Susceptibility to Ventricular Arrhythmias Resulting from Mutations in , , and Evaluated in HiPSC Cardiomyocytes

Background: We report an inherited cardiac arrhythmia syndrome consisting of Brugada and Early Repolarization Syndrome associated with variants in , , and . The proband inherited the 3 mutations and exhibited palpitations and arrhythmia-mediated syncope, whereas the parents and sister, who carried one or two of the mutations, were asymptomatic.

Methods And Results: We assessed the functional impact of these mutations in induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) derived from the proband and an unaffected family member. Current and voltage clamp recordings, as well as confocal microscopy analysis of Ca transients, were evaluated in hiPSC-CMs from the proband and compared these results with hiPSC-CMs from undiseased controls. Genetic analysis using next-generation DNA sequencing revealed heterozygous mutations in , , and in the proband. The proband displayed right bundle branch block and exhibited episodes of syncope. The father carried a mutation in , whereas the mother and sister carried the mutation. None of the 3 family members screened developed cardiac events. Action potential recordings from control hiPSC-CM showed spontaneous activity and a low upstroke velocity. In contrast, the hiPSC-CM from the proband showed irregular spontaneous activity. Confocal microscopy of the hiPSC-CM of the proband revealed low fluorescence intensity Ca transients that were episodic in nature. Patch-clamp measurements in hiPSC-CM showed no difference in but reduced in the proband compared with control. Coexpression of -R391Q with -WT displayed lower density compared to -WT. In addition, coexpression of -R391Q with -WT displayed significantly higher density compared to -WT.

Conclusion: , , and variants appeared to alter spontaneous activity in hiPSC-CM. Only the proband carrying all 3 mutations displayed the ERS/BrS phenotype, whereas one nor two mutations alone did not produce the clinical phenotype. Our results suggest a polygenic cause of the BrS/ERS arrhythmic phenotype due to mutations in these three gene variants caused a very significant loss of function of and and gain of function of .