Kidney Week

Abstract: TH-OR041

NPHP1 Gene Deletions Cause ESRD in 0.9% of Adult-Onset Cases

Session Information

• Cystic Kidney Diseases: Genes, Mechanisms, Interventions
  November 02, 2017 | Location: Room 390, Morial Convention Center
  Abstract Time: 04:30 PM - 04:42 PM

Category: Genetic Diseases of the Kidney

• 801 Cystic Kidney Diseases

Authors

• Snoek, Rozemarijn, University Medical Center Utrecht, Utrecht, Netherlands

Rozemarijn Snoek, MD



PhD-student in the nephrogenetics research group of prof. Nine Knoers (Utrecht, the Netherlands), working on genetic causes for end-stage renal disease in adults.

• Van setten, Jessica, University Medical Center Utrecht, Utrecht, Netherlands

Jessica Van setten,

• Van der zwaag, Bert, University Medical Center Utrecht, Utrecht, Netherlands

Bert Van der zwaag,

• Keating, Brendan, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Brendan Keating,

• Knoers, Nine V., University Medical Center Utrecht, Utrecht, Netherlands

Nine V. Knoers,

• De Borst, Martin H., University Medical Center Groningen, Groningen, Netherlands

Martin H. De Borst,

• van Eerde, Albertien M., University Medical Center Utrecht, Utrecht, Netherlands

Albertien M. van Eerde,

Group or Team Name

• International Genetics & Translational Research in Transplantation Network

Background

Nephronophthisis (NPH) is the most prevalent (15%) genetic cause for end-stage renal disease (ESRD) in children. ~16% is caused by homozygous full gene deletions of the autosomal recessive NPHP1 gene. However, little is known about the prevalence of these mutations in adult-onset ESRD. With data generated to perform genome-wide association studies in adult-onset ESRD patients, we aimed to determine the prevalence of homozygous NPHP1 full gene deletions.

Methods

Renal transplant recipients were genotyped using the Affymetrix Axiom Tx GWAS Array, containing ~780,000 markers accross the genome with probes to cover a priori copy number variant (CNV) regions. CNVs (e.g. deletions and duplications) were determined based on median log2 ratios and B-allele frequency patterns. All findings were independently validated.
In this abstract we report on 1272 cases, all Caucasian, from the TransplantLines-Genetics cohort. As we are currently analyzing ~4300 additional samples of various ethnicities, from the DeKAF Genomics, GoCAR, Dublin and Vienna cohorts (part of iGeneTRAiN), we will soon be able to report on ~5500 cases.
Cases are included in the analysis when they had adult-onset ESRD, defined as start of renal replacement therapy (RRT) at any age ≧18 years.

Results

1250 cases in the TransplantLines-Genetics cohort met the age criteria, of whom 11 (0.9%) showed a homozygous deletion of the NPHP1 gene. Median age at start of RRT was 35 years (range 18-42), with eight cases aged ≧30. Notably only three out of 11 cases (27%) were diagnosed as having NPH. The other cases (8/11, 73%) were noted as chronic kidney disease with unknown etiology (n=5), glomerulonephritis (n=1), sporadic primary reflux nephropathy (n=1) and autosomal dominant polycystic kidney disease (n=1).

Conclusion

NPH is a classical pediatric kidney disease. However, we show that homozygous NPHP1 full gene deletions alone cause 0.9% of all adult-onset ESRD in our dataset, with the majority of NPHP1 cases ≧30 years of age. Considering that other types of mutations in NPHP1 were not analyzed, and the other 19 known NPH genes were not even investigated, NPH is a relatively frequent cause of adult-onset ESRD. As only 27% of NPHP1 cases were registered clinically as NPH, these results warrant wider application of genetic testing in adult-onset ESRD.