Exome Sequencing to Identify Novel Genes in Hypertension

Study HypothesisPrevious genetic studies of patients with Mendelian forms of hypertension have identified causal genes involving renal electrolyte transport, highlighting new mechanisms for the regulation of blood pressure in humans. Pseudohypoaldosteronism type II (PHAII), a rare genetic disorder causing hypertension, hyperkalemia, and metabolic acidosis, has been found, in some cases, to be caused by mutations in WNK1 or WNK4 , but most cases remained unexplained at the time of the study. The authors proposed that exome sequencing and gene resequencing of a number of unrelated individuals with PHAII would uncover novel causal genes. How Was the Hypothesis Tested?Boyden et al recruited 52 kindreds with 126 patients with PHAII, of which just 7 kindreds were found to have WNK1 or WNK4 mutations. They performed exome sequencing of DNA samples of 11 unrelated PHAII index cases from 11 kindreds. They simultaneously performed genomewide genotyping of single nucleotide polymorphisms (SNPs) in all members of the kindreds, in order to perform linkage studies that would …