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 years, 28 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-LQTS-affected family member were studied using patch clamp techniques. Ventricular action potential duration (APD90) was prolonged in iPSC-CMs obtained from the AF-LQTS-affected patient (Figure), but normal in the patient with AF-only (not shown), consistent with the patients’ QT intervals. Atrial APD10 was shorter and APD90 longer in iPSC-CMs from the AF-LQTS-affected patient, compared to unaffected control. Evaluation of atrial properties of AF-only iPSC-CMs is ongoing, together with determination of KCNQ1 protein expression and functional properties.
Conclusions: Our preliminary data suggest that human iPSC-CMs may recapitulate the clinical phenotypes observed in a multigenerational family manifesting early-onset AF and LQTS. These data provide a framework to study the molecular mechanisms underlying variable expressivity in an inherited arrhythmia syndrome.
Author Disclosures: C.J. Jou: None. M. Riedel: None. N. Bowles: None. C. Arrington: None. S. Bleyl: None. B. Kennedy: None. M. Yandell: None. S. Etheridge: Consultant/Advisory Board; Modest; SADS Foundation Vice President and Board. E. Saarel: None. T. Pilcher: None. S. Lai: None. C. Pribble: None. B. Bacon: None. J. Saunders: None. L. Meyers: None. A. Lopez-Izquierdo: None. S. Cho: None. S. Knight: None. J. Muhlestein: None. J. Carlquist: None. J. Anderson: None. I. Benjamin: None. M. Tristani-Firouzi: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.