Genetic study in patients with nephrocalcinosis

Abstract

Nephrocalcinosis can be inherited or acquired and may progress to chronic kidney disease.

Objective: To analyze the clinical, biochemical, and genetic characteristics of patients with genetic nephrocalcinosis and to establish a correlation between genotype and phenotype.

Patients and Method: Patients under 18 years of age with nephrocalcinosis followed up in a tertiary hospital in Madrid between 2013 and 2022 were studied. Inclusion criteria: nephrocalcinosis of monogenic etiology. Exclusion criteria: incomplete data. Demographic, biochemical, and imaging data were collected; a genetic study was performed with a gene panel in five patients, exome and splicing regions in one patient, and PCR amplification and Sanger sequencing in four patients. The study was approved by the ethics committee.

Results: Ten patients (70% male) with a median age at diagnosis of 21.5 months were included. A mutation in the CYP24A1 gene was detected in four patients, three of whom also had a mutation in the SLC34A1 gene, causative of infantile idiopathic hypercalcemia; three patients had mutations in the SLC34A3 gene, causing hereditary hypophosphatemic rickets with hypercalciuria and nephrocalcinosis; one patient diagnosed with distal renal tubular acidosis type 1 presented two pathogenic variants in heterozygosis in the ATP6V0A4 gene; one patient diagnosed with Bartter syndrome presented two variants in the CLCNKB gene; finally, a homozygous mutation in the CLDN19 gene was detected in a patient with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Sixteen family members were studied and mutations were detected in 11 of them, all with no symptoms.

Conclusions: The genetic study of patients with nephrocalcinosis allows etiological diagnosis, detection of asymptomatic affected relatives, and establishing treatment, which improves long-term renal prognosis. It also allows genetic counseling and advice to be given.