Clinical phenotypic and genotypic analysis of Gitelman syndrome in children

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Gitelman syndrome (GS) is a rare autosomal recessive tubulopathy caused by SLC12A3 variants, leading to hypokalemic metabolic alkalosis and other electrolyte disturbances. This study aimed to investigate the genotype and clinical phenotype in pediatric patients with GS. This study consisted of a retrospective clinical analysis and prospective functional validation of a novel variant. Clinical data and whole-exome sequencing results from 29 pediatric patients enrolled between 2012 and 2022 in China were retrospectively reviewed. Functional characterization of the novel SLC12A3 variant N227S was conducted using in vitro assays, including cell culture, plasmid transfection, qRT-PCR, and Western blot. The initial manifestations were short stature, neuromuscular symptoms and fatigue. More than half of the children were diagnosed incidentally. Hypomagnesemia was present in 15 patients (52%), while 14 (48%) 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 ( P = 0.006). Fractional excretion of sodium was generally within the normal range, while fractional excretion of chloride and potassium were increased. Missense variants were most frequent (47%), with T60M being the most common (8%). Eight novel SLC12A3 variants was identified. Patients with splicing variants had higher bicarbonate levels ( t = 2.521, P = 0.018). Functional studies showed that the N227S variant caused significant downregulation of SLC12A3 mRNA and Na + -Cl − cotransporter (NCC) protein expression, providing supportive functional evidence consistent with a deleterious effect. Pediatric GS often presents insidiously, and nearly half of children 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 supportive functional characterization of the N227S variant was confirmed for the first time.