Abstract
Objective
To evaluate metabolic and genetic abnormalities in children with nephrolithiasis attending a referral center in North India.
Methods
The patients aged 1–18 y old with nephrolithiasis underwent biochemical evaluation and whole-exome sequencing. The authors evaluated for monogenic variants in 56 genes and compared allele frequency of 39 reported polymorphisms between patients and 1739 controls from the GenomeAsia 100 K database.
Results
Fifty-four patients, aged 9.1 ± 3.7 y were included. Stones were bilateral in 42.6%, familial in 33.3%, and recurrent in 25.9%. The most common metabolic abnormalities were hypercalciuria (35.2%), hyperoxaluria (24.1%), or both (11.1%), while xanthinuria (n = 3), cystinuria (n = 1), and hyperuricosuria (n = 1) were rare. Exome sequencing identified an etiology in 6 (11.1%) patients with pathogenic/likely pathogenic causative variants. Three variants in MOCOS and one in ATP7B were pathogenic; likely pathogenic variants included MOCOS (n = 2), AGXT, and SLC7A9 (n = 1, each). Causality was not attributed to two SLC34A1 likely pathogenic variants, due to lack of matching phenotype and dominant family history. Compared to controls, allele frequency of the polymorphism TRPV5 rs4252402 was significantly higher in familial stone disease (allele frequency 0.47 versus 0.53; OR 3.2, p = 0.0001).
Conclusion
The chief metabolic abnormalities were hypercalciuria and hyperoxaluria. A monogenic etiology was identified in 11% with pathogenic or likely pathogenic variants using a gene panel for nephrolithiasis. Heterozygous missense variants in the sodium-phosphate cotransporter SLC34A1 were common and required evaluation for attributing pathogenicity. Rare polymorphisms in TRPV5 might increase the risk of familial stones. These findings suggest that a combination of metabolic and genetic evaluation is useful for determining the etiology of nephrolithiasis.
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AM, PK: Collection, analysis and interpretation of clinical and sequencing data, manuscript preparation, clinical care; TSG, SM: Genetic sequencing and bioinformatic analysis; JM: Data collection and clinical care; A Seth, A Sinha, MJ, RK, PH: Critical revision of the manuscript, clinical care; AB: Conceptualization and design of the study, manuscript revision for important intellectual content. The final manuscript was approved by all authors. AB will act as the guarantor for this paper.
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Mandal, A., Khandelwal, P., Geetha, T.S. et al. Metabolic and Genetic Evaluation in Children with Nephrolithiasis. Indian J Pediatr 89, 1243–1250 (2022). https://doi.org/10.1007/s12098-022-04234-9
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DOI: https://doi.org/10.1007/s12098-022-04234-9