Novel Intronic Mutations of the SLC12A3 Gene in Patients with Gitelman Syndrome

AIM: Mutations in the SLC12A3 gene have been reported to cause Gitelman syndrome (GS), characterized by hypokalemic metabolic alkalosis. The aim of this research is to investigate the genetic mutations and clinical features of patients with clinical suspicion of GS. METHODS: Six families were enrolled. The symptoms, clinical examination, laboratory results, genotypes, and effect of mutations on mRNA splicing were analyzed. Genomic DNA was screened for gene variations using whole exome sequence and Sanger sequencing. DNA sequences were compared with reference sequences. RESULTS: Genetic analysis revealed nine genetic variants of SLC12A3, including three novel heterozygous mutations (c.1096–2A>G, c.1862A>G, and c.2747+4del) and six previously characterized mutations (c.965–1_976delinsACCGAAAATTTT, c.506–1G>A, c.602–16G>A, c.533C >T, c.1456 G>A, and c.1108 G>C). Probands presented with the clinical syndrome of hypokalemia, increased plasma renin, hypocalciuria and hypokalemic alkalosis. CONCLUSION: These clinical manifestations and genotypes were consistent with the diagnostic criteria of GS. The study described the phenotypes and genotypes of six pedigrees involving GS patients, demonstrating the importance of SLC12A3 gene screening for GS. This study expands the mutation spectrum of SLC12A3 gene in GS.