儿童Alport综合征COL4A5基因4种新突变分析

目的 分析4例儿童Alport综合征的基因型和临床表型特点。方法 总结4例患儿的临床特点，采用外显子捕获-第二代测序技术对4例诊断为Alport综合征患儿的COL4A5、COL4A4和COL4A3基因进行突变检测。结果 4例均为男性，年龄6～8岁，首发症状均为血尿，均伴有不同程度的蛋白尿。1例表现为高频听力区受损，1例右侧视网膜脱色素改变。4例肾功能均正常。肾穿刺活检电镜检查均显示典型Alport综合征基底膜病变。在4个家系中发现4种COL4A5基因突变，分别为Gly132Glu、Gly1238Arg、Gly267Arg和Gly1033Ser， 均为未报道的新突变。经家系验证Gly132Glu和Gly1033Ser为新生突变。用 SIFT 和PolyPhen 软件进行蛋白功能预测均显示4种突变为有害突变。结论 本研究采用外显子捕获-第二代测序技术共检测到4种COL4A5基因新突变，其中2种为新生突变。为人类Alport综合征基因突变数据库增添了4个新成员，对进一步研究中国人群Alport综合征的发病机制以及遗传咨询和产前诊断有重大意义。

Analysis of 4 novel mutations of COL4A5 gene in children with Alport syndrome

Objective To analyze the clinical features and gene mutation of 4 Chinese children with Alport syndrome． Methods The clinical and laboratory data of 4 children with Alport syndrome were summarized. COL4A5, COL4A4 and COL4A3 genes were analyzed using next-generation sequencing. Results Four patients all presented an atypical clinical picture with onset of hematuria accompanied with different degrees of proteinuria . Ophthalmology, otolaryngology and renal function studies showed no abnormalities, except for a sensorineural hearing loss detected in case 2. Characteristic ultrastructual changes of the glomerular basement membrane were found in all patients. Four pathogenic mutations were identified in COL4A5 gene in the 4 families, including Gly132Glu, Gly1238Arg, Gly267Arg and Gly1033Ser. The 4 mutations were not reported previously, two of which were the novel mutations. Conclusions The 4 novel mutations in coding DNA of COL4A5 gene identified in our study contribute to further study of pathogenesis of Alport syndrome , genetic counselling and prenatal diagnosis in Chinese population.