Abstract: TH-PO0412
Unmasking of a Heterozygous SLC12A3 Mutation
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Clinical - 1
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid, Electrolytes, and Acid-Base Disorders
- 1102 Fluid, Electrolyte, and Acid-Base Disorders: Clinical
Authors
- Rohatgi, Rajeev, James J Peters VA Medical Center, New York, New York, United States
- Xu, Chang, James J Peters VA Medical Center, New York, New York, United States
Introduction
Most renal Na channel- and transporter-opathies are recessively inherited and, thus, carriers are phenotypically silent, but heterozygous carriers can be unmasked by diuretics. Gitelman’s syndrome is an autosomal recessive disorder caused by mutations in thiazide-sensitive NaCl cotransporter (SLC12A3). It is the most common genetic, Na losing-tubulopathy with a prevalence of 1 per 40,000 and a heterozygous prevalence of ~1% in the population. Due to the prevalence and common use of diuretics, physicians should be aware that diuretics may illicit an amplified response in carriers.
Case Description
Past medical history was significant for hypertension (HTN) and hyperlipidemia. The patient had been prescribed amlodipine, and 12.5 mg hydrochlorothiazide (HCTZ) was added, but later changed to 25 mg chlorthalidone (CTD). Twelve weeks later the patient presented to the hospital with a 30 lb weight loss, hyponatremia, hypokalemia, bicarbonatemia and hyperglycemia (Fig. 1A,B). Serum magnesium and calcium were normal. Bicarbonatemia was associated with a compensated metabolic alkalosis. The patient received 936 meq of KCl and 406 meq of NaCl, of which, ~50% of the KCl and all the NaCl were administered in the first 48 hrs. Figure 1A, B shows the response to treatment. Natera® Renasight testing demonstrated a heterozygous, pathogenic missense mutation of the NaCl cotransporter (SLC12A3 c.363G>C (p.Glu121Asp)).
Discussion
There are several interesting aspects to this case. First, the patient carries a heterozygous mutation of SLC12A3, which is purported to reduce systemic blood pressure, yet our patient presents with HTN necessitating the HCTZ/CTD intervention. CTD administration led to a Gitelman’s-like metabolic profile, unmasking the carrier state. Second, CTD exposed the carrier status which reflects the long acting pharmacology and pharmacokinetics of CTD vs. HCTZ. Finally, glucose intolerance is associated with thiazide diuretics and is attributable, in part, to K depletion.
Changes in serum electrolytes (A) and glucose (B) in response to K repletion
and insulin, respectively