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.

Cardiology and

Center for Molecular Medicine University Medical Center Utrecht Utrecht University Utrecht The Netherlands

College of Pharmacy and

Department of Genetics and Genomic Sciences

Department of Medicine Hennepin County Medical Center

Department of Medicine University of Alabama at Birmingham Birmingham Alabama

Department of Molecular and Cellular Therapeutics Royal College of Surgeons Dublin Ireland

Department of Nephrology Beaumont Hospital Dublin Ireland; and

Department of Nephrology Transplant Center Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Surgery Penn Transplant Institute Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania

Department of Surgery University of Minnesota Minneapolis Minnesota

Departments of Genetics and

Departments of Nephrology

Division of Genetics The Children's Hospital of Philadelphia Philadelphia Pennsylvania

Division of Nephrology and Dialysis Department of Internal Medicine 3 Medical University of Vienna Vienna Austria

Division of Nephrology Department of Medicine Icahn School of Medicine at Mount Sinai New York New York

Epidemiology and

Genetica University Medical Center Groningen University of Groningen Groningen The Netherlands

Icahn Institute for Genomics and Multiscale Biology and

J Am Soc Nephrol. 2018 Jun;29(6):1583-1584. doi: 10.1681/ASN.2018040441. PubMed

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