Pediatric Liddle Syndrome Caused by a Novel SCNN1G Variant in a Chinese Family and Characterized by Early-Onset Hypertension

Abstract

BACKGROUND Liddle syndrome (LS), an autosomal dominant disorder, is a common monogenic hypertension in pediatrics. In this study, we reported a novel SCNN1G variant in a Chinese family with pediatric LS, and conduct a systematic review of epithelial sodium channel (ENaC)-gene-positive LS cases to conclude the clinical genetic features of LS in childhood. METHODS Next-generation sequencing and in silico analysis were performed in the proband to discover candidate variants. Sanger sequencing was used to identify the predicted likely pathogenic variant. LS patients in this family were treated with amiloride. The Medline database was searched to summarize clinical features of pediatric LS cases whose age at genetic diagnosis was not more than 18 years. RESULTS Genetic analysis identified a novel SCNN1G missense variant (c.1874C>T, p.Pro625Leu) in the proband with LS in childhood. In silico analysis revealed this heterozygous variant was highly conserved and deleterious. A total of 38 publications described pediatric LS associated with 25 pathogenic variants in SCNN1B and SCNN1G in 54 children. Despite the phenotypic heterogeneity, early-onset hypertension is the most common feature. All LS patients in this family or the reviewed cases showed significantly improvements in hypertension and hypokalemia after treatment with ENaC inhibitors. CONCLUSIONS This study identified a novel SCNN1G missense variant in a patient with pediatric LS, expanding the genetic spectrum of SCNN1G and demonstrating the PY motif of γ-ENaC as a potential mutant region. Early identification and specific management of LS in children and adolescents are important to prevent the development of hypertensive end-organ disease.

Pathogenicity and Long-Term Outcomes of Liddle Syndrome Caused by a Nonsense Mutation of SCNN1G in a Chinese Family

“…Inadequate symptoms and insufficient awareness of children with monogenic hypertension leading to fail to intervene in time, and most of them have developed complications in youth ( 12 ). According to the previous study, 90% pediatric patients had LS family history, so genetic screening can provide definitive confirmation of adult, and pediatric LS ( 22 , 35 ). Additionally, investigation of the pathogenicity of variants based on amiloride-sensitive currents is needed.…”

“…There are 29 mutation sites linked to LS, and nearly all mutations delete or alter PY motifs, and include frameshift, nonsense, or missense mutations ( 12 , 20 , 22 – 24 ). Among the SCNN1G genetic spectrum, 10 sites have been detected ( 3 , 13 , 22 , 23 ), including four nonsense mutations, three missense mutations, and three frameshift mutations ( Table 2 ).…”

“…There are 29 mutation sites linked to LS, and nearly all mutations delete or alter PY motifs, and include frameshift, nonsense, or missense mutations ( 12 , 20 , 22 – 24 ). Among the SCNN1G genetic spectrum, 10 sites have been detected ( 3 , 13 , 22 , 23 ), including four nonsense mutations, three missense mutations, and three frameshift mutations ( Table 2 ). The first identified SCNN1G mutation was a nonsense mutation (p.Trp573*) reported by Hansson et al; Xenopus oocytes expressing mutant p.Trp573* displayed 7.5-fold increase in amiloride-sensitive sodium current than wild-type ( 25 ).…”

A Novel Frame-Shift Mutation in SCNN1B Identified in a Chinese Family Characterized by Early-Onset Hypertension

“…Even patients in the same family carrying the same pathogenic mutation may present with mild hypertension or even normotension ( 22 ). In terms of the serum potassium condition, hypokalemia was observed in 71.8% of Liddle syndrome patients, and 78% of pediatric Liddle syndrome patients ( 37 , 38 ). In this study, subjects IV-3 and III-1 presented typically with early-onset severe hypertension, whereas subjects III-7 and III-5 showed mild hypertension, and subjects IV-1 and IV-2 had normal blood pressure.…”

Differentiated mouse kidney tubuloids as a novel in vitro model to study collecting duct physiology

“…However, these studies suggest that some mechanisms of, e.g., AQP2 trafficking remain to be unveiled ( Olesen and Fenton, 2021 ). Because these diseases have low prevalence, patient sample size and lack of clinical data are limitations to further unveil the pathophysiology and improved (personalized) treatments ( Enslow et al, 2019 ; Fan et al, 2020 ). Here, tubuloids from existing mouse models can be of added value to study these tubulopathies.…”