What question did this study set out to answer?

The study aims to assess the prognostic significance of rare genetic variants associated with kidney stone disease in adults.

March 4, 2026Open Access

Deep biochemical phenotyping reveals prognostic value of rare genetic variants in adult kidney stone disease

Key Points

The study aims to assess the prognostic significance of rare genetic variants associated with kidney stone disease in adults.
Conducted a longitudinal observational study within the Swiss Kidney Stone Cohort.
Analyzed blood and urine samples from kidney stone formers and non-kidney stone formers over three years.
Performed whole-exome sequencing to identify rare genetic variants in established kidney stone disease genes.
Classified variants using ACMG/AMP criteria and correlated with biochemical phenotyping results.
Identified rare pathogenic variants in 6.8% of kidney stone formers, correlating with increased disease risk.
Heterozygous LP/P SLC34A3 variants significantly increased hyperphosphaturia in affected individuals.
Monoallelic LP/P variants in specific genes did not show expected biochemical alterations, challenging their causative role.
Monoallelic SLC7A9 variants were identified as intermediate risk factors, influencing biochemical changes but not strongly linked to disease occurrence.
Presence of strong genetic risk factors correlated with increased kidney stone recurrence over three years.

Abstract

BACKGROUNDKidney 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.METHODSThe 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.RESULTSCollectively, 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.CONCLUSIONSCorrelation of genetic findings with thorough biochemical phenotyping and comparison with NKSFs redefines the clinical relevance of variants in KSD genes and has prognostic value.

Deep biochemical phenotyping reveals prognostic value of rare genetic variants in adult kidney stone disease

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Abstract

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