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Abstract Background and Aims Molecular mechanisms of kidney stone formation remain unknown in most patients. Previous studies showed high heritability of nephrolithiasis, but analysis of Mendelian disease in selected cohorts and genome-wide analysis were yet unable to entirely explain heritability. While prevalence of Mendelian disease in selected nephrolithiasis cohorts has already been studied, data on prevalence and characteristics of genetic disease in unselected adults with nephrolithiasis are lacking. This study was conducted to fill this important knowledge gap. Method 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). An exome-based panel of 34 established nephrolithiasis genes was analyzed and variants assessed according to ACMG criteria. Pathogenic (P) or likely pathogenic (LP) variants were considered diagnostic. Results Mean age of KSF was 47 ± 15 years, and 18% were first time KSF. A Mendelian kidney stone disease was present in 2.9% (23 of 787) of KSF. The most common genetic diagnoses were cystinuria (SLC3A1, SLC7A9; n = 13), Vitamin D-24 hydroxylase deficiency (CYP24A1; n = 5) and primary hyperoxaluria (AGXT, GRHPR, HOGA1; n = 3). 8.1% (64 of 787) of KSF were monoallelic for LP/P variants predisposing to nephrolithiasis, most frequently in SLC34A1/A3 or SLC9A3R1 (n = 37), CLDN16 (n = 8) and CYP24A1 (n = 8). KSF with Mendelian disease had a lower 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. The phenotype of KSF with variants predisposing to nephrolithiasis was subtle and showed significant overlap with KSF without diagnostic variants. In NKSF, no Mendelian disease was detected, and LP/P variants were significantly less prevalent compared to KSF (1.8% vs. 8.1%). Conclusion Mendelian disease is uncommon in unselected adult KSF, yet variants predisposing to nephrolithiasis are significantly enriched in adult KSF. While the identified variants predisposing to nephrolithiasis may explain some of the unresolved heritability, likely additional intermediate effect size variants in known and yet unknown kidney stone genes remain to be discovered for us to fully understand the genetic factors leading to the high heritability of nephrolithiasis.
Anderegg et al. (Wed,) studied this question.