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We report an inherited cardiac arrhythmia syndrome consisting of Brugada and Early Repolarization Syndrome associated with variants in <jats:italic>SCN9A<\/jats:italic>, <jats:italic>PXDNL<\/jats:italic>, and <jats:italic>FKBP1B<\/jats:italic>. 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. <jats:italic>Methods and Results<\/jats:italic>. 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<jats:sup>2+<\/jats:sup> 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 <jats:italic>SCN9A<\/jats:italic>, <jats:italic>PXDNL<\/jats:italic>, and <jats:italic>FKBP1B<\/jats:italic> in the proband. The proband displayed right bundle branch block and exhibited episodes of syncope. The father carried a mutation in <jats:italic>FKBP1B<\/jats:italic>, whereas the mother and sister carried the <jats:italic>SCN9A<\/jats:italic> 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<jats:sup>2+<\/jats:sup> transients that were episodic in nature. Patch-clamp measurements in hiPSC-CM showed no difference in <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M1\"><mml:msub><mml:mrow><mml:mi>I<\/mml:mi><\/mml:mrow><mml:mrow><mml:mtext>Na<\/mml:mtext><\/mml:mrow><\/mml:msub><\/mml:math> but reduced <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M2\"><mml:msub><mml:mrow><mml:mi>I<\/mml:mi><\/mml:mrow><mml:mrow><mml:mtext>Ca<\/mml:mtext><\/mml:mrow><\/mml:msub><\/mml:math> in the proband compared with control. Coexpression of <jats:italic>PXDNL<\/jats:italic>-R391Q with <jats:italic>SCN5A<\/jats:italic>-WT displayed lower <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M3\"><mml:msub><mml:mrow><mml:mi>I<\/mml:mi><\/mml:mrow><mml:mrow><mml:mtext>Na<\/mml:mtext><\/mml:mrow><\/mml:msub><\/mml:math> density compared to <jats:italic>PXDNL<\/jats:italic>-WT. In addition, coexpression of <jats:italic>PXDNL<\/jats:italic>-R391Q with <jats:italic>KCND3<\/jats:italic>-WT displayed significantly higher <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M4\"><mml:msub><mml:mrow><mml:mi>I<\/mml:mi><\/mml:mrow><mml:mrow><mml:mtext>to<\/mml:mtext><\/mml:mrow><\/mml:msub><\/mml:math> density compared to <jats:italic>PXDNL<\/jats:italic>-WT. <jats:italic>Conclusion<\/jats:italic>. <jats:italic>SCN9A<\/jats:italic>, <jats:italic>PXDNL<\/jats:italic>, and <jats:italic>FKBP1B<\/jats:italic> 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 <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M5\"><mml:msub><mml:mrow><mml:mi>I<\/mml:mi><\/mml:mrow><mml:mrow><mml:mtext>Na<\/mml:mtext><\/mml:mrow><\/mml:msub><\/mml:math> and <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M6\"><mml:msub><mml:mrow><mml:mi>I<\/mml:mi><\/mml:mrow><mml:mrow><mml:mtext>Ca<\/mml:mtext><\/mml:mrow><\/mml:msub><\/mml:math> and gain of function of <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M7\"><mml:msub><mml:mrow><mml:mi>I<\/mml:mi><\/mml:mrow><mml:mrow><mml:mtext>to<\/mml:mtext><\/mml:mrow><\/mml:msub><\/mml:math>.<\/jats:p>","DOI":"10.1155\/2020\/8842398","type":"journal-article","created":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T23:34:03Z","timestamp":1599003243000},"page":"1-16","source":"Crossref","is-referenced-by-count":10,"title":["Susceptibility to Ventricular Arrhythmias Resulting from Mutations in <i>FKBP1B<\/i>, <i>PXDNL<\/i>, and <i>SCN9A<\/i> Evaluated in hiPSC Cardiomyocytes"],"prefix":"10.1155","volume":"2020","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2704-3807","authenticated-orcid":true,"given":"Hector","family":"Barajas-Martinez","sequence":"first","affiliation":[{"name":"Department of Experimental Cardiology, Masonic Medical Research Institute, Utica, NY, USA"},{"name":"Department of Cardiovascular Research, Lakenau Institute for Medical Research, Wynnewood, PA, 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