Abstract 96: A Unique Jervell Lange-Nielsen Syndrome Mutation Modeled in Induced Pluripotent Stem Cell Derived Cardiomyocytes

Abstract

Introduction: Current screening for mutations in human disease is turning increasingly to next-generation methods that map short reads to a reference sequence. We report here an unusual variant that was undetected by next generation sequencing in a patient diagnosed with Jervell Lange-Nielsen syndrome (JLNS) and initial results in an induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model. Methods and Results: A diagnosis of JLNS was made in a middle-aged woman with congenital deafness and QT intervals as long as 800 msec. However, next-generation sequencing found only a heterozygous KCNQ1 mutation, R518X. Convinced by the clinical phenotype that a second causative variant was highly likely, we used Sanger sequencing of PCR KCNQ1 amplicons to identify a 36-basepair poly-adenine tract, encoding 12 lysines, inserted within the coding sequence at the 5’ end of exon 15. Electrophysiological studies in patient-specific IPSC-CMs revealed marked prolongation of ventricular-like action potentials (Figure). Conclusion: Long inserts of the type we identified here have not been previously reported in the long QT syndromes. We speculate that next generation-based short reads containing this variant could not be mapped to a reference sequence and thus this type of variant will be missed by next-generation analysis unless bioinformatics filters are specifically modified to include this possibility. Validation of this long QT syndrome iPSC-CM model provides a human cell based platform for drug discovery and mechanistic studies to further our understanding of disease pathogenesis.