NPHP1 (Nephrocystin-1) gene deletions cause adult-onset ESRD

Rozemarijn Snoek, Jessica Van Setten, Brendan J. Keating, Ajay K. Israni, Pamala A. Jacobson, William S. Oetting, Arthur J. Matas, Roslyn B. Mannon, Zhongyang Zhang, Weijia Zhang, Ke Hao, Barbara Murphy, Roman Reindl-Schwaighofer, Andreas Heinzl, Rainer Oberbauer, Ondrej Viklicky, Peter J. Conlon, Caragh P. Stapleton, Stephan J.L. Bakker, Harold SniederEdith D.J. Peters, Bert Van Der Zwaag, Nine V.A.M. Knoers, Martin H. De Borst, Albertien M. Van Eerde

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1772-1779
Number of pages8
JournalJournal of the American Society of Nephrology
Volume29
Issue number6
DOIs
StatePublished - Jun 2018

Bibliographical note

Funding Information:
The authors thank Affymetrix Inc. (Santa Clara, CA) for performing part of the copy number variant calling using their BRLMM-P algorithm.21 All images in Figure 4 were purchased from thenoun-project.com under a royalty-free license. For two images, the color was changed from black to gray, and one image was cropped to ensure adequate fit. The DeKAF-Genomics cohort and the GEN03 cohort were supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases grants 5U19-AI070119 and 5U01-AI058013. R.S., N.V.A.M.K., and A.M.v.E. are supported by Dutch Kidney Foundation grants KSTP12.010, 15OP14, and Kouncil CP11.18, and A.M.v.E. is supported by NutsOhra Foundation grant 070-1303. Z.Z. is partially supported by the Translational Collaborative Research Initiative Grant from the Icahn School of Medicine at Mount Sinai.

Funding Information:
The DeKAF-Genomics cohort and the GEN03 cohort were supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases grants 5U19-AI070119 and 5U01-AI058013. R.S., N.V.A.M.K., and A.M.v.E. are supported by Dutch Kidney Foundation grants KSTP12.010, 15OP14, and Kouncil CP11.18, and A.M.v.E. is supported by NutsOhra Foundation grant 070-1303. Z.Z. is partially supported by the Translational Collaborative Research Initiative Grant from the Icahn School of Medicine at Mount Sinai.

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