Susceptibility to Ventricular Arrhythmias Resulting from Mutations in FKBP1B , PXDNL , and SCN9A Evaluated in hiPSC Cardiomyocytes.

Background: We report an inherited cardiac arrhythmia syndrome consisting of Brugada and Early Repolarization Syndrome associated with variants in SCN9A , PXDNL , and FKBP1B . 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 ²⁺ 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 SCN9A , PXDNL , and FKBP1B in the proband. The proband displayed right bundle branch block and exhibited episodes of syncope. The father carried a mutation in FKBP1B , whereas the mother and sister carried the SCN9A 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 ²⁺ transients that were episodic in nature. Patch-clamp measurements in hiPSC-CM showed no difference in I _Na but reduced I _Ca in the proband compared with control. Coexpression of PXDNL -R391Q with SCN5A -WT displayed lower I _Na density compared to PXDNL -WT. In addition, coexpression of PXDNL -R391Q with KCND3 -WT displayed significantly higher I _to density compared to PXDNL -WT.
Conclusion: SCN9A , PXDNL , and FKBP1B 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 I _Na and I _Ca and gain of function of I _to .
Competing Interests: The authors report no relationships that could be construed as a conflict of interest.
(Copyright © 2020 Hector Barajas-Martinez et al.)