Phenotype-genotype analysis in two Chinese families with Liddle syndrome

The families with Liddle syndrome show marked phenotypic variation in blood pressure, serum potassium and other clinical manifestations. Here we analyzed the correlation of genotype-phenotype in two Chinese families with Liddle syndrome. The sequence of C-terminus of SCNN1B and SCNN1G were screened in the two families with likely Liddle syndrome. In addition to hypertension and hypokalemia, one of the two pedigrees had sudden death in their family members, so the exons of 428 reported genes-related to cardiovascular diseases were screened as well in the family. A heterozygous beta R566X nonsense mutation was found in the proband-1 in the first pedigree, and the proband's sister and father. They showed mild phenotype with hypertension under control. In contrast, two of the four previous studies report that the mutation causes severe phenotype. A heterozygous beta R597PfrX607 frameshift mutation was identified in the proband-2 in the second pedigree, showing malignant phenotype including resistant hypertension, hypokalemia, higher PRA and plasma angiotensin II levels. Both the proband-2 and the proband-2's father had sudden death in their twenties, but no meaningful mutations were found by screening of the exons in 428 cardiovascular disease-related genes. However, the same mutation has been related to moderate phenotype in previous studies. Our results confirmed that the phenotypes of Liddle syndrome are varied significantly even with the same mutation. The mechanisms why the same mutation causes very different phenotype need to be explored because intervention of these modifiers may change the disease course and prognosis accordingly.