NPHP1 (Nephrocystin-1) Gene Deletions Cause Adult-Onset ESRD
NPHP1 (Nephrocystin-1) Gene Deletions Cause Adult-Onset ESRD
复制标题
DOI：
10.1681/asn.2017111200
复制
发表时间：
2018-06-01
影响因子：
13.6
通讯作者：
van Eerde, Albertien M.
中科院分区：
文献类型：
--
作者：
Snoek, Rozemarijn;van Setten, Jessica;van Eerde, Albertien M.
背景 肾结核 (NPH) 是儿童 ESRD 最常见的遗传原因。然而，对于成人发病的 ESRD 中 NPH 的患病率知之甚少。编码 nephrocystin-1 的 NPHP1 基因的纯合全基因缺失是 NPH 的一个主要原因。我们通过评估成人发病的 ESRD 中的纯合 NPHP1 全基因缺失来确定成人 NPH 的患病率。方法对来自国际移植遗传学和转化研究网络 (iGeneTRAiN) 五个队列的成人肾移植受者进行单核苷酸多态性基因分型。质量控制后，我们根据中值 log2 比率和 B 等位基因频率模式确定常染色体拷贝数变异（例如缺失）。研究结果在一组中得到了独立验证。如果患者患有成人发病的 ESRD（定义为≥ 18 岁开始 RRT），则将其纳入分析。结果 我们纳入了 5606 名成人发病的 ESRD 患者； 26 例 (0.5%) 显示纯合 NPHP1 缺失。没有供体对照显示出该缺失的纯合性。 NPH 患者 ESRD 发病的中位年龄为 30 岁（范围 18-61），其中 54% 的患者年龄 >= 30 岁。值得注意的是，只有 3 名 (12%) 患者在表型上被归类为患有 NPH，而大多数患者被定义为患有病因不明的 CKD (n=11；42%)。 结论 考虑到 NPHP1 中的其他突变类型或其他 NPH 致病基因中的突变未进行分析，NPH 是成人发病 ESRD 的相对常见的单基因原因。由于 88% 的患者尚未被临床诊断为 NPH，因此可能需要在成人发病的 ESRD 中更广泛地应用基因检测。
Background Nephronophthisis (NPH) is the most prevalent genetic cause for ESRD in children. However, little is known about the prevalence of NPH in adult-onset ESRD. Homozygous full gene deletions of the NPHP1 gene encoding nephrocystin-1 are a prominent cause of NPH. We determined the prevalence of NPH in adults by assessing homozygous NPHP1 full gene deletions in adult-onset ESRD.Methods Adult renal transplant recipients from five cohorts of the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN) underwent single-nucleotide polymorphism genotyping. After quality control, we determined autosomal copy number variants (such as deletions) on the basis of median log2 ratios and B-allele frequency patterns. The findings were independently validated in one cohort. Patients were included in the analysis if they had adult-onset ESRD, defined as start of RRT at >= 18 years old.Results We included 5606 patients with adult-onset ESRD; 26 (0.5%) showed homozygous NPHP1 deletions. No donor controls showed homozygosity for this deletion. Median age at ESRD onset was 30 (range, 18-61) years old for patients with NPH, with 54% of patients age >= 30 years old. Notably, only three (12%) patients were phenotypically classified as having NPH, whereas most patients were defined as having CKD with unknown etiology (n=11; 42%).Conclusions Considering that other mutation types in NPHP1 or mutations in other NPH-causing genes were not analyzed, NPH is a relatively frequent monogenic cause of adult-onset ESRD. Because 88% of patients had not been clinically diagnosed with NPH, wider application of genetic testing in adult-onset ESRD may be warranted.