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Purpose: To compare the clinical characteristics of pediatric urolithiasis patients with positive and negative molecular diagnoses. Methods: The clinical characteristics corresponding to pediatric urolithiasis patients that had undergone exome sequencing at our hospital between January 2016 and May 2021 were collected. Genetic analysis results were used to separate patients into positive and negative molecular diagnosis groups. Multivariate logistic regression analyses adjusted for visiting age, sex, ethnicity, province, and body mass index were used to compare differences in medical history, diagnostic imaging findings, and renal function between individuals with and without molecular diagnoses. Results: In total, 194 patients with pediatric urolithiasis of unknown etiology underwent exome sequencing and were included in the present study, of whom 63 obtained urolithiasis-related molecular diagnoses. Relative to cases without a molecular diagnosis, those with a positive molecular diagnosis were more likely to be associated with a positive family history (OR 2.84, 95% CI 1.29–6.29, p = 0.008), consanguineous parents (OR 24.7, 95% CI 1.34–454, p = 0.002), early onset (OR 1.26, 95% CI 1.09–1.45, p < 0.001), nephrocalcinosis (OR 10.6, 95% CI 3.06–36.6, p < 0.001), cast stone (OR 18.9, 95% CI 4.40–81.1, p < 0.001), multiple stones (OR 13.9, 95% CI 6.39–30.2, p < 0.001), bilateral stones (OR 7.04, 95% CI 3.47–14.2, p < 0.001), a lower estimated glomerular filtration rate (OR 1.17, 95% CI 1.07–1.28, p < 0.001), and chronic kidney disease (OR 26.9, 95% CI 1.42–526, p < 0.001). Conclusion: A positive family history, consanguineous parents, early onset, nephrocalcinosis, severe stone burden, and impaired renal function are signals of concern that are suggestive of inherited urolithiasis. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the prevalence of inherited causes in an early onset urolithiasis cohort and each metabolic subgroup. Methods: 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 in the entire cohort and each metabolic subgroup (hyperoxaluria, hypocitraturia, hypercalciuria, hyperuricosuria and cystine stone subgroups). The conformity between molecular diagnoses and metabolic evaluation was also evaluated. Results: The present study involved a cohort of 105 pediatric patients with urolithiasis, from which diagnostic variants were identified in 38 patients (36%), including 27 primary hyperoxaluria and 11 cystinuria. In the metabolic subgroup analyses, 41% hyperoxaluria cases were primary hyperoxaluria caused by monogenic defects, and 100% of the causes of cystine stones could be explained by monogenic defects. However, no appropriate inherited causes were identified for hypocitraturia, hypercalciuria, or hyperuricosuria in the cohort. A high conformity (100%) was obtained between the molecular diagnoses and metabolic evaluation. Conclusion: Exome sequencing in a cohort of 105 pediatric patients with urolithiasis yielded a genetic diagnosis in 36% of cases and the molecular diagnostic yield varies substantially across different metabolic abnormalities. [ABSTRACT FROM AUTHOR]

[Display omitted] • Assessing variants in non-canonical splicing sites is important during the process of exome sequencing-based primary hyperoxaluria diagnosis. • Capture sequencing-based copy number variant detection should be conducted in patients undergoing exome sequencing to diagnose suspected primary hyperoxaluria. • Exome sequencing will become a standard approach to diagnosing primary hyperoxaluria in pediatric urolithiasis patients. Next generation sequencing-based exome sequencing can be used to identify genetic abnormalities in patients believed to be suffering from primary hyperoxaluria. We outline our efforts to improve the diagnostic capacity of exome sequencing for these patients. We conducted a retrospective analysis of exome sequencing data from 77 pediatric urolithiasis patients with hyperoxaluria of unknown origin. Canonical exome sequencing analysis was performed to identify pathogenic variants in three known primary hyperoxaluria-related genes (AGXT , GRHPR , HOGA1) as per the guidelines of the American College of Medical Genetics. Then, extended exome sequencing analyses of 5′-untranslated region, non-canonical splicing site and copy number variant were performed on patients with negative diagnostic results in these three genes. Canonical exome sequencing analyses led to the diagnosis of primary hyperoxaluria in 20/77 (26%) patients, including eight, four, and eight patients diagnosed with type 1, 2 and 3 primary hyperoxaluria, respectively. Non-canonical splicing site analyses discovered a pathogenic variant in the HOGA1 gene, which led to the diagnosis of six additional patients with type 3 primary hyperoxaluria, while copy number variant analyses from exome sequencing data identified a 1.8 kb copy number loss that impacted the AGXT gene, resulting in the diagnosis of an additional type 1 primary hyperoxaluria case. Extended non-canonical splicing site and copy number variant analyses improve the diagnostic yield of canonical exome sequencing analysis for primary hyperoxaluria from 26% (20/77) to 35% (27/77) in 77 pediatric urolithiasis patients with hyperoxaluria. [ABSTRACT FROM AUTHOR]