Variants of unknown significance are common in brushite stone formers undergoing genetic testing for nephrolithiasis.

Abstract

Up to 40% of all kidney stone disease may have an underlying genetic contribution. Brushite stone formers are known to have high rates of stone recurrence and urine chemistry abnormalities, suggesting a possible intrinsic kidney abnormality which may contribute to brushite stone formation. In this study, we sought to determine the burden of genetic variants amongst brushite stone formers. An IRB approved prospective study of brushite stone formers was conducted. Patients with any brushite on stone analysis were eligible for enrollment. Genetic testing was done on peripheral blood derived DNA and assessed using a clinically available nephrolithiasis gene panel. Primary analysis assessed rates of genetic variants amongst brushite stone formers. Secondary analysis assessed for distinct patterns in urine chemistries in different genotypes. 15 patients (8 males) with a median age of 32 years (range 22-69) underwent genetic testing. 12 patients (80%) were reported to have a genetic variant, with 6 (40%) having multiple variants. Two patients had a heterozygous pathogenic or likely pathogenic variant in a gene that causes autosomal recessive disease. 9 (60%) patients had a variant of unknown significance. 10 (67%) patients had genetic variants associated with hypophosphatemic rickets. Genetic variants of unknown significance are common in brushite stone formers. Further work is needed to assess the significance of these variants and their role in the lithogenic process.