Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis

Abstract

Background and objectives Nephrolithiasis is a prevalent condition that affects 10%-15% of adults in their lifetime. It is associated with high morbidity due to colicky pain, the necessity for surgical intervention, and sometimes progression to CKD. In recent years, multiple monogenic causes of nephrolithiasis and nephrocalcinosis have been identified. However, the prevalence of each monogenic gene in a pediatric renal stone cohort has not yet been extensively studied.Design, setting, participants, & measurements To determine the percentage of cases that can be explained molecularly by mutations in one of 30 known nephrolithiasis/nephrocalcinosis genes, we conducted a high-throughput exon sequencing analysis in an international cohort of 143 individuals ,18 years of age, with nephrolithiasis (n=123) or isolated nephrocalcinosis (n=20). Over 7 months, all eligible individuals at three renal stone clinics in the United States and Europe were approached for study participation.Results We detected likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 16.8% (24 of 143) of affected individuals; 12 of the 27 detected mutations were not previously described as disease causing (44.4%). We observed that in our cohort all individuals with infantile manifestation of nephrolithiasis or nephrocalcinosis had causative mutations in recessive rather than dominant monogenic genes. In individuals who manifested later in life, causative mutations in dominant genes were more frequent. ConclusionsWe present the first exclusively pediatric cohort examined for monogenic causes of nephrolithiasis/ nephrocalcinosis, and suggest that important therapeutic and preventative measures may result from mutational analysis in individuals with early manifestation of nephrolithiasis or nephrocalcinosis.

Mutational Spectrum of <b><i>CYP24A1</i></b> Gene in a Cohort of Italian Patients with Idiopathic Infantile Hypercalcemia

“…These affected patients, in addition to hypercalcemia and suppressed PTH levels, also exhibit hypophosphatemia due to renal phosphate wasting [20]. In addition, Braun et al [21] analysed by targeted next-generation sequencing 30 known genes in an international cohort with nephrolithiasis or isolated nephrocalcinosis, identifying a likely pathogenic mutation in 16.8% of affected individuals.…”

Cystinuria: A Review of Inheritance Patterns, Diagnosis, Medical Treatment and Prevention of Stones

“…Interestingly, patients with underlying mutations in SLC3A1 and SLC7A9 may sometimes present with calcium stones [9]. Genetic screening in paediatric stone formers may allow for precise diagnosis and earlier opportunities for therapeutic and preventative measures to be adopted [10].…”

Pediatric Nephrolithiasis: Trend, Evaluation and Management: A Systematic Review

“…Among them, hypercalciuria, hyperuricosuria and cystinuria make 34 to 50%, 20% and 20% of metabolic abnormalities, respectively in pediatric nephrolithiasis (36-38). In the recurrence of nephrolithiasis, we need to evaluate the patients for inherited disorder such as PH, cystinuria, Dent disease and familial hypomagnesemia (20,39 (44), in a populationbased study on 2871 patients aged 2 months to 18 years revealed that 420 (14.6%) were overweight and 440 (15.3%) were obese. They concluded that increased BMI in children was associated with increased overall complications.…”

“…Among them, hypercalciuria, hyperuricosuria and cystinuria make 34 to 50%, 20% and 20% of metabolic abnormalities, respectively in pediatric nephrolithiasis (36)(37)(38). In the recurrence of nephrolithiasis, we need to evaluate the patients for inherited disorder such as PH, cystinuria, Dent disease and familial hypomagnesemia (20,39). Moreover, mutations of CYP24A1, encoding the enzyme that influences conversion of active forms of vitamin D to inactive metabolites, induce idiopathic infantile hypercalcemia (40).…”

“…Medication may be a part of management of children with recurrent nephrolithiasis, solitary kidney, or metabolic disorders. In this context, the result of stone analysis or a 24-hour urine collection analysis plays an important role (33,39,69,70). Thiazides and potassium-sparing diuretics are on top of the list.…”