Molecular complexity analysis of the diagnosis of Gitelman syndrome in China

Gitelman syndrome (GS) is an autosomal recessive renal tubal disease characterized by hypomagnesemia, hypokalemia, and hypocalciuria. The disease is caused by defects in the SLC12A3 gene, which encodes the thiazide diuretic-sensitive sodium chloride cotransporter (NCCT). In this study, a 20-year-old female patient with recurrent hypokalemia was tested for a hypokalemia-related panel using Next Generation Sequencing. Pedigree analysis was performed on her parents (non-consanguineous) and sister using Sanger sequencing. The results revealed that the patient carried compound heterozygous variants of the SLC12A3 gene: c.179C > T (p.T60M) and c.1001G > A (p.R334Q). Furthermore, her asymptomatic 6-year-old sister also carried both mutations. While the p.T60M mutation had been reported previously, the p.R334Q mutation was novel, and amino acid position 334 was identified as a mutation hotspot. Our findings provide an accurate molecular diagnosis that is essential for the diagnosis, counseling, and management of not only the symptomatic patient but also her asymptomatic sister. This study contributes to our understanding of the GS, which has a prevalence of approximately 1 in 40,000 and a heterozygous mutation carrier rate of 1% in Caucasians. Specifically, we observed a compound heterozygous mutation of the SLC12A3 gene in a 20-year-old female patient presenting with clinical symptoms consistent with GS.