Prevalence of Monogenic Aetiologies of Kidney Stone Disease in Selected and Unselected Kidney Stone Cohorts

Background and objectiveKidney stone disease (KSD) is common and distinct monogenic forms with well-defined treatment pathways exist. However, it is unclear which patients should undergo genetic testing and the significance of monoallelic variants in SLC34A1, SLC34A3, CYP24A1, SLC7A9, and SLC3A1. We aimed to define monogenic KSD inheritance patterns, determine the diagnostic yield of genetic testing in selected and unselected cohorts, and establish the utility of standard serum biochemistry in highlighting those at risk of monogenic KSD. MethodsWe compared genetic and phenotypic data from individuals with and without KSD in the UK Biobank to determine inheritance patterns. We established the "number needed to test" (NNTT) to identify monogenic KSD in the UK Biobank and a specialist adult kidney stone nephrology clinic where patients had genetic testing based on age, recurrence, and family history. We examined the utility of standard serum biochemistry in identifying monogenic KSD in both settings. Key findings and limitationsMonogenic KSD associated with SLC34A3, SLC7A9, and SLC3A1 is inherited in an autosomal dominant manner and monogenic KSD associated with SLC34A1 and CYP24A1 in an autosomal recessive manner. A monogenic diagnosis was made in [~]1% of KSD in the UK Biobank (NNTT[~]90) and 15% of KSD in a specialist nephrology clinic (NNTT[~]7). In both settings, standard serum biochemistry failed to identify individuals at risk of monogenic KSD. Conclusions and clinical implicationsGenetic testing for monogenic KSD has utility in specialist settings where there is clinical suspicion of an inherited disorder even in the absence of biochemical abnormalities.