Abstract

The objective of this study was to clinically and genetically characterize a pedigree with Liddle syndrome (LS). A LS pedigree comprising with one proband and seven family members was enrolled. The subjects’ symptoms, laboratory results and genotypes were analyzed. Peripheral venous samples were collected from the subjects, and genomic DNA was extracted. DNA library construction and exome capture were performed on an Illumina HiSeq 4000 platform. The selected variant sites were validated using Sanger sequencing. The mutation effects were investigated using prediction tools. The proband and her paternal male family members had mild hypertension, hypokalemia and muscle weakness, including the absence of low renin and low aldosterone. Genetic analysis revealed that the proband carried a compound heterozygous mutation in SCNN1A, a novel heterozygous mutation, c.1130T > G (p.Ile377Ser) and a previously characterized polymorphism, c.1987A > G (p.Thr633Ala). The novel mutation site was inherited in an autosomal dominant manner and was predicted by in silico tools to exert a damaging effect. Alterations in the SCNN1A domain were also predicted by protein structure modeling. After six months of follow-up, treatment had significantly improved the patient’s limb weakness and electrolyte levels. The novel mutation c.1130T > G of the SCNN1A gene was detected in the pedigree with LS. The clinical manifestations of the pedigree were described, which expand the phenotypic spectrum of LS. This result of this study also emphasizes the value of genetic testing for diagnosing LS.

摘要

本研究的目的是对患有 Liddle 综合征 (LS) 的家系进行临床和遗传特征分析。登记了由一名先证者和七名家庭成员组成的 LS 谱系。分析了受试者的症状、实验室结果和基因型。采集受试者外周静脉样本，提取基因组DNA。DNA 文库构建和外显子组捕获在 Illumina HiSeq 4000 平台上进行。使用 Sanger 测序验证选定的变异位点。使用预测工具研究突变效应。先证者和她父亲的男性家庭成员有轻度高血压、低血钾和肌无力，包括没有低肾素和低醛固酮。遗传分析显示，先证者携带复合杂合突变SCNN1A，一种新的杂合突变，c.1130T > G (p.Ile377Ser) 和先前表征的多态性，c.1987A > G (p.Thr633Ala)。新的突变位点以常染色体显性方式遗传，并通过计算机工具预测会产生破坏性影响。蛋白质结构建模也预测了SCNN1A结构域的改变。经过六个月的随访，治疗显着改善了患者的四肢无力和电解质水平。SCNN1A 的新突变 c.1130T > G用 LS 在系谱中检测到基因。描述了家系的临床表现，扩展了LS的表型谱。这项研究的结果也强调了基因检测对诊断 LS 的价值。