Genetic diagnosis of polycystic kidney disease, Alport syndrome, and thalassemia minor in a large Chinese family
Genetic diagnosis of polycystic kidney disease, Alport syndrome, and thalassemia minor in a large Chinese family
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中国大家族多囊肾、阿尔波特综合征、轻型地中海贫血的基因诊断
DOI：
10.1042/cs20170245
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发表时间：
2017
期刊：
影响因子：
6
通讯作者：
Xiong F
中科院分区：
文献类型：
--
作者：
Miao Y;Xiong J;Zhang XL;Huang HJ;Yu LX;Chen JF;Deng WF;Xu HL;Liu RM;Xiang CL;Xu XM;Xiong F
多囊肾病（PKD）和阿尔波特综合征（AS）是与肾脏疾病相关的严重遗传性疾病，地中海贫血是中国南方地区高发的遗传性血液病。在这里，我们报告了一个中国大家庭中轻微地中海贫血和 AS（基因诊断）的罕见 PKD 重合。对先证者进行了全基因组下一代测序（NGS），所有家庭成员都接受了临床评估。使用桑格测序来验证NGS区分的突变。通过多态性表型 v2 (PolyPhen-2)、从耐受中筛选不耐受 (SIFT) 算法和 MutationTaster 来评估变异的致病潜力。采用免疫组织化学、蛋白质印迹、免疫荧光和 TdT 介导的 dUTP 缺口末端标记 (TUNEL) 分析来研究先证者和正常对照肾组织中多囊蛋白 1 (PC1) 的表达以及细胞增殖和凋亡。一种新的移码多囊肾病 1 (PKD1) 突变（c.3903delC、p.A1302Pfs）被确定与该家族的肾脏疾病有关。先证者肾组织中PC1表达、细胞增殖和凋亡显着增加。此外，大约 19.3 kb 的 α-珠蛋白基因 DNA 缺失 (_ _SEA) 与该家族中的轻型地中海贫血有关。此外，在 4 个无 AS 临床特征的家庭成员中发现了 IV 型胶原 α 5 链 (COL4A5) 变异体 (c.2858G>T，rs78972735)，在 dbSNP 和人类基因突变数据库 (HGMD) 中注释为致病性突变。发现一种新的致病性 PKD1 突变 (c.3903delC) 和 (_ _SEA) 地中海贫血缺失是该家族临床症状的原因。报道的致病性 COL4a5 变异（c.2858G>T，rs78972735）并不是单独致病的。
Polycystic kidney disease (PKD) and Alport syndrome (AS) are serious inherited disorders associated with renal disease, and thalassemia is a hereditary blood disease with a high prevalence in south China. Here, we report an exceptional PKD coincidence of thalassemia minor and AS (diagnosed genetically) in a large Chinese family. Whole genome next-generation sequencing (NGS) was performed on the proband, and all family members underwent clinical evaluation. Sanger sequencing was used to validate the mutations distinguished by NGS. The pathogenic potential of the variants were evaluated by Polymorphism Phenotyping v2 (PolyPhen-2), Sorting Intolerant From Tolerant (SIFT) algorithm, and MutationTaster. Immunohistochemical, Western blot, immunofluorescent, and TdT-mediated dUTP nick-end labeling (TUNEL) analyses were performed to investigate polycystin 1 (PC1) expression, and cell proliferation and apoptosis in kidney tissues from the proband and normal control. A novel frameshift polycystic kidney disease 1 (PKD1) mutation (c.3903delC, p.A1302Pfs) was identified to be responsible for renal disease in this family. PC1 expression, and cell proliferation and apoptosis were significantly increased in the kidney tissues of the proband. Moreover, a deletion of approximately 19.3 kb of DNA with α-globin genes (_ _SEA) was associated with thalassemia minor in the family. In addition, a collagen type IV α 5 chain (COL4A5) variant (c.2858G>T, rs78972735), annotated as a pathogenic mutation in dbSNP and human gene mutation database (HGMD), was found in four family members with no clinical traits of AS. A novel pathogenicPKD1mutation (c.3903delC) and (_ _SEA) thalassemia deletion were found to be responsible for the clinical symptoms in this family. The reported pathogenic COL4a5 variant (c.2858G>T, rs78972735) was not pathogenic alone.