男性X连锁Alport综合征COL4A5突变嵌合体病例报道及文献复习  

Analysis and literature review of COL4A5 mutation mosaicism in male patients with X⁃linked Alport syndrome

作　　者：邓海月 王聪 王晓媛 武国红[1] 张琰琴[1] 丁洁[1] 王芳[1] Deng Haiyue;Wang Cong;Wang Xiaoyuan;Wu Guohong;Zhang Yanqin;Ding Jie;Wang Fang(Department of Pediatrics,Peking University First Hospital,Beijing 100034,China)

机构地区：[1]北京大学第一医院儿科,北京100034

出　　处：《中华肾脏病杂志》2021年第11期865-871,共7页Chinese Journal of Nephrology

基　　金：国家重点研发计划精准医学研究重点专项基金(2016YFC0901505);儿科遗传性疾病分子诊断与研究北京市重点实验室基金(BZ0317)。

摘　　要：目的报道4例男性X连锁Alport综合征COL4A5突变嵌合体病例,为该病的家庭诊断、遗传咨询和再生育提供科学依据与指导,增强临床医生对Alport综合征突变嵌合体的认识。方法回顾性检索和收集来自北京大学第一医院遗传性肾脏病注册登记系统数据库并在2018年4月至2019年4月就诊于北京大学第一医院的病例资料。入选符合Alport综合征临床诊断,经二代测序或Sanger测序有COL4A5突变,Sanger测序验证突变位点有突变型峰与野生型峰同时存在,疑似COL4A5突变嵌合体的男性患者进入本研究。收集患者临床资料及染色体核型分析结果;试剂盒法提取多组织基因组DNA,采用Sanger测序验证基因突变位点。检索Pubmed、中国知网及万方数据库相关文献并复习。结果4例COL4A5突变体细胞合并生殖细胞嵌合体男性患者入选本研究。例1表型表现为血尿、蛋白尿,外周血染色体核型正常,多组织(外周血、唾液、尿液)DNA检测到COL4A5 c.3455⁃1G>A嵌合突变。例2表现为血尿、微量白蛋白尿,外周血染色体核型正常,多组织(外周血、唾液、皮肤成纤维细胞)DNA发现COL4A5 c.4994+1G>A嵌合突变。例3表型表现为血尿、无蛋白尿,外周血和毛发柄DNA检测到COL4A5 c.3535G>A嵌合突变。例4表型表现为血尿,无蛋白尿,肾功能正常,无身材高大、睾丸小等,皮肤成纤维细胞DNA测序示COL4A5 c.3106G>A嵌合突变。例3和例4因无法获取标本未进行染色体核型分析,但结合其生育史及无身材高大和睾丸小的临床表现,不考虑47,XXY或46,XY/47,XXY嵌合。文献复习显示COL4A5突变等位基因占比及突变类型与男性X连锁Alport综合征突变嵌合体患者的肾脏表现相关。结论男性X连锁Alport综合征突变嵌合体患者的表型较半合突变者轻,且表型与突变等位基因占比、基因突变类型有关。Objective To report four male COL4A5 mutation mosaicism patients with X⁃linked Alport syndrome,and to provide evidence for diagnosis,genetic counseling,and reproduction in the respective families and improve our knowledge of mosaicism in Alport syndrome.Methods Suspected male mosaic patients for COL4A5 who met the following criteria:clinical diagnosis of Alport syndrome,harbored COL4A5 mutations detected using next generation sequencing or Sanger sequencing,heterozygosity for the mutant and normal COL4A5 alleles in the DNA demonstrated by Sanger sequencing,registered in the on⁃line registry of hereditary kidney diseases,and admitted to Peking University First Hospital during the period of April 2018 to April 2019 were enrolled.Clinical data and karyotypes were retrospectively analyzed.Genetic DNA isolated from multiple tissues was analyzed for COL4A5 gene mutations by using PCR and Sanger sequencing.Related literatures published in PubMed,CNKI and Wanfang databases were reviewed.Results Four COL4A5 somatic and germline mosaic male patients with Alport syndrome were included in the study.Patient 1 was characterized by hematuria and proteinuria.His karyotype of peripheral blood was normal.COL4A5 c.3455⁃1G>A mosaicism was detected in multiple tissues(peripheral blood,saliva and urine).Patient 2 presented with hematuria and microalbuminuria.His karyotype of peripheral blood was normal.COL4A5 c.4994+1G>A mosaicism was detected in multiple tissues(peripheral blood,saliva and skin fibroblasts).Patients 3 showed hematuria without proteinuria.COL4A5 c.3535G>A mosaicism was found in genomic DNA of peripheral blood and hair.Laboratory and physical examinations of patient 4 showed hematuria and normal renal function,without proteinuria,megasoma or small testes.COL4A5 c.3106G>A mosaicism was detected in genomic DNA of skin fibroblasts.Although without karyotype analysis due to unavailable specimens,47,XXY or 46,XY/47,XXY mosaicism was not considered according to the reproductive history and lack of clinical manifestatio

关 键 词：遗传性疾病 X连锁 肾炎 遗传性 表型 COL4A5基因 嵌合体 ALPORT综合征 

分 类 号：R692[医药卫生—泌尿科学]