Novel frameshift variant in the β subunit of epithelial sodium channels uncovers Liddle syndrome in a young patient with metabolic syndrome: a case report with review of literature

Abstract

Liddle syndrome is a rare monogenic form of hypertension that can be misdiagnosed as essential hypertension or, in the context of obesity, be mistaken for metabolic syndrome. This case report describes a 19-year-old Chinese male with obesity, hypertension, insulin resistance, impaired glucose tolerance, dyslipidemia, and hyperuricemia—a classic presentation of metabolic syndrome. However, the early onset of severe hypertension and a strong family history prompted further investigation. Laboratory evaluation revealed mild hypokalemia, suppressed plasma renin activity and normal aldosterone levels, raising suspicion for Liddle syndrome. Whole exome sequencing was performed to explore monogenic causes of hypertension, which identified a novel heterozygous frameshift variant in the SCNN1B gene (NM_000336.3:c.1711_1713delinsAA). This variant leads to the loss of the PY motif—a functionally critical and indispensable structural element of the epithelial sodium channel (ENaC) β-subunit—and was classified as likely pathogenic in accordance with the ACMG/AMP guidelines. The patient was initiated on targeted therapy with amiloride, which rapidly normalized his blood pressure and hypokalemia, thereby confirming the diagnosis. This case highlights the diagnostic challenge of distinguishing monogenic hypertension from metabolic syndrome in young, obese individuals. It emphasizes the necessity of systematically investigating for secondary causes in this population. Key steps include obtaining a family history, screening for hypokalemia, evaluating renin and aldosterone levels, and assessing the response to standard therapy. Identifying a rare disorder like Liddle syndrome allows for a paradigm shift in management from empiric to targeted treatment, which is essential for preventing the debilitating long-term sequelae of chronic hypertension.

Graphical Abstract

Introduction

Hypertension is the leading modifiable risk factor for global cardiovascular morbidity and premature mortality, with secondary causes accounting for 5%–15% of all cases of hypertension [1, 2]. While genetic causes of secondary hypertension are rare, identifying them is crucial as they often guide targeted therapeutic interventions [1, 3]. Liddle syndrome (OMIM #177200) is an autosomal dominant disorder caused by gain-of-function pathogenic variants in genes encoding epithelial sodium channel (ENaC) subunits, particularly the β subunit encoded by the SCNN1B gene [4, 5]. Pathogenic variants in these genes typically disrupt the conserved PY motif in ENaC subunits, impairing channel degradation and leading to excessive sodium reabsorption. This syndrome is characterized by early-onset hypertension, hypokalemia, metabolic alkalosis, and suppressed levels of aldosterone and renin, and it typically responds well to ENaC blockers [6]. To date, over 100 familial or sporadic cases of genetically confirmed Liddle syndrome have been reported in the literature, predominantly involving SCNN1B variants, with novel variants continuing to expand the genetic spectrum of this disorder [7].

Notably, in young patients with obesity, the clinical features of Liddle syndrome can closely mimic those of metabolic syndrome, a common condition characterized by obesity, insulin resistance, dyslipidemia, and early blood pressure elevation. This phenotypic overlap may lead to misdiagnosis or delayed recognition of the underlying monogenic disorder.

Given the variable phenotypic presentation of Liddle syndrome, high-throughput sequencing has emerged as a powerful diagnostic tool. Here, we present the case of a Chinese male patient manifesting early-onset hypertension and hypokalemia in the context of obesity and other metabolic features, in whom exome sequencing revealed a novel frameshift variant in the SCNN1B gene, expanding the mutational landscape of this condition.

Case presentation

Patient information and clinical features

A 19-year-old male patient was referred to the Department of Endocrinology and Metabolism at the First Affiliated Hospital of China Medical University with an eight-year history of hypertension. Despite receiving a combined antihypertensive regimen of nifedipine (30 mg daily) and losartan (80 mg daily), his blood pressure remained inadequately controlled, consistently reaching 150/100 mmHg. His father was diagnosed with hypertension at an unknown age and was on antihypertensive treatment; however, detailed biochemical profiles (serum potassium, renin, and aldosterone levels) were unavailable.

Clinical findings

On physical examination, the patient was 180.0 cm tall, weighed 102.0 kg, and had a body mass index (BMI) of 31.48 kg/m². Persistent mild hypokalemia (3.15–3.35 mmol/L) and mild alkalemia (HCO₃^–: 26.5–30.8 mmol/L; reference range: 22.0–29.0 mmol/L) were identified, prompting further diagnostic evaluation. Laboratory tests revealed a normal serum aldosterone level (0.15 ng/mL) but a notably low plasma renin activity (0.31 ng/mL/h; normal range: 0.93–6.56 ng/mL/h). Arterial gas analysis revealed a pH of 7.39 (normal range, 7.35–7.45), which was within the normal range. Additional evaluations, including thyroid hormones, adrenocorticotropic hormone, cortisol, metanephrine, and normetanephrine, were all within normal limits. The oral glucose tolerance test indicated a fasting blood glucose level of 4.59 mmol/L, a fasting insulin level of 14.14 mIU/L, a HOMA-IR of 2.88, and a 2-hour plasma glucose level of 9.9 mmol/L, suggesting impaired glucose tolerance and insulin resistance. The patient also presented with hyperuricemia (546 μmol/L; normal range: 208–428 umol/L) and reduced HDL cholesterol levels (0.75 mmol/L; normal range: 0.91–1.92 mmol/L). Enhanced 3D computed tomography showed no abnormalities in the adrenal glands. Echocardiography and color Doppler ultrasound of the carotid and renal arteries revealed no significant structural or functional changes.

Genetic testing

After obtaining written informed consent from the patient and his family members, peripheral blood samples were collected. Genomic DNA was extracted using a commercial blood DNA extraction kit (product of Tianjing Biochemical Technology Co., Ltd., Beijing, China). Genetic testing was conducted via whole-exome sequencing (WES) with high-throughput technology on the Illumina platform. For data analysis, the VeritaTrekker^® Variant Site Detection System and Enliven^® Variant Site Annotation & Interpretation System (both developed by Berry Genetics) were employed; these systems were based on the latest versions of the following databases: dbSNP, 1,000 Genomes Project, gnomAD, CADD, ClinVar, and HGMD. Sequencing results identified a novel heterozygous variant in the SCNN1B gene (reference transcript: NM_000336.3; variant notation: c.1711_1713delinsAA, which corresponds to the protein change p.Tyr571Lysfs*105). Subsequent pedigree analysis confirmed that this variant was inherited from the patient`s father (Fig. 1). This variant results in the loss of the PY motif (amino acids 616–620: PPPNY) at the C-terminus of the β-subunit of epithelial sodium channels (ENaCs) (Fig. 2). According to the 2015 ACMG/AMP guidelines, this variant was classified as likely pathogenic based on the following criteria: PM1 (variant localizes to the functionally critical PY motif of ENaC β-subunit), PM2 (variant absent from the latest version of genomic databases including ClinVar, dbSNP, HGMD, LitVar, and gnomAD v4.1.0), PM4 (frameshift variant leading to PY motif loss and truncated protein), and PP1 (variant cosegregates with hypertension in the proband and his father).

Fig. 1. Pedigree of the family and electropherogram of the SCNN1B gene variant.

(A) Pedigree of the family with Liddle syndrome. Males and females are represented by squares and a circle, respectively. Half-filled symbols denote heterozygous carriers. The proband is indicated by a black arrow.

(B) Electropherogram of the SCNN1B gene sequence, revealing a heterozygous variant c.1711_1713delinsAA (p.Tyr571Leufs*105) of paternal origin.

Fig. 2. Schematic Diagram of SCNN1B Protein Structure.

This diagram shows the structure of the SCNN1B transmembrane protein, generated via Protter (https://wlab.ethz.ch/protter/start/) with protein 3D structural data from AlphaFold3 (AlphaFold ID: AF-P51168-F1); blue denotes extracellular and transmembrane segments, gray denotes intracellular segments, and red highlights the PY motif (PPPXY). Nonsense or frameshift variants that disrupt the C-terminal PY motif, as well as variants within the PY motif itself, lead to the loss of this conserved motif, thereby causing Liddle syndrome; the position marked with “#” indicates the variant identified in the present report.

Diagnosis and treatment

Primary aldosteronism was excluded based on normal serum aldosterone levels, unremarkable adrenal imaging, and absence of pathogenic variants in associated genes. Based on the patient’s clinical manifestations and genetic test results, a diagnosis of Liddle syndrome was confirmed. The patient was advised to implement lifestyle modifications, including adopting a low-salt diet, engaging in regular exercise, and reducing body weight. His antihypertensive regimen was adjusted to include amiloride/hydrochlorothiazide (5 mg/50 mg daily) in combination with nifedipine (30 mg daily).

Follow-up

At 4 weeks of follow-up after the initiation of these therapeutic and lifestyle interventions, his blood pressure was well controlled at 120/70 mmHg, and his serum potassium level normalized to 3.85 mmol/L.

Discussion

Genetic forms of secondary hypertension typically manifest with distinct clinical characteristics, including early onset in children, adolescents, or young adults, and a strong familial predisposition. The majority of monogenic hypertensive disorders share a common pathogenic mechanism, which involves enhanced sodium reabsorption in the renal tubules [2, 8]. Consequently, the detection of suppressed plasma renin concentration (PRC) or plasma renin activity (PRA) should prompt clinical suspicion of secondary hypertension mediated by sodium retention [2]. Among the spectrum of rare genetic hypertensive disorders, Liddle syndrome represents one of the more prevalent forms, particularly within the Chinese population [9, 10]. We reviewed familial and sporadic cases of Liddle syndrome genetically confirmed with SCNN1B variants that have been reported in the literature, with Chinese patients accounting for more than half of the reported cases (33 of 64 families, Supplementary Table 1), highlighting the importance of considering this diagnosis in patients of Chinese ancestry presenting with early-onset hypertension.

The main clinical features of Liddle syndrome are often distinct and obvious; however, some atypical cases exhibit significant phenotypic variability, highlighting the heterogeneity of the condition [11]. We reviewed 143 patients with Liddle syndrome carrying SCNN1B gene variants from 64 families, among whom 30.7% had normal aldosterone levels, 21.4% had normal blood potassium levels, and even 3.6% had normal blood pressure (Supplementary Table 1). These findings underscore the limitations of phenotype-based diagnosis and emphasize the critical role of next-generation sequencing in identifying monogenic forms of hypertension. The precise molecular diagnosis enables implementation of targeted therapeutic strategies: ENaC inhibitors (amiloride or triamterene) for Liddle syndrome, thiazide diuretics for Gordon syndrome (pseudohypoaldosteronism type II), and mineralocorticoid receptor antagonists for glucocorticoid-remediable aldosteronism [2]. This precision medicine approach not only optimizes blood pressure control but also minimizes adverse effects, ultimately improving long-term cardiovascular outcomes.

The primary mechanism underlying Liddle syndrome is the hyperactivation of the ENaCs in renal tubules. Mechanistic studies have demonstrated that among the three ENaC subunits, the β and γ subunits play a crucial role in channel activity modulation [6]. Structurally, each ENaC subunit contains a highly conserved PY motif (PPPXY) in its cytoplasmic carboxyl-terminal domain. This motif serves as a critical binding site for the WW domain of the ubiquitin protein ligase NEDD4-2, thereby regulating channel degradation through ubiquitination [12]. Genetic analyses have revealed that most cases of Liddle syndrome result from nonsense or frameshift variants in the C-terminal cytoplasmic regions of the SCNN1B and SCNN1G genes [4]. Currently, 30 distinct pathogenic variants have been identified in the SCNN1B gene, with variants either disrupting the upstream region leading to PY motif loss or directly altering the PY motif itself, particularly affecting residues 616–620 (Fig. 2, Supplementary Table 1).

Essential hypertension frequently coexists with secondary hypertension, significantly complicating both diagnosis and clinical management. In the present case, the patient exhibited metabolic syndrome, including obesity, hypertriglyceridemia, and hyperuricemia, alongside Liddle syndrome—highlighting the coexistence of monogenic and acquired metabolic drivers in his hypertension, and the resulting diagnostic challenge that necessitates a multifaceted treatment approach.

Notably, there is no direct evidence that ENaC overactivity induces insulin resistance or obesity. However, ENaC overactivation can lead to hypokalemia; if monogenic hypertension is accompanied by long-term hypokalemia, this electrolyte disturbance may impair insulin secretion and reduce insulin sensitivity [13]. Conversely, individuals with obesity and insulin resistance often experience ENaC overactivation due to underlying metabolic abnormalities [14]—creating bidirectional associations between Liddle syndrome, metabolic syndrome, obesity, and insulin resistance. These connections underscore the need for future research to explore glucose metabolism disorder data and related mechanisms in a larger cohort of patients with monogenic hypertension, to further clarify the interplay between these conditions.

This case illustrates that its features can be mistaken for, or coexist with, metabolic syndrome, requiring a high index of suspicion. As such, lifestyle modifications are a critical component in the comprehensive management of secondary hypertension. Key interventions, including sodium restriction (targeting <2 g/day), moderation of alcohol intake, adoption to a balanced diet, engagement in regular physical activity (≥150 minutes/week of moderate-intensity activity), effective weight management (targeting 5–10% of initial body weight), and smoking cessation, not only contribute to improved blood pressure control but also offer extensive health benefits that extend well beyond hypertension management [2].

In summary, we present a Chinese pedigree with genetically confirmed Liddle syndrome caused by a novel heterozygous variant in the SCNN1B gene, leading to the complete deletion of the functionally critical PY motif (Graphical Abstract). Although Liddle syndrome is classically characterized by early-onset hypertension, hypokalemia, and suppressed renin activity, its clinical presentation can exhibit significant heterogeneity. This case illustrates that Liddle syndrome can be misdiagnosed as, or coexist with, metabolic syndrome in young obese patients, emphasizing the need for a high index of suspicion in this population. The implementation of next-generation sequencing technologies has revolutionized the diagnostic approach to monogenic hypertension, enabling accurate molecular diagnosis in young hypertensive patients. This precision medicine strategy not only facilitates the initiation of targeted therapy with ENaC inhibitors but also supports comprehensive management through dietary sodium restriction, potassium supplementation, and long-term surveillance to prevent cardiovascular and renal complications.

Graphical Abstract.

Ethics statement

This study protocol was reviewed and approved by the First Affiliated Hospital of China Medical University. The patient and his family members provided written informed consent for publication of their clinical details and clinical images.

Funding

No Funding was received for the research and/or publication of this article.

Conflict of interest

No commercial or financial conflict of interest was identified for this research.

Generative AI statement

The authors declare that no Generative AI was used in the creation of this manuscript.

Supplementary Material

Supplementary Table 1

Variants type, clinical characteristics and follow-up data of patients with Liddle syndrome carrying SCNN1B mutations