Genetic testing enables a precision medicine approach for nephrolithiasis and nephrocalcinosis in pediatrics: a single-center cohort

Abstract

Objective Hereditary factors are the main cause of pediatric nephrolithiasis (NL)/nephrocalcinosis (NC). We summarized the genotype–phenotype correlation of hereditary NL/NC in our center, to evaluate the role of genetic testing in early diagnosis. Methods The clinical data of 32 NL/NC cases, which were suspected to have an inherited basis, were retrospectively analyzed from May 2017 to August 2020. The trio-whole exome sequencing was used as the main approach for genetic testing, variants were confirmed by Sanger sequencing, and pathogenicity analysis according to protein function was predicted with custom-developed software. Results Causative monogenic mutations were detected in 24 of 32 NL/NC patients, and copy number variation was detected in one patient. A summary of manifestations in patients with inherited diseases revealed a significant degree of growth retardation, increased urinary excretion of the low-molecular weight protein, hypercalciuria, electrolyte imbalances, and young age of onset to be common in heredity disease. In addition, some patients had abnormal renal function (3 ppm 25). The most frequent pathology identified was distal renal tubular acidosis (with inclusion of SLC4A1, ATP6V1B1, and ATP6VOA4 genes), followed by Dent disease (CLCN5 and OCRL1 genes), primary hyperoxaluria (PH) (AGXT and HOGA1 genes) and Kabuki syndrome (KMT2D gene), which was more likely to present as NC or recurrent stone and having a higher correlation with a specific biochemical phenotype and extrarenal phenotype. Conclusion The etiology of NL/NC is heterogeneous. This study explored in depth the relationship between phenotype and genotype in 32 patients, and confirmed that genetic testing and clinical phenotype evaluation enable the precision medicine approach to treating patients.

The role of genetic testing in the diagnostic workflow of pediatric patients with kidney diseases: the experience of a single institution

“…Overall, these results confirm the relevance of including routine genetic testing and counselling in the diagnostic workflow of pediatric patients affected by nephropathies Ciliopathies 74.4 § 23.9 [19] 78 [20] 47.7 [21] Glomerulopathies 24.2 § 7.2 [19] 62 [20] Nephrolithiasis 45.5 § 14.9 [22] 16.8 [23] 29.4 [24] 33 [25] 75 [26] Tubulopathies 45 § 64 [27] 61.1 [21] Others 7.1 § 28.6 [21] where a monogenic condition is suspected or with a positive family history. For these patients genetic testing should be considered at the beginning of their diagnostic journey, as it may improve clinical management, spare unnecessary treatments, or diagnostic procedures, identify other family members potentially at risk of having the same genetic variants and, in case of kidney transplant, lead to optimal live-donor selection.…”

A molecular journey on the pathogenesis of primary hyperoxaluria

“…Both approaches present major shortcomings as Vitamin B6 is poorly effective, while liver transplant comes with numerous side-effects [21 & ]. In the last decade, the in-depth analysis of the pathways generating endogenous oxalate have led to the approval of two novel drugs based on RNA silencing that target either GO or LDH [ Although the new therapies have dramatically improved the prognosis of PH1 patients, their high costs and the individual different responsiveness [34] have highlighted the problem of correct diagnosis and patient stratification [35][36][37]. Indeed, the molecular pathogenesis of PH1 is quite complex.…”

“…Although the new therapies have dramatically improved the prognosis of PH1 patients, their high costs and the individual different responsiveness [34] have highlighted the problem of correct diagnosis and patient stratification [35–37]. Indeed, the molecular pathogenesis of PH1 is quite complex.…”

Navigating the Evolving Landscape of Primary Hyperoxaluria: Traditional Management Defied by the Rise of Novel Molecular Drugs

“…The latest consensus statement on PHs from OxalEurope and the European Rare Kidney Disease Reference Network (ERKNet), published in 2023, emphasizes that genetic testing is the definitive diagnostic gold standard for all PH types [8]. The effective integration of genetic testing and clinical phenotype assessment enhances the application of precision medicine [21]. A daily urine oxalate level exceeding 1 mmol/1.73 m 2 strongly indicates PH.…”