Clinical and genetic features in 30 children with Gitelman syndrome.

BACKGROUND

Gitelman syndrome (GS) is a rare autosomal recessive renal tubular disorder caused by SLC12A3 gene variants. This study aimed to retrospectively analyze the clinical and genetic characteristics of pediatric GS patients and validate the function of a novel splicing variant.

METHODS

Thirty genetically confirmed GS patients admitted to the Children’s Hospital of Nanjing Medical University between August 2017 and October 2025 were enrolled. We systematically reviewed clinical data, biochemical profiles, and SLC12A3 variants. We performed Minigene splicing analysis to verify the functional impact of the novel intronic variant c.1925 + 5G > T (NM_000339.3).

RESULTS

All 30 patients presented with hypokalemia, and 90% (27/30) had hypomagnesemia. Fatigue (43.3%, 13/30) and short stature (36.7%, 11/30) were the most common clinical manifestations. A total of 37 SLC12A3 variants were identified, including 20 missense variants (54%), eight splicing variants (21.6%), six frameshift variants (16.2%), one synonymous variant, one deletion, and one duplication. We discovered four novel variants: c.2531T > G (NM_000339.3) (p.(Leu844Arg)), c.1925 + 5G > T(NM_000339.3), c.2960_2962dup(NM_000339.3) (p.(Ser987_Ser988insCys)), and p.(Phe535Cysfs*108). Minigene splicing assay confirmed that c.1925 + 5G > T induced complete skipping of exon 15, leading to in vitro validated truncated mRNA due to abnormal splicing of the SLC12A3 transcript.

CONCLUSIONS

Pediatric GS presents with an insidious onset, and fatigue and short stature are the most common clinical manifestations in this single-center cohort. SLC12A3 variants are highly heterogeneous, with p.(Asp486Asn) and p.(Thr60Met) being frequent hotspots in the Chinese pediatric population. The novel splicing variant c.1925 + 5G > T contributes to GS pathogenesis by disrupting mRNA splicing. This study expands the SLC12A3 variant spectrum and provides clinical and experimental evidence for the early diagnosis and genetic counseling of pediatric GS.