频率相对高。本研究发现的80个不同ABCA4基因致病突变中,错义突变46个(57.5%),无义突变12个(15%),小片段缺失或插入突变15个(18.8%),剪接位点突变7个(8.8%)。28个(35%)为首次报道。结论:ABCA4基因突变能够引起STGD、CRD、RP三种表型,且同一表型的不同患者在发病年龄、严重程度、进展速度等方面也存在比较明显的表型差异性。STGD和CRD临床表现存在交叉,不典型病例及晚期病例的临床诊断存在一定难度。我国ABCA4基因突变谱与其他族群存在较大差别。尚需继续探索ABCA4相关视网膜变性疾病表型与基因型的关系。在遗传病基因检测领域二代测序是一种准确、高效的方法。
[Abstract]:Objective: to summarize the clinical manifestations of ABCA4 gene-related retinal degenerative diseases, and to investigate the relationship between phenotypes and genotypes by molecular genetic analysis. Methods: from 2010 to 2016, we collected the patients who were diagnosed with retinal degeneration in Peking Union Hospital from 2010 to 2016. 1 Clinical and genetic research methods: ask the patient's medical history and family history, and carry out visual acuity, anterior segment, and so on. Results\ The second generation sequencing (NGS) technique was used to detect the pathogenicity of ABCA4 and to screen all patients with ABCA4 mutation and to summarize its molecular genetic characteristics. Results: a total of 64 patients from 57 families were included, including 35 males and 29 females, aged 6 years or 67 years, with a median age of 21 years. Clinical results: among the 64 patients, 49 cases were diagnosed as STGD. 9 cases showed macular atrophy, and some of them had yellow spots or peripheral pigmentation in the fundus. The results of full field ERG were as follows: retina function was decreased in different degree. The results showed that the decrease of cone cell function was more serious than that of rod cell. The patients showed slight fundus change and ERG change. RP patients showed extensive atrophy of retina and osteocytoid pigmentation. The changes of ERG with ERG flat-wave or with the decline of rod function were also observed. In this group, there were 4 cases of late onset STGD and 5 families with two consecutive generations or two generations of patients. The results of molecular genetics showed that the frequency of ABCA4 mutation was relatively high in 57 proband patients with ABCA4 pathogenicity mutation (c. 2424 CGP: p.Y808X). In this study, 46 (57.5%) missense mutations, 12 (15%) nonsense mutations, 15 (18.8%) small fragment deletion or insertion mutations, 7 (8.8%) splice site mutations and 28 (35%) splicing site mutations were first reported. Conclusion the mutation of the 1 / ABCA4 gene can cause three phenotypes of STGDD-CRDN RP, and there are obvious phenotypic differences in age, severity and progression rate of the same phenotype. The clinical manifestations of STGD and CRD are intersected. It is difficult to diagnose atypical cases and late cases. The ABCA4 gene mutation patterns in China are different from those in other ethnic groups. It is necessary to continue to explore the relationship between phenotype and genotype of ABCA4 associated retinal degeneration disease. Second generation sequencing is an accurate and efficient method in the field of genetic disease gene detection.
【学位授予单位】：北京协和医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R774.1

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