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. 2025 May 30;40(6):1225-1233.
doi: 10.1093/ndt/gfae270.

Genetic testing in a national cohort of adults with chronic kidney disease of unknown origin

Amber de Haan  1 , Mark Eijgelsheim  1 , Liffert Vogt  2 , Ewout J Hoorn  3 , Joris I Rotmans  4 , Gijs Fortrie  5 , Roos F J Marsman  2 , Tonia C Rothuizen  6 , H Siebe Spijker  4 , Laura R Claus  7 , Constantijn J A M Konings  8 , Femke Waanders  9 , Joan Doornebal  9 , Andrea B Kramer  10 , Aaltje Y Adema  11 , Bert van der Zwaag  7 , Albertien M van Eerde  7 , Nine V A M Knoers  12 , Martin H de Borst  1
Affiliations

Genetic testing in a national cohort of adults with chronic kidney disease of unknown origin

Amber de Haan et al. Nephrol Dial Transplant. .

Abstract

Background: Chronic kidney disease (CKD) remains unexplained in at least 20% of patients. Massively parallel sequencing (MPS) can be a valuable diagnostic tool in patients with unexplained CKD, but prospective data from routine clinical practice are limited. We aimed to determine the diagnostic yield and relevance of MPS-based gene panel testing in patients with unexplained CKD in a real-world context. We additionally examined barriers to implementation of genetic testing.

Methods: In this prospective cohort study, we recruited patients with unexplained CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2 without underlying clinical diagnosis) with onset at <50 years of age who underwent MPS-based multigene panel testing from 11 academic and non-academic hospitals across the Netherlands. In patients with a (likely) pathogenic variant, we verified that the variant likely explained the clinical phenotype. A nationwide online survey was sent to all Dutch nephrologists and residents to investigate potential barriers for gene panel testing.

Results: A diagnostic variant was identified in 59/340 participants (17%). Most common diagnostic variants were in NPHP1 (13 patients), COL4A3 (12 patients), COL4A4 (5 patients), COL4A5 (6 patients) and PAX2 (5 patients). A genetic diagnosis led to at least one clinical consequence in 73% of patients. Main barriers reported by Dutch nephrologists (N = 71) included genetic illiteracy (53%), difficulties with test selection (51%) and a lack of time (43%).

Conclusions: MPS-based multigene panel testing yielded a genetic diagnosis in 17% of patients with unexplained CKD. Our findings support the relevance of MPS in the diagnostic workup of adults with unexplained CKD with onset at <50 years of age. Additionally, our results underline the need to improve genetic education among nephrologists to better the implementation of MPS-based diagnostic testing in clinical practice.

Keywords: chronic kidney disease; diagnostic yield; exome sequencing; genetics; massively parallel sequencing.

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