Abstract 20339: Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Recapitulate Clinical Phenotypes in a Multigenerational Family With Early Onset Atrial Fibrillation and Long Qt Syndrome

Introduction: Early-onset atrial fibrillation (AF) and Long QT Syndrome (LQTS) are associated with gain- and loss-of-function mutations in cardiac potassium channel genes, respectively. Counterintuitively, AF and LQTS clinical phenotypes have been reported within individuals sharing the same mutation. Here, we test the hypothesis that human induced-pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) recapitulate the clinical phenotypes in a multigenerational family with early-onset AF and LQTS. Methods and Results: Whole-exome sequencing of 2 early-onset AF pedigrees revealed a KCNQ1 (R231H) missense mutation. Using the Utah Population Database, we expanded the 2 families to an 8-generational pedigree, with founders dating to the 1820s and confirmed the co-segregation of R231H with the clinical phenotype. Ascertainment revealed 10 members with AF onset 45 or unknown, 5 with LQTS, and 3 with young onset AF and LQTS. Human iPSC-CMs derived from an unaffected, AF-only and AF-...