Diagnostic pitfalls in Gitelman syndrome: interpreting a single SLC12A3 variant

Gitelman syndrome (GS) is an autosomal recessive salt-losing tubulopathy caused by biallelic SLC12A3 variants. However, 10-30% of patients with an obvious clinical and biochemical GS phenotype carry only a single detectable variant on routine genetic testing. In such cases, identification of a heterozygous pathogenic variant does not confirm but strongly supports the clinical diagnosis, as the second allele likely remains undetected due to deep intronic mutations, copy number variations, or other non-canonical variants. We report a 5-year-old boy with classic GS features: recurrent hypokalemia and hypomagnesemia unmasked during intercurrent illnesses, metabolic alkalosis (pH 7.47, HCO₃⁻ 30.5 mmol/L), renal potassium wasting (fractional excretion of potassium 29.7%), hypocalciuria (urine calcium-to-creatinine ratio 0.07), and hyperreninemic hyperaldosteronism. Despite this robust phenotype, genetic testing identified only a single heterozygous pathogenic splice-site variant in SLC12A3 (c.1180+1G>T), inherited from the unaffected mother; additionally, a variant of uncertain significance in ATP6V0A4 (c.842G>A; p.Arg281His) was inherited from the healthy father. With potassium and magnesium supplementation, electrolyte balance normalized and catch-up growth was achieved over 5 years of follow-up. In patients with an unequivocal GS phenotype, a monoallelic finding supports rather than refutes the diagnosis and should prompt extended genetic analysis, including deep intronic sequencing and CNV assessment, to identify the missing second allele.