Clinical and Translational Medicine | 2021
A consistent arrhythmogenic trait in Brugada syndrome cellular phenotype
Abstract
To the Editor: Brugada syndrome (BrS) is an inherited arrhythmic disease predisposing to sudden cardiac death (SCD), characterized by a typical electrocardiogrampattern that includes a J point elevation with a coved type ST segment.1 BrS is a complex genetic disease in which ∼20% of patients carry rare variants in SCN5A gene, whereas the others remain genetically unresolved.2 Despite this genetic complexity, we hypothesize that a common cellular phenotypic trait is at the root of this specific BrSECGpattern. In this study,we identified a phenotype that is common to human-induced pluripotent stem cell-derived ventricular cardiomyocytes (hiPSC-CMs) generated from six Brugada patientswith different genetic backgrounds. Our results unmasked a cellular arrhythmogenic phenotype combining gene expression and electrical abnormalities, including an increase in late sodium current. Six patients affected by type I BrS (BrS1-6; Figure S1; Tables S1 and S2) with a familial history of SCD or syncope were selected, among whom two carry SCN5A variants (marked with a + symbol). An additional individual, not affected by BrS (non-BrS), carrying the same SCN5A variant as BrS2, was also recruited, as well as four control (Ctrl) subjects. Somatic cells from all studied subjects were reprogrammed into hiPSC lines and differentiated into cardiomyocytes (Figure 1). Transcriptional expression profiling identified 133 differentially expressed genes in BrS hiPSC-CMs (Figure 2A). gene set enrichment analyses showed that transcripts of transmembrane transporters and channels were significantly overrepresented (Figure 2B), including genes encoding sodium, calcium, and potassium channels (Figure 2C). High-throughput real-time RT-PCR3 on 96 genes related to cardiac electrical function (Table S3) identified 13 differentially expressed genes in BrS, in comparison to Ctrl and non-BrS hiPSC-CMs (Figure 2D). Importantly, the expression of SCN5A, the main BrS culprit gene identified to date,4 remained unchanged, excluding