Tang Xiaoshan, Xu Hong, Shen Qian, Li Guoming, Rao Jia, Chen Jing, Zhai Yihui, Miao Qianfan
Clin Nephrol. 2019 Aug;92(2):89-94. doi: 10.5414/CN109571.
Nephronophthisis (NPH) is an autosomal recessive cystic kidney disease. Its onset is obscure, and its early clinical manifestations and pathological changes lack specificity, which makes clinical diagnosis difficult. At present, as many as 90 genetic alterations can result in NPH, which exhibits significant genetic heterogeneity. Therefore, high-throughput sequencing technology provides an effective method to identify and characterize novel NPH pathogenic genes when compared to Sanger sequencing. This study summarizes the gene mutations and clinical data of whole exome sequencing, which was used to diagnose 5 NPH patients to improve the understanding of the causative genes and clinical phenotypes of NPH.
The clinical manifestations, laboratory examination indexes, and imaging data of 5 patients of NPH were reported. Whole exome sequencing was performed in 5 children, and the causative genes and mutation sites were analyzed by bioinformatics and genetics. The mutation sites were verified in children and their parents using Sanger direct sequencing.
Among the 5 patients (3 male and 2 female), 2 patients had infantile NPH, and 3 patients had juvenile NPH. The 2 infantile NPH patients were characterized by the onset of liver dysfunction accompanied by hypertension and left ventricular change, and the renal function progressed to end-stage renal disease (ESRD) after 7 months and 9 months, respectively. The 2 cases of infantile NPH had mutations, with one carrying compound heterozygous mutations (c.1358A>G, c.2369A>G) and the other simultaneously carrying a c.1174C>T IVS26-3A>G cleavage site mutation from the father and a nonsense mutation (p.392R>X, 939) from the mother. The 2 juvenile NPH children had entered ESRD at the onset of the disease, including 1 patient with Joubert syndrome. The 2 patients with juvenile NPH had frameshift mutations (c.1583 to 1596: deletion) and homozygous point mutations (7 c.640G>T) of the gene. In addition, another patient with frequent urination and nocturia resulting in stage CKD3 renal function had a complex heterozygous mutation of the gene (c.2686G>A, c.1943A>G). The urine A1MU/creatinine and urinary transferrin increased in all 5 patients without hematuria.
Whole exome sequencing identified the causative genes of NPH in 5 children. In NPH children with gene mutations, renal functional damage was characterized by early onset and rapid progression to ESRD, often accompanied by liver dysfunction and hypertension.
肾单位肾痨（NPH）是一种常染色体隐性遗传性囊性肾病。其起病隐匿，早期临床表现及病理改变缺乏特异性，导致临床诊断困难。目前，多达90种基因改变可导致NPH，表现出显著的遗传异质性。因此，与桑格测序相比，高通量测序技术为鉴定和表征新的NPH致病基因提供了一种有效方法。本研究总结了用于诊断5例NPH患者的全外显子测序的基因突变及临床资料，以提高对NPH致病基因及临床表型的认识。
报告5例NPH患者的临床表现、实验室检查指标及影像学资料。对5名儿童进行全外显子测序，并通过生物信息学和遗传学方法分析致病基因及突变位点。利用桑格直接测序法在患儿及其父母中验证突变位点。
5例患者（3男2女）中，2例为婴儿型NPH，3例为青少年型NPH。2例婴儿型NPH患者以肝功能异常伴高血压及左心室改变起病，肾功能分别在7个月和9个月后进展至终末期肾病（ESRD）。2例婴儿型NPH患者存在突变，1例携带复合杂合突变（c.1358A>G，c.2369A>G），另1例同时携带来自父亲的c.1174C>T IVS26-3A>G剪切位点突变和来自母亲的无义突变（p.392R>X，939）。2例青少年型NPH患儿在疾病起病时已进入ESRD，其中1例伴有乔伯综合征。2例青少年型NPH患者存在移码突变（c.1583至1596：缺失）和该基因的纯合点突变（7 c.640G>T）。此外，另1例因尿频、夜尿导致CKD3期肾功能的患者存在该基因的复合杂合突变（c.2686G>A，c.1943A>G）。所有5例患者尿A1MU/肌酐及尿转铁蛋白升高，均无血尿。
全外显子测序鉴定了5名儿童NPH的致病基因。在存在该基因突变的NPH儿童中，肾功能损害的特点是起病早且迅速进展至ESRD，常伴有肝功能异常和高血压。
