Molecular landscape of medullary nephrocalcinosis in children – a nationwide, prospective cohort study

Abstract Background This study aimed to investigate the genetic landscape and to identify predictors of a molecular diagnosis in pediatric nephrocalcinosis. Methods This prospective, nationwide cohort study enrolled 79 unrelated pediatric patients with ultrasound-based medullary nephrocalcinosis of unknown etiology. Genetic evaluation was conducted using whole-exome sequencing ( n = 75) or targeted (Sanger) sequencing ( n = 4). Only (likely)pathogenic variants were considered diagnostic. Results A molecular diagnosis of Mendelian disease (MD) was established in 16% of patients, which included infantile hypercalcemia type 1 ( CYP24A1 , n = 3) and type 2 ( SLC34A1 , n = 2), familial hypomagnesemia, hypercalciuria and nephrocalcinosis ( CLDN16 , n = 2; CLDN19 , n = 1), distal renal tubular acidosis ( ATP6V0A4 , n = 1; ATP6V1B1 , n = 1), Bartter syndrome type 2 ( KCNJ1 , n = 1) and type 3 ( CLCNKB , n = 1), and Dent disease type 1 ( CLCN5 , n = 1). Monoallelic (MA) variants, possibly predisposing to nephrocalcinosis, were found in 16% of patients, encompassing four genes, predominantly within the SLC34A1 and SLC34A3 (61%). In patients with MD, except for two patients with Bartter syndrome, typical phenotypes were observed, in contrast to carriers of MA variants, in whom the majority had subtle abnormalities. Clinical parameters, prematurity and family history for nephrocalcinosis/lithiasis were not associated with MD diagnoses. Conclusions This study clarifies the distinct genetic architecture of pediatric nephrocalcinosis. The data may possibly explain the etiology in approximately 30% of cases, when considering both MD and MA variants. Disease-specific phenotypes are associated with MD; however, the absence of typical features should not preclude a genetic diagnosis.