A novel variant of SLC12A3 in Gitelman syndrome with hypertension: a case report

Introduction

Background

Gitelman syndrome (GS) is a rare autosomal recessive inherited renal tubular disorder firstly reported by Gitelman in 1966 (1). It is caused by variants in the SLC12A3 gene located on the long arm of chromosome 16. This gene encodes the thiazide-sensitive sodium-chloride cotransporter (NCC), which is abnormal, leading to renal ion channel abnormalities. The reduced reabsorption of sodium, chloride, and magnesium causes hypochloremia, hypomagnesemia, hypokalemia, metabolic alkalosis, hypovolemia, hypocalciuria, and secondary aldosteronism (2). Patients with GS are typically asymptomatic or exhibit muscle weakness or tetany triggered by hypomagnesemia, and it is more common in adolescents and adults (3). The prevalence of GS is approximately 1/40,000, with heterozygotes of the SLC12A3 gene accounting for 1% in Caucasians and about 3% in Chinese individuals. The clinical manifestations are diverse and lack specificity (4).

Rationale and knowledge gap

Beyond the widely cited figure, some cohort studies suggested that the true prevalence of GS in Asian populations is probably underestimated, owing to variable clinical penetrance and limited access to molecular diagnostics (5,6). Nevertheless, more than 180 pathogenic variants have already been identified across the entire coding region of SLC12A3 (7). To date, several different SLC12A3 variants have been reported, including missense, frame shift, and nonsense variants. Apparently negative genetic testing could involve large genomic rearrangements that are missed by direct sequencing that usually accounts for 5–15% of the molecular defects responsible by autosomal recessive disease (6,8,9). Besides, hypertension is regarded as exceptional in GS and may lead to misdiagnosis. Fewer than ten hypertensive cases have been genotyped (2). The pathophysiology of elevated blood pressure (BP) in GS remains speculative, and optimal management is not defined.

Objective

To describe the clinical course, genetic findings and targeted treatment of a hypertensive GS patient with a novel SLC12A3 variant, and to discuss mechanisms and therapeutic implications. In this case report, c.254C>T (p.Thr85Ile) is found as a novel variant of SLC12A3 in the patient diagnosed as GS with hypertension. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-303/rc).

Case presentation

A previously healthy 19-year-old male was incidentally found to have hypokalemia, hypochloremia, hypomagnesemia, and elevated bicarbonate; however, these findings did not receive significant attention and no therapeutic intervention was undertaken at that time. Three months later he presented with bilateral lower-limb weakness and myalgia, followed by acute flaccid paralysis necessitating emergency evaluation. Severe electrolyte depletion and transient dipstick proteinuria/haematuria were documented (Table 1), and symptoms resolved promptly after intravenous potassium supplementation. He was discharged on oral potassium and subsequently referred to our tertiary center for further diagnostic work-up.

On admission, we confirmed the biochemical abnormalities (Table 1), documented hypocalciuria and documented markedly elevated renin-aldosterone levels in the absence of any antihypertensive medication (Table 1), systematically excluding alternative causes of hypokalaemic hypertension (normal renal imaging, negative autoimmune screen). Serum 302 mOsm/kg and urine 420 mOsm/kg (urine/serum 1.4) show intact concentration. These findings were consistent with a mildly volume-depleted state, supporting the diagnosis of secondary hyperaldosteronism. Bidirectional Sanger sequencing revealed compound-heterozygous pathogenic variants in SLC12A3 (Figure 1). Targeted therapy with oral potassium chloride, magnesium aspartate plus low-dose amiloride (after the discharge) was instituted. BP and serum electrolytes normalized after treatment for 12 days (Tables 2,3), and the patient remains asymptomatic at the telephone follow-up.

Figure 1 Confirmation of compound-heterozygous SLC12A3 variants by Sanger sequencing. The proband’s NGS analysis identified two heterozygous variants in the SLC12A3 gene: a missense variation (c.254C>T) resulting in the amino acid substitution p.Thr85Ile, and a deletion variation c.390del leading to the amino acid changes p.Glu131Argfs*12, respectively. These genetic findings were confirmed by Sanger sequencing as depicted in the electropherograms. NGS, next generation sequencing.

Besides, in accordance with the Chinese expert consensus on the diagnosis and treatment of GS [2021] (4), we have classified the severity of the patient’s condition using two distinct classification systems, one based on blood potassium and magnesium levels, and another based on clinical manifestations. Here, we listed the GS severity scale the patient at initial presentation (day 0) and post-treatment re-classification (day 12) in Table 4.

Variant interpretation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards (10). Specifically, (i) c.254C>T (p.Thr85Ile): PM2_Supporting (absent in gnomAD v.4, ExAC, 1000G, ChinaMAP), PP3 (multiple in-silico tools predict damaging), PP1 (co-segregation with phenotype in mother) → variant of uncertain significance (VUS). (ii) c.390del (p.Glu131Argfs*12): PVS1 (frameshift, NMD expected), PM2_Supporting (absent in population databases), PP1 (segregation in father) → likely pathogenic. The compound heterozygous state satisfies autosomal recessive inheritance (PM3). As depicted in the Figure 1, the variant of chr16:56899401 c.254C>T(p.Thr85Ile) was verified to be inherited from the mother. This sample has a variation c.254C>T(p.Thr85Ile) in exon1 of the SLC12A3 gene (OMIM:600968) at position 16q13. This variation is preliminarily determined to be of unknown clinical significance (PM2_Supporting; not recorded in GnomAD, ExAC, 1000 Genomes Project, or local databases), which is also predicted by multiple algorithms (SIFT, PolyPhen-2, REVEL, AlphaFold2 pLDDT, ESM-1v) to be harmful to gene or gene product function. The other variant of chr16:56901089 c.390del(p.Glu131Argfs*12) was verified to be inherited from the father. This sample has a variation c.390del(p.Glu131Argfs*12) in exon2 of the SLC12A3 gene (OMIM:600968) at position 16q13. This variation is preliminarily determined to be a likely pathogenic variant (PVS1, this variation is a null variant (frameshift variant), which may lead to loss of gene function. Besides, these above two variants are located on the patients’ two chromosomes, constituting the premise for autosomal recessive inheritance compound heterozygous disease. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient and his parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

For clarity, the variants c.254C>T (p.Thr85Ile) and c.390del (p.Glu131Argfs*12) are hereafter designated M1 and M2, respectively. As depicted in Figure 2, in silico algorithms (AlphaFold2) helps us to predict highly deleterious structural change at the transmembrane domain 1 and transmembrane domain2 (TMD1-TMD2) interface of NCC encoded by M1 and M2 variants (https://alphafold.ebi.ac.uk/). The family pedigree provided illustrates of the distribution of these SLC12A3 variants among the members. Individuals carrying the compound heterozygous variants are indicated with marked symbols. Besides, as GS is autosomal recessive, both parents are asymptomatic carriers of a single SLC12A3 variant and are of unrelated Han-Chinese ancestry, showing no evidence of consanguinity.

Figure 2 AlphaFold models and pedigree of SLC12A3 variants. (A) The proteins’ 3D structure of the M1 and M2 variants predicted by AlphaFold AI system. (B) The family pedigree of the distribution of these SLC12A3 variants among the patients’ members. AI, artificial intelligence; pLDDT, Predicted Local Distance Difference Test.

Discussion

Key findings

In this case report, a 19-year-old male with GS presented with the unusual phenotype of hypertension (154/101 mmHg) instead of the expected normotension/hypotension. Besides, compound-heterozygous SLC12A3 variants were identified: a novel missense change c.254C>T (p.Thr85Ile) inherited from the mother and a frameshift c.390del (p.Glu131Argfs*12) inherited from the father.

Strengths and limitations

Strengths

SLC12A3 gene pathogenic variations can cause GS (MIM:263800). The disease is inherited in an autosomal recessive manner (7). We identified compound heterozygous variants in SLC12A3: c.390del (p.Glu131Argfs*12) (likely pathogenic, PVS1 + PM2) and c.254C>T (p.Thr85Ile), absent from all population databases and located at the TMD1-TMD2 interface of NCC. In-silico algorithms predict a highly deleterious conformational change, while the rapid biochemical and haemodynamic response to low-dose amiloride supports residual but mis-localized NCC activity, consistent with previously described TMD1 mutants (8,11). Thus, the therapeutic rescue itself constitutes clinical-level functional evidence for the pathogenicity of the novel allele, obviating the need for invasive biopsy studies. In conclusion, this case enlarges the genotypic and phenotypic spectrum of GS, and underscores the importance of considering GS in adolescents with hypokalaemic hypertension.

Limitations

We admit that there are limitations of our case report. Firstly, transient dipstick proteinuria and hematuria (both graded 3+) were documented only on the day of presentation, when serum potassium was 2.6 mmol L⁻¹. Repeat urinalysis performed 24 h after potassium repletion showed complete resolution of both abnormalities, and a subsequent 24-h urine collection yielded 0.33 g protein per day, close to the upper-normal limit of 0.15 g/24 h but still within the non-nephrotic range. Renal ultrasonography, serum complement profile, antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA) and anti-glomerular-basement-membrane (anti-GBM) antibodies were all normal, and no red-cell casts were observed on phase-contrast microscopy. We therefore did not proceed to formal nephrology consultation. Nevertheless, we acknowledge that the absence of a specialist nephrological work-up represents a minor limitation of this report; should the abnormalities recur, comprehensive renal evaluation including biopsy would be indicated. Secondly, after the discharge, the patient took the treatment included potassium chloride sustained-release tablets (0.5 g three times a day) and potassium magnesium aspartate (0.596 g three times a day) plus amiloride 5 mg twice daily. The outpatient follow-up examination results indicated BP fell from 154/101 to 126/78 mmHg while serum potassium rose from 2.6 to 3.8 mmol/L and magnesium from 0.49 to 0.82 mmol/L. However, the combination of high travel costs, academic schedule constraints made repeated face-to-face visits unfeasible. Despite many attempts on scheduled telephone calls, we were still unable to establish further contact, so the patient was declared lost to follow-up. Consequently, we cannot provide temporal information on electrolyte stability, blood-pressure trajectory or long-term renal outcome. A multi-center registry that includes geographically dispersed participants is being planned to capture these missing data in future studies. Besides, although the patient’s BP normalized following electrolyte repletion and amiloride initiation, we acknowledge that the initial hypertensive episode may have been partially stress-related. A future trial of amiloride withdrawal under controlled conditions would help clarify its true antihypertensive efficacy. In addition, future functional assays, such as cRNA expression in Xenopus oocytes, are warranted to determine whether the c.254C>T variant impairs NCC membrane localization or cotransporter activity. Additionally, electrolyte profiling of the asymptomatic parents could provide further insights into variant penetrance, although such data are currently unavailable.

Comparison with similar research

Contrary to the typical presentation of GS, our patient exhibited elevated BP recently. In fact, the co-occurrence of GS and hypertension, while atypical, has been previously reported. Compared with the eight previously reported Gitelman-hypertensive cases (Table 5) (9,12-16), our patient’s initial BP of 154/101 mmHg and serum K⁺/Mg²⁺ nadirs of 2.6 and 0.49 mmol/L, respectively, lie within the published ranges (BP 148–162/94–105 mmHg; K⁺ 2.2–2.6 mmol/L; Mg²⁺ 0.50–0.62 mmol/L). However, while most earlier patients required one or two antihypertensive agents [angiotensin-converting-enzyme inhibitor/angiotensin-II receptor blocker (ACEI/ARB) ± calcium-channel blocker (CCB) or diuretic], electrolyte repletion plus single-dose amiloride (5 mg bid) was sufficient to reduce BP to 126/78 mmHg in the present case. This exclusive reliance on an epithelial sodium channel (ENaC) blocker supports the functional relevance of the novel trans-membrane domain 1 variant (c.254C>T) identified here.

Explanations of findings

The clinical course is summarized in Table 6. Although GS was genetically confirmed in our patient, several causes of hypokalemic hypertension should be distinguished. Specifically, firstly, Bartter syndrome (BS). BS shares features of hypokalemia and metabolic alkalosis with GS but typically presents with normo- or hypercalciuria and earlier onset. Our patient had hypocalciuria (24-hour urinary calcium: 0.48 mmol/24 h; normal range, 2.5–7.5 mmol/24 h), which is characteristic of GS and not typical of BS. In addition, BS patients often have hyperreninemia and hyperaldosteronism from infancy, whereas our patient was asymptomatic until adolescence. Secondly, primary aldosteronism (PA). PA can cause hypokalemia and hypertension, but is typically associated with suppressed renin activity. In contrast, our patient had markedly elevated renin and aldosterone levels, indicating secondary hyperaldosteronism, consistent with GS. Imaging of the adrenal glands was not performed but would be considered if PA was suspected. Thirdly, Liddle syndrome. This rare autosomal dominant condition presents with hypertension, hypokalemia, and metabolic alkalosis, but is distinguished by low renin and low aldosterone levels. Our patient showed high renin and aldosterone, effectively ruling out Liddle syndrome. Fourthly, diuretic abuse or laxative use, which mimic GS biochemically but were excluded based on negative history, normal anion gap, and absence of gastrointestinal symptoms. The patient denied using diuretics or laxatives, and no clinical signs of volume depletion were present. Fifthly, apparent mineralocorticoid excess (AME). AME, including licorice ingestion, can cause hypertension and hypokalemia. However, the patient denied licorice consumption, and no history of exogenous steroid use was reported. Additionally, AME is typically associated with low renin and aldosterone, which was not the case here. Sixthly, renal tubular acidosis (RTA) or other tubulopathies: RTA was considered but ruled out due to the presence of metabolic alkalosis rather than acidosis. Other rare tubulopathies [e.g., Epilepsy, Ataxia, Sensorineural deafness, Tubulopathy (EAST) syndrome, Gordon syndrome] were not consistent with the patient’s biochemical profile. Therefore, the combination of hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and elevated renin-aldosterone strongly supported a diagnosis of GS.

As for how to explain why this patient with classical GS (expected to be normo- or hypotensive) presented with sustained hypertension, we compared the two best-documented, but mechanistically distinct, scenarios. The most frequent explanation is long-standing secondary hyperaldosteronism: chronic volume depletion stimulates renin release, and the ensuing aldosterone excess activates the mineralocorticoid receptor, leading to sodium re-absorption via the ENaC and thus to salt-sensitive hypertension that may outweigh the initial hypovolemic tendency as the patient ages (12). An alternative, recently demonstrated in two studies, is somatic, clonal ENaC-activating mutations in the distal nephron; in these cases, plasma renin and aldosterone may be only modestly elevated or even normal, and the hypertension responds almost exclusively to ENaC blockade (8,11). Our patient exhibited a >20 mmHg falls in BP after supplementation with potassium and magnesium plus the ENaC inhibitor amiloride, without any ACEI/ARB or diuretic. The normal-range aldosterone despite elevated renin fits the “renin-dependent, normal-aldosterone” secondary hyperaldosteronism pattern described in Endotext (17), reinforcing the diagnosis and explaining the rapid phenotypic rescue. Besides, we emphasize that the antihypertensive and electrolyte-correcting effect of amiloride itself constitutes clinically relevant functional evidence. After three days of amiloride 5 mg twice daily, BP fell from 154/101 to 126/78 mmHg while serum potassium rose from 2.6 to 3.8 mmol/L and magnesium from 0.49 to 0.82 mmol/L, all on the same salt and supplement regimen. Because ENaC is the final effector shared by both secondary hyperaldosteronism and gain-of-function NCC variants that leak residual current, the rapid phenotypic rescue supports the contention that the novel TMD1 allele (c.254C>T; p.Thr85Ile) disrupts NCC folding enough to enhance distal sodium delivery yet leaves sufficient activity to be amenable to ENaC blockade. Thus, the therapeutic response furnishes level-III functional data that complement the bioinformatic predictions and fulfill the clinical-level functional evidence recommended for variants that cannot be studied in vitro. Besides, the initial hypertensive episode may also have been partially attributable to severe hypomagnesemia or to an acute stress response. On the one hand, although hypomagnesemia is classically associated with vasodilation and hypotension, severe deficiency can paradoxically elevate BP by enhancing vascular smooth muscle tone, impairing endothelium-dependent vasodilation, and amplifying sympathetic activity (18). In the present case, the serum magnesium nadir of 0.49 mmol/L may have potentiated the hypertensive effect of chronic secondary hyperaldosteronism by increasing vascular reactivity and sodium sensitivity (19). Correction of hypomagnesemia coincided with a >20 mmHg reduction in systolic pressure, suggesting that magnesium repletion contributed to the observed antihypertensive response. One the other hand, sympathetic overdrive acute stress may transiently elevate BP via the activity of renin-angiotensin system (RAS). Angiotensin II exerts central sympathoexcitatory effects, while pharmacologic blockade of RAS with ACE inhibitors or ARBs consistently reduces sympathetic outflow (19). Thus, the documented hyper-reninaemia in our patient could have further potentiated the hypertensive spike via sympathetic over-drive.

Implications and actions needed

This case report highlights several important clinical practice and genetic test implications arising from the atypical presentation of GS with hypertension and a novel SLC12A3 variant. The findings warrant specific actions across multiple domains: Firstly, GS is traditionally associated with normotension or hypotension. The presence of hypertension in this case challenges the conventional diagnostic criteria and may lead to underdiagnosis or misdiagnosis. Thus, actions needed to be taken on (i) updating clinical guidelines to include GS in the differential diagnosis of hypertension with hypokalemia, especially in young patients. (ii) Educating clinicians (especially in primary care, nephrology, and endocrinology) on the variable phenotypic expression of GS. (iii) Encouraging screen for GS in adolescents or young adults with unexplained hypokalemia and hypertension, even in the absence of classic hypotension. Secondly, the identification of a novel SLC12A3 variant (c.254C>T) with potential functional significance expands the genotypic spectrum of GS. From this aspect, actions needed to be taken on (i) functional validation of novel variants using in vitro or in silico models, especially when clinical evidence is suggestive but not definitive. (ii) Reporting to public databases (e.g., ClinVar, gnomAD) to improve variant interpretation and global data sharing. (iii) Development of national registries for rare renal tubular disorders to track genotype-phenotype correlations and long-term outcomes.

Conclusions

In this case presentation, we detail an adult patient with GS who exhibited fatigue and muscle weakness. Owing to the condition’s infrequent occurrence and the infrequency with which clinicians encounter it, the diagnosis of GS is often overlooked, resulting in misdiagnoses and subsequent suboptimal treatment. Notably, our patient, contrary to the common presentations, had hypertension. In addition, this study highlights the identification of two novel variants within the SLC12A3 gene [c.254C>T(p.Thr85Ile) and c.390del(p.Glu131Argfs*12)], contributing to the broader understanding of GS genetic diversity. We highlight the importance of including GS in the differential diagnosis for patients exhibiting the characteristic electrolyte disturbances and a spectrum of clinical signs. Laboratory tests revealed ongoing hypokalemia and hypomagnesemia, along with the increased levels of renin and aldosterone that are indicative of GS. Further renal evaluations did not disclose any structural irregularities. The patient’s management includes potassium and magnesium supplementation to ameliorate symptoms, as well as the use of antihypertensive medications to regulate BP if necessary.

Acknowledgments

We are especially grateful to Mrs. Ting Wang, the attending physician from The First Affiliated Hospital of Anhui Medical University, for conducting the follow-up investigations of the patient.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-303/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-303/prf

Funding: This study was supported by the Research Funding for Doctoral Talents of The First Affiliated Hospital of Anhui Medical University (grant No.1952).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-303/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient and his parents for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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