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Kidney Week

Abstract: SA-PO536

Diagnostic Yield of Massively Parallel Sequencing in Patients With CKD of Unknown Etiology: The Dutch Nationwide Prospective VARIETY Cohort Study

Session Information

  • Genetic Diseases: Diagnosis
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic


  • de Haan, Amber, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Eijgelsheim, Mark, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Vogt, Liffert, Amsterdam UMC Locatie AMC, Amsterdam, North Holland, Netherlands
  • Hoorn, Ewout J., Erasmus MC, Rotterdam, Zuid-Holland, Netherlands
  • Rotmans, Joris I., Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • van Eerde, Albertien M., Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
  • Knoers, Nine V., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • De Borst, Martin H., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

The cause of chronic kidney disease (CKD) remains unknown in at least 20% of patients. While retrospective studies, most in research setting, indicate that massively parallel sequencing (MPS) may lead to a genetic diagnosis in 12-56% of patients with unexplained CKD, the diagnostic yield in clinical practice is unclear. Here, we aimed to determine the diagnostic yield of MPS-based gene panel testing in patients with unexplained CKD in a routine healthcare setting.


A prospective nationwide observational cohort study was conducted in 13 hospitals throughout the Netherlands. Patients with unexplained CKD who had an eGFR <60mL/min/1.73 m2 before the age of 50 years were included. Informed consent was obtained from all participants. Diagnostic genetic testing was performed using the whole-exome sequencing (WES) based CKD-Y (Chronic Kidney Disease in Young patients; 256 genes) or broad hereditary kidney disease (495 genes) multi-gene panels at the University Medical Center Utrecht.


As of May 2022, 370 patients have been included (>90% of the target inclusion, n=400). In an interim analysis involving 233 patients with complete data available, mean age was 44±12 years, mean age at diagnosis CKD was 31±12 years, 39% were female, 62% had proteinuria, 24% had hematuria, 84% had hypertension, 68% had undergone kidney transplantation and 37% reported a positive family history for CKD. A diagnostic variant, defined as (likely) pathogenic variants explaining the clinical phenotype, was identified in 45/233 participants (19%). Most diagnostic variants were identified in NPHP1 (N=12), COL4A3 (N=7), COL4A4 (N=5), COL4A5 (N=4), and PAX2 (N=3). A genetic diagnosis subsequently led to at least one clinical consequence (e.g. change in therapy, search for extrarenal features, implications for transplantation, family planning/counseling,) in 75% of patients.


In this study, WES-based panel testing yielded a genetic diagnosis in 19% of cases, highlighting the relevance of MPS as a tool in the diagnostic workup of adult patients with CKD of unknown origin. Most common genetic diagnoses in this population were nephronophthisis and Alport spectrum disease. Complete data analysis (n=400) is expected by October 2022.


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