Prevalence and characteristics of monogenic disease in adult kidney stone formers

Anderegg, Manuel A.; Olinger, Eric G.; Bargagli, Matteo; Geraghty, Rob; Pohlmeier, Lea; Nater, Alexander; Bruggmann, Rémy; Sayer, John A.; Vogt, Bruno; Schaller, André; Fuster, Daniel G. (27 July 2023). Prevalence and characteristics of monogenic disease in adult kidney stone formers (medRxiv). Cold Spring Harbor Laboratory 10.1101/2023.07.23.23292924

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Molecular mechanisms of kidney stone formation remain unknown in most patients. Previous studies showed a high heritability of nephrolithiasis, but data on prevalence and characteristics of monogenic disease in unselected adults with nephrolithiasis are lacking.

We performed whole exome sequencing in 787 participants of the Bern Kidney Stone Registry, an unselected cohort of adults with ≥ 1 past kidney stone episode (KSF), and 114 non-stone- forming individuals (NKSF). A panel of 34 established nephrolithiasis genes was analyzed and variants were assessed according to ACMG criteria. Pathogenic or likely pathogenic variants were considered diagnostic.

Mean age of KSF was 47±15 years, and 18 % were first time KSF. A monogenic kidney stone disease was present in 8.4 % (66 of 787) of KSF and in 0.9 % (1 of 114) of NKSF. The most common genetic diagnoses were cystinuria (SLC3A1, SLC7A9; n=16), renal phosphate wasting (SLC34A1 or SLC34A3; n=20), Vitamin D-24 hydroxylase deficiency (CYP24A1; n=13) and renal magnesium wasting with hypercalciuria (CLDN16; n=8). KSF with monogenic disease had a lower mean age at the first stone event (30±14 years vs. 36±14 years, p=0.003), were more likely to have cystine stones (23.4 % vs. 1.4 %) and less likely to have calcium oxalate monohydrates stones (31.9 % vs. 52.5 %) compared to KSF without genetic diagnosis. All other clinical parameters were similar between the two groups.

Thus, monogenic disease is prevalent in unselected adult KSF. The usefulness of clinical parameters for the prediction of monogenic disease is limited in adult KSF.

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