Variants of Unknown Significance Are Common in Brushite Stone Formers Undergoing Genetic Testing for Nephrolithiasis

Historically, medical studies have sought to identify therapies that worked for most patients to guide treatment recommendations. Yet, even with meticulous interviews, examinations, and testing, this approach still does not consider all patient and disease-specific factors. In stone disease specifically, patients with apparently similar metabolic profiles often experience very different recurrence patterns, procedural burden, and treatment responses, suggesting that conventional clinical evaluation alone may not fully capture disease biology. Incorporating additional data elements may allow for a more tailored, “precision” medicine approach to be employed when making treatment decisions. Rather than asking, “Does this work for most?” the question can be reframed as “Will this work for you?”

Precision medicine has largely been explored to date via medical genetics. With improvements in sequencing efficiency and cost, the threshold to perform genetic testing has been significantly lowered. The most robust literature regarding the impact of genetic testing on treatment has come from the urologic oncology literature. Genetic evaluation now has a role in the assessment of tumor aggressiveness in prostate cancer and has even led to the development of novel therapeutics for prostate (BRCA) and urothelial (FGFR3-mutated) cancers. Yet, this type of exploration has been limited to the oncologic arenas of urology.

In this pilot study, we sought to assess the rate of genetic variants in brushite kidney stone formers. We chose brushite stone formers due to their particularly aggressive clinical phenotype, often associated with marked hypercalciuria, frequent recurrence, resistance to shock wave lithotripsy, and substantial procedural burden over time. All of these make an especially compelling group to explore possible genetic drivers. Fifteen patients were recruited (non-randomized) from our clinical practice and underwent phlebotomy. Blood samples underwent testing for 37 genes as part of the ‘Nephrolithiasis/Nephrocalcinosis’ sub-panel of the KidneySeqTM renal genetic testing (Iowa Institute of Human Genomics, Iowa City, IA), an accredited, CLIA-certified, commercially available test. Patient-level data were also abstracted from the electronic medical record.

We identified 12 of 15 (80%) patients harbored a genetic variant, and 6 patients (40%) had multiple variants. Interestingly, 10 (67%) had a variant associated with hypophosphatemic rickets, and 6 were specifically SLC34A3 variants (those associated with hypophosphatemic rickets with hypercalciuria). While the cohort was small, the degree of clustering around phosphate-handling pathways is biologically intriguing and raises the possibility that brushite stone formation may reflect a more specific molecular phenotype than previously appreciated. Additionally, in the subset with available 24hr urines, there were notable differences in the 24-hour urine parameters based upon whether the variant was SLC34A3 or not (specifically, higher volume, calcium, and lower phosphorus were noted in the SLC34A3 group).¹

While this is only pilot data, it is exciting to see the identification of a phenotype (brushite stones) with a genotype pattern (variants for hypophosphatemic rickets). We acknowledge the hypothesis-generating nature of this work and recognize that it does not mean all patients with stone disease should undergo genetic testing. However, if confirmed in larger studies, future stone evaluation may increasingly incorporate genotype alongside stone composition and metabolic testing to better define recurrence risk and guide individualized prevention strategies, particularly in difficult-to-manage populations.

Written by: Ryan L. Steinberg, MD, and Chad R. Tracy, MD

Department of Urology, University of Iowa Health Care, Iowa City, IA

Reference:

Paneque T, Berst K, Sambharia M, Swee M, Kimble M, Mansilla MA, et al. Variants of unknown significance are common in brushite stone formers undergoing genetic testing for nephrolithiasis. Urolithiasis. 2025;53(1):183.

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