NPHP1 (Nephrocystin-1) Gene Deletions Cause Adult-Onset ESRD

Abstract

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 gene encoding nephrocystin-1 are a prominent cause of NPH. We determined the prevalence of NPH in adults by assessing homozygous full gene deletions in adult-onset ESRD. 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. We included 5606 patients with adult-onset ESRD; 26 (0.5%) showed homozygous 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 (=11; 42%). Considering that other mutation types in 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.

PKD1 mutation may epistatically ameliorate nephronophthisis progression in patients with NPHP1 deletion

“…Albeit rare, other similar patients of NPHP‐induced delayed/adult‐onset ESRD have previously been observed . More recently, 26 (0.5%) patients harboring a homozygous NPHP1 full gene deletion were identified among 5606 patients that underwent kidney transplantation . The average age at which these patients developed ESRD was 30 years (range, 18‐61 years), and 54% of the patients were aged greater than 30 years at ESRD onset.…”

“…[10][11][12][13] More recently, 26 (0.5%) patients harboring a homozygous NPHP1 full gene deletion were identified among 5606 patients that underwent kidney transplantation. 5 The average age at which these patients developed ESRD was 30 years (range, 18-61 years), and 54% of the patients were aged greater than 30 years at ESRD onset. In many of these previous reports, the presence of NPHP-modifier genes was discussed as a probable cause of the late ESRD onset.…”

“…Specifically, infantile NPHP onsets between 0 and 3 years, whereas the average age of onset for juvenile and adolescent‐type NPHP is 13 and 19 years, respectively . While most patients with NPHP1‐ associated juvenile NPHP progress to ESRD by an average age of 18 years, a recent study reported that some do not exhibit ESRD until they reach adulthood …”

“…1 While most patients with NPHP1-associated juvenile NPHP progress to ESRD by an average age of 18 years, a recent study reported that some do not exhibit ESRD until they reach adulthood. 5 Autosomal dominant polycystic kidney disease (ADPKD) has similarly been shown to be a ciliopathy that is characterized by the progressive development and accumulation of | 337…”

Targeted Next-Generation Sequencing Identifies Pathogenic Variants in Kidney Disease-Related Genes in Patients with Diabetic Kidney Disease

“…Interestingly, previous studies have shown that homozygous deletion of NPHP1, arising from homologous recombination between 45-kilobasepair repeats flanking this gene, is the most frequent mutation observed in familial juvenile nephronophthisis (MIM 256100), a rare progressive tubulointerstitial kidney disorder with autosomal recessive inheritance (28; 29). More than 85% of patients with nephronophthisis, however, are clinically diagnosed as having other nephropathies (52).…”