A FRAMESHIFT MUTATION IN THE SCNN1B GENE CAUSING LIDDLE SYNDROME AND A GENOTYPE-PHENOTYPE CORRELATION OF 18 CASES WITH THE P603 RESIDUE VARIANT

Abstract

Objective: Liddle syndrome is an autosomal dominant form of monogenic hypertension caused by mutation of the SCNN1A, SCNN1B, and SCNN1G genes, which respectively encode various subunits of the epithelial sodium channel. In this report, we describe a frameshift mutation in SCNN1B in a Chinese family with early-onset hypertension and hypokalemia. Design and method: DNA was extracted from leucocytes in peripheral blood obtained from all family members. Whole-exome sequencing and Sanger sequencing were performed to verify the candidate variant and conduct co-segregation analysis. We also reviewed the clinical and biochemical characteristics of patients with the same mutation described in the literature and performed a genotype–phenotype correlation analysis. Results: Whole-exome sequencing identified a c.1806dupG frameshift variant in SCNN1B leading to substitution of alanine for proline at position 603 and premature emergence of a stop codon at position 607. Phenotypic heterogeneity is evident in patients with the mutation reported in the literature and is reflected in the proportions with hypertension (94.4%), hypokalemia (58.9%), hypoaldosteronemia (52.9%), and hyporeninemia (41.1%). Patients with the mutation have a good response to targeted ENaC inhibitor therapy. Conclusions: We have identified a frameshift mutation (c.1806dupG) in SCNN1B in a Chinese family characterized by early-onset hypertension and hypokalemia. Confirmatory genetic testing is necessary and targeted therapy should be used to prevent premature onset of clinical endpoints events in patients suspected to have mutation. Genotype-phenotype correlation analysis involving the P603 residue variant provides further evidence of phenotypic heterogeneity and guidance for clinical management of Liddle syndrome.