Abstract 1094: Transcription Signature of Ion Channel Genes in Brugada Syndrome
The Brugada syndrome is an inherited arrhythmia syndrome associated with a high risk for sudden cardiac death. Diagnosis of Brugada syndrome is made by a unique electrocardiographic pattern in the right precordial leads. However, in many cases, the diagnosis of the syndrome remains uncertain and mutation detection in the cardiac sodium channel gene SCN5A is helpful in only about 20% of probands. In order to identify novel molecular markers for Brugada syndrome, we performed transcriptional profiling in right ventricular septal endomyocardial biopsies from 11 unrelated probands with Brugada syndrome, 11 non-diseased organ donors (control 1 group) and 7 patients early after heart transplantation (control 2 group). When analyzed for 81 genes encoding ion channel and transporter subunits, hierarchical clustering showed that patients with Brugada syndrome clustered separately from the two control groups and fully discriminated Brugada syndrome patients from controls based on transcriptional fingerprint. Fifteen genes showed differential expression between Brugada syndrome and both control groups. These included Nav1.5 which was down-regulated, and Nav1.3 and Nav2.1, which were up-regulated in Brugada syndrome. Also typical for Brugada syndrome was an up-regulation of Cx43 and the T-type Ca2+ channel alpha-subunit Cav3.1. Alterations in the expression of transcripts involved in Ca2+-homeostasis included up-regulation of RYR2. Among K+ channel genes, the two-pore domain channel genes TWIK1 and TASK2 were up-regulated in Brugada syndrome. The molecular profile of the 5 Brugada syndrome patients with a mutation in SCN5A did not differ from that of the remaining 6 patients without a SCN5A mutation. We conclude that patients with Brugada syndrome exhibit a common ionic molecular signature irrespective of the culprit gene. We provide first evidence that genomics with transcriptional profiling may become a diagnostic tool in an arrhythmia syndrome.