Exome sequencing in patients with medullary sponge kidney

BACKGROUND: Medullary sponge kidney (MSK) is characterized by precalyceal dilatation of the renal tubules. This entity is associated with recurrent kidney stone disease (KSD). Although etiopathogenesis is unknown, genetic origin is suspected. HYPOTHESIS: The aim of the study was to describe the variants identified in genes associated with urolithiasis and/or cystic kidney disease in MSK using whole-exome sequencing (WES) in patients diagnosed with MSK.Moreover, one hypothesis supported by the only available genetic cohort study is that MSK is due to disruptions in kidney organogenesis involving the GDNF, RET, or GFRα1 genes. We wanted to test that hypothesis in our population. METHODS: WES was performed between January 2023 and June 2024 in 42 patients diagnosed with MSK. The pathogenicity was assessed using American College of Medical Genetics guidelinesPositive WES group was defined by one or more "likely pathogenic" or "pathogenic"' variants in genes associated with monoallelic urolithiasis and/or cystic kidney disease and/or already described in MSK according to the mode of inheritance.We also searched for rare truncating and missense variants in the RET, GDNF, and GFRα1 from a variant datastore which contains unsorted and unfiltered WES results from ∼8000 French patients. We then checked whether the patients identified had an MSK phenotype. RESULTS: Ten patients were identified as WES-positive, involving nine genes: IFT140, PRKCSH, PKHD1, SLC34A3, SLC34A1, SLC26A1, UMOD, COL4A3, and MT-TL1. A total of 140 rare variants of RET (n = 107), GDNF (n = 11), and GFR α1 (n = 22) were identified in the variant datastore, none was associated with MSK. CONCLUSIONS: MSK was associated with a diverse set of genes related to KSD and/or cystic kidney diseases that underscore the heterogeneity of MSK, both in its presentation and its underlying genetic basis. MSK may represent a macroscopic phenotype with polygenic origins rather than a distinct entity.