Clinical phenotypic and genotypic analysis of Gitelman syndrome in children

Background Gitelman syndrome (GS) is a rare autosomal recessive tubulopathy caused by SLC12A3 mutations, leading to hypokalemic metabolic alkalosis and other electrolyte disturbances. This study aimed to investigate the genotype and clinical phenotype in pediatric patients with GS. Methods This retrospective study enrolled 29 pediatric patients from 2012 to 2022 in China. The clinical data and whole-exome sequencing results were collected. Functional validation of the novel SLC12A3 variant N227S was conducted using in vitro assays, including cell culture, plasmid transfection, RT-PCR, and Western blot. Results The initial manifestations were short stature, respiratory symptoms, and fatigue. Hypomagnesemia was present in 15 patients (51.7%), while 14 (48.3%) had normal serum magnesium levels. Serum magnesium correlated negatively with bicarbonate (r=-0.387, P=0.038), and children with hypomagnesemia had lower body weight (χ²=6.371, P=0.046). Missense mutations were most frequent (46.8%), with T60M being the most common (7.8%). Eight novel SLC12A3 variants were identified. Patients with splicing mutations had higher base excess (BE) and bicarbonate levels (t=-2.268, P=0.032 and t=-2.521, P=0.018, respectively). Functional studies showed that the N227S variant caused significant downregulation of SLC12A3 mRNA and Na+-Cl- cotransporter (NCC) protein expression, confirming its pathogenicity. Conclusions Pediatric GS often presents insidiously, and nearly half of patients do not exhibit hypomagnesemia, increasing the risk of misdiagnosis or delayed diagnosis. Splicing variants may be associated with more severe alkalosis. Eight novel SLC12A3 variants were identified, and the pathogenicity of the N227S variant was confirmed for the first time.