Understanding the clinical genetics of kidney stone disease using the Natera Renasight panel

We aimed to characterize the underlying genetics of kidney stone disease (KSD) in an urban and diverse population using the Natera Renasight genetic panel. This was a single-center prospective study of high-risk KSD patients, defined as recurrent stone formers or those with a family history with KSD. Buccal saliva DNA samples were collected with the commercially available Natera Renasight genetic panel and were analyzed using next-generation sequencing. The panel assesses 385 kidney disease related genes, including 45 linked to KSD. One hundred eleven high-risk KSD patients were enrolled. The majority were female (56%) with a median age of 50 (IQR 39.5–59.5), compromising a diverse ethnic background with 62% Hispanic, 23% White and 11% Black. Patients had median 3 (IQR 2–5) lifetime stone episodes, and 41% had family history of KSD. Genetic analysis was possible for 105 patients (95%). Eight (8%) had positive tests with only one patient found to have a pathogenic mutation associated with KSD (SLC7A9, cystinuria). The other 7 positive tests included amyloidosis (TTR, N = 3), Alport syndrome (COL4A3, N = 2), polycystic kidney disease (PKD1, N = 1), and susceptibility to ESRD (APOL1, N = 1). Patients with positive tests were more likely to have chronic kidney disease (38% vs 5%, p < 0.01), gout (13% vs 1%, p = 0.02) and carbonate apatite stones (38% vs 7%, p < 0.01). Our study sheds light on genetic factors of KSD in a diverse patient population. The results suggest that KSD is unlikely monogenetic in nature, but is more likely due to a complex interplay of polygenetic and environmental influences. Genetic testing may be most useful in KSD patients with chronic kidney disease.