Prevalence and characteristics of monogenic disease in adult kidney stone formers

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement MAA was supported by a grant for protected research time by the InselGruppe. EGO was supported by Postdoc MobilityStipendien of the Swiss National Science Foundation (grants # P2ZHP3\_195181 and P500PB\_206851), and Kidney Research UK ((grants # Paed\_RP\_001\_20180925). DGF was supported by the Swiss National Science Foundation (grants # 31003A\_172974 and 33IC30\_166785/1) and the Swiss National Centre of Competence in Research Kidney.CH. JAS is supported by the Northern Counties Kidney Research Fund (22/01), Kidney Research UK (Paed\_RP\_001\_20180925), LifeArc, and the Medical Research Council (MR/Y007808/1). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethical committee of the Kanton of Bern gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data supporting the findings of the present study are available upon reasonable request to the corresponding author.