Novel Pathogenic Genotype in SLC12A3 Associated to Gitelman Syndrome: A Case Report

Gitelman syndrome (GS) is considered one of the most common hereditary renal tubular disorders, characterised by hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. The primary cause of this disorder resides in the SLC12A3 gene, which encodes the NaCl cotransporter in the distal convoluted tubule, and for which more than 500 mutations associated with GS have been described. We present the case of a 51-year-old female referred for evaluation of recurrent hypokalemia and hypomagnesemia, with no clinical symptoms. The blood test also revealed hypocalciuria and metabolic alkalosis. Oral supplementation with potassium and magnesium was prescribed. A next-generation sequencing (NGS) test was performed on her and her child (no other relatives alive), who was also asymptomatic with no obvious electrolytic abnormalities. Two mutations confirmed as pathogenic were found in the SLC12A3 gene (NM_000339.3) of the mother, c.704C>G and c.704C>T, as well as a new heterozygous variant in trans not reported before, c.704C>A p.(Thr235Lys), and identified as a variant of uncertain significance (VUS). This new VUS (c.704C>A p) was also present in the child, increasing evidence of its potential pathogenicity. The new SLC12A3 gene variant could represent a pathogenic mutation associated with GS. The use of NGS-based panel is recommended to cover the large genotypic variability associated with this disease, in an attempt to identify novel SLC12A3 gene variants of potential pathogenicity.