Abstract
BACKGROUND Kidney stone disease (KSD) affects approximately 10% of the population. While genetic factors are known to play a role in KSD, determining the clinical relevance of rare variants in KSD genes identified in adults remains challenging.METHODS The Swiss Kidney Stone Cohort is a multicenter longitudinal, observational study consisting of kidney stone formers (KSFs) (n = 701) and non-kidney stone formers (NKSFs) (n = 200). Blood and urine samples were collected at enrollment and over 3 years for deep biochemical phenotyping. Results were correlated with rare genetic variants in established KSD genes identified through whole-exome sequencing and classified according to American College of Medical Genetics and Genomics and the Association of Molecular Pathology (ACMG/AMP) criteria.RESULTS Collectively, we found rare (likely) pathogenic (LP/P) variants representing strong KSD risk factors in 6.8% of KSFs, predominantly in genes involved in renal phosphate handling and cystinuria. Detailed biochemical analyses confirmed that KSFs carrying heterozygous LP/P SLC34A3 variants exhibited significant hyperphosphaturia. In contrast, monoallelic LP/P variants in SLC34A1, SLC9A3R1, or CYP24A1, which were also frequent in NKSFs, did not result in the expected biochemical alterations, calling into question their causative role as strong KSD risk factors. In cystinuria, monoallelic SLC7A9 variants represented intermediate risk factors, since they caused biochemical alterations but required additional factors for KSD occurrence, based on frequent LP/P variants in NKSFs. The presence of strong risk factors was associated with higher kidney stone (KS) recurrence over the 3-year observation period, supporting a predictive value for genetic testing.CONCLUSIONS Correlation of genetic findings with thorough biochemical phenotyping and comparison with NKSFs redefines the clinical relevance of variants in KSD genes and has prognostic value.
Authors
Johannes Münch, Jana Petrovska, Joana Figueiro-Silva, Isabel Rubio-Aliaga, Elena M. Cabello, Ivan Ivanovski, Michael Papik, Beatrice Oneda, Daniel G. Fuster, Harald Seeger, Thomas Ernandez, Florian Buchkremer, Gregoire Wuerzner, Nasser A. Dhayat, Alexander Ritter, Stephan Segerer, Beat Roth, Anita Rauch, Pietro Manuel Ferraro, Olivier Bonny, Carsten A. Wagner, Ruxandra Bachmann-Gagescu
Figure 4
The presence of LP/P variants in KSD genes is associated with higher KS recurrence.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)