Genetic causes of nephrolithiasis and nephrocalcinosis in a pediatric population in Saudi Arabia

Nephrolithiasis (NL) and nephrocalcinosis (NC) are common, recurrent conditions globally. While monogenic causes are increasingly recognized, data on their prevalence and spectrum remain limited in Saudi pediatric populations.

This retrospective cross-sectional study was conducted in our tertiary care center from January 2008 to April 2023. Pediatric patients (0-18 years) with radiologically confirmed NL/NC who underwent genetic testing were included. Clinical, biochemical, radiological, and genetic data were analyzed. Genetic variants were classified using ACMG criteria, and segregation analysis was performed when available.

Of 186 pediatric patients diagnosed with NL/NC, 54 (29.03%) underwent genetic testing. Median age at diagnosis was 3 months [IQR: 3-60], with median follow-up 56 months [IQR: 24-108]. Genetic mutations related to NL/NC were identified in 35/54 patients (64.81%), most commonly in CLDN16 (28.57%), SLC2A2 (17.14%), AGXT (11.43%), and SLC12A1 (8.57%). Thirteen novel variants were identified, with eleven linked to NL/NC phenotypes. Eight patients (14.81%) developed kidney failure requiring kidney replacement therapy; CLDN16 was significantly associated with kidney failure and transplant (P = 0.003), and AGXT with liver transplant (P < 0.001). Notably, the MOCS1 gene was found in a patient with early-onset neurological symptoms, hypouricemia, and later confirmed NL/NC.

Monogenic causes were identified in 35 of 54 (64.81%) Saudi pediatric patients with NL/NC who underwent genetic testing, a prevalence higher than reported internationally, likely due to the high consanguinity rate. Our findings underscore the importance of genetic testing in early-onset NL/NC. We recommend adding MOCS1 to the list of genes associated with monogenic NL/NC.