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.

背景性肾病（NPH）是儿童ESRD的最普遍遗传原因。然而，关于NPH在成年性ESRD中的患病率知之甚少。编码nephrocystin-1的NPHP1基因的纯合全基因缺失是NPH的重要原因。我们通过评估成人发病ESRD中的纯合NPHP1全基因缺失来确定成人中NPH的患病率。

方法对来自国际移植遗传学和转化研究组织（iGeneTRAiN）的五个队列的成年肾移植接受者进行单核苷酸多态性基因分型。经过质量控制后，我们根据中位数log2比率和B等位基因频率模式确定了常染色体拷贝数变异（例如缺失）。一项研究结果对结果进行了独立验证。如果患者患有成人性ESRD，即定义为≥18岁的RRT开始，则将其包括在分析中。

结果我们纳入了5606例成人性ESRD患者；26（0.5％）位显示纯合NPHP1缺失。没有供体对照显示出该缺失的纯合性。NPH患者ESRD发作的中位年龄为30岁（18-61岁），≥30岁的患者中有54％。值得注意的是，在表型上只有三名（12％）患者被分类为患有NPH，而大多数患者被定义为病因不明的CKD（n = 11; 42％）。

结论考虑到未分析NPHP1中的其他突变类型或其他引起NPH的基因中的突变，NPH是成人ESRD发病的相对常见的单基因病因。由于88％的患者尚未在临床上被诊断为NPH，因此可能需要在成年ESRD中广泛应用基因检测。