Integrating Patient-Specific Cardiomyocyte Function With Population Multi-Omics Identifies A Novel Arrhythmia Pathway

Introduction: In a family with Brugada Syndrome (BrS) and no mutation in the most common disease gene SCN5A, we identified a rare hypofunctional missense variant (G145R) in the transcription factor TBX5. Methods: Transcriptional and functional results (detailed below) in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from patients (TBX5G145R/WT), isogenic controls (i.e. after CRISPR/Cas9 correction of G145R), and population controls implicated platelet-derived growth factor (PDGF) as an arrhythmia mediator. We developed SNP-based predictors of serum PDGF from Framingham Heart Study data and deployed these in a phenome wide association study (PheWAS) in 41,911 electronic health records in the eMERGE network. Results: TBX5G145R/WT iPSC-CMs displayed reduced peak sodium current (INa), the hallmark of BrS (-58±4.9 pA/pF at -30 mV), compared to the controls (isogenic: -133±6.5; population: -124±8.0, Pu003c0.05). TBX5G145R/WT iPSC-CMs also displayed increased late INa(2.2±0.3% vs 0.24±0.05% and 0.1...