#3320 GENETIC TESTING FOR MOLECULAR DIAGNOSIS OF NEPHROLITHIASIS AND NEPHROCALCINOSIS IN ADULT PATIENTS: A SINGLE-CENTER COHORT
Authors: Rusu Elena Emanuela , Lungu Adrian Catalin , Pandele Gabriel-Robert , Iordache Alexandru , Bobeica Raluca , Ciobotaru Lucia Mihaela , Balanica Sonia , Zilisteanu Diana , Blaga Andreea , Costea George Claudiu , Ismail Gener 
Published: June 2023

Abstract

Background and Aims
Hereditary factors represent an important cause of nephrolithiasis which will generate stone disease in adult. Molecular analysis in patients with nephrolithiasis (NL) and/or nephrocalcinosis (NC) for a genetic mutation has become more accessible and the benefits are highlighted by an increasing number of publications. The aim of the paper was to study genetic screening for 36 NL and/or NC patients in order to identify the cases that can be confirmed by mutations in known kidney stone genes.

Method
Between 2020–2022 we included 35 adult patients with NL/NC with onset on pediatric age or in young adults, plus one of the following criteria: family history for NL/NC, indicative phenotype, recurrent NL. All the patients were diagnosed with NL and/or NC by ultrasound or computed tomography scan. Inform consent was signed and dated before blood samples and we performed genetic testing using nephrolithiasis panel (that include 45 genes) from 2 laboratories. In addition, we performed clinical assessment in a multidisciplinary team, underwent metabolic assessment, and caring out the genealogical tree.

Results
The study included 18 females and 17 males. The mean age of studied patients was 34.9 ± 10.3 years (range 18 – 54 years), although mean age of NL/NC diagnosis was 19.4 ± 12.0 years (range 0.5 – 34 years). 29 patients presented NL of any type, 12 patients presented both NL and NC, and 3 patients isolated NC. All the patients presented positive family history of NL/NC, 17 (48.5%) patients had pediatric age of onset, 17 (48.5%) patients presented indicative phenotype and 19 (54.2%) recurrent stone disease. Causative monogenic mutations were detected in 25 of 35 NL/NC. We identified 20 deleterious variants in 12 out of 45 analyzed genes. Genetic testing was positive with a definite diagnosis (had pathogenic variant) in 17 (48.6%) of cases, while 3 (8.6%) patients presented likely pathogenic variants, and 5 (14.3%) patients had variants of uncertain significance (VUS). In our cohort, the most common cause of kidney stone disease was cystine nephrolithiasis in 8 (22.8%) patients, followed by hereditary distal renal tubular acidosis in 4 patients, Dent disease in 3 patients, primary hyperoxaluria type 1 in 2 patients, familial hypomagnesaemia with hypercalciuria and nephrocalcinosis in 2 patients. Other causes of kidney stone disease included: renal hypouricemia type 1, hereditary hypophosphatemic rickets with hypercalciuria, primary mitochondrial disorders, autosomal dominant familial idiopathic hypercalciuria, Bartter syndrome type 3, and autosomal dominant tubulo-interstitial disease with hyperuricemia. Pathogenic mutations were detected in the following 5 dominant disease genes: SLC7A9 (4 patients), SLC4A1 (3 patients), ADCY10 (1 patient), HNF1B (2 patients), POLG (1 patient). Also, we identified pathogenic mutations in the following 7 recessive disease genes: CLCN5 (3 patients), AGXT (2 patients), CLDN16 (2 patients), SLC3A1 (3 patients), SLC34A3 (1 patient), WDR72 (1 patient), CLCNKB (1 patient). The mean eGFR for the study group was 71.2 ± 37.6 ml/min/1.72 m2. Seventeen patients presented eGFR &lt; 60 ml/min/1.73 m2: seven patients CKD stage 3, four patients CKD stage 4, two patients CKD stage 5, and two patients were with renal replacement therapy.

Conclusion
Genetic kidney stone disease is an underdiagnosed condition. Although 48.5% of the patients had NL/NC onset on pediatric age, the molecular diagnosis was performed in adulthood, and, for some of them, when they suffer of advanced kidney disease. In our cohort, genetic testing had a high rate of positive molecular diagnosis of NL/NC due to selection criteria. Five of our patients presented VUS, but with disease-specific phenotype. We emphasize the importance of reporting these cases to generate additional evidence that could allow the reclassification of these variants. We conclude that the molecular diagnosis improves patient management, prevent or delay chronic kidney disease, offer possibility of genetic counseling and an extended screening to the family. Thus, our study showed the potential benefits of genetic testing, especially in high-risk groups for stone disease.