Integration of metabolic evaluation and exome sequencing for the diagnosis of children with urolithiasis

Abstract

Metabolic evaluation and exome sequencing are both important etiological diagnostic methods for pediatric urolithiasis. There is a lack of integrated analysis of metabolic evaluation and exome sequencing in a pediatric urolithiasis cohort. A retrospective analysis of both metabolic and genomic data was performed for the first 105 pediatric urolithiasis patients who underwent exome sequencing at our hospital from February 2016 to October 2018. Measurements included the diagnostic yield of exome sequencing and the conformity between molecular diagnoses and metabolic evaluation. Exploratory data analyses were performed to compare the phenotypic differences between cases with positive and negative genetic findings. The present study involved a cohort of 105 pediatric patients with urolithiasis, from which diagnostic variants were identified in 37 patients (35%). In subgroup analyses, 39% hyperoxaluria cases are primary hyperoxaluria caused by monogenic defects, and 100% of the causes of cystine stones can be explained by monogenic defects. However, no appropriate inherited causes were identified for hypocitraturia, hypercalciuria, and hyperuricosuria in the cohort. A high conformity (100%) between molecular diagnoses and metabolic evaluation was obtained. Compared with negative cases, cases with positive genetic findings were correlated with an early onset age (median difference: -1.25 yr; 95% CI: -2.33 to -0.33, P < 0.001), a lower eGFR (median difference: -25 ml/min/1.73 m2; 95% CI: -41 to -9, P = 0.002), and a more severe stone burden (odds ratio: 10.7; 95% CI: 4.13 to 27.7, P < 0.001). Exome sequencing is an effective and reliable diagnostic method for inherited urolithiasis in children, and the molecular diagnostic yield varies greatly across different metabolic abnormalities. Early onset, lower eGFR, or severe stone burden are “red flag” conditions, suggestive of inherited urolithiasis.