Abstract 481: Investigation into the Genetic Cause of Congenital Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells

Abstract

Congenital dilated cardiomyopathy (cDCM) is a rare but typically fatal disease. In most cases, its etiology is unknown, but a genetic root cause is often suspected. The objective of current study is to determine whether a novel non-structural gene causes cDCM. We hypothesized that rare genetic mutations caused cDCM, which could be modeled using patient-derived induced pluripotent stem cells (iPSCs). We generated the cardiomyocytes from iPSCs of a cDCM proband and found significant impairment in contractility and mitochondrial function, compared to those of healthy controls. To identify the causal mutations, we performed a whole exome sequencing of the cDCM patient and his parents (“trio”). Based on the assumption of recessive mode of inheritance or a de novo mutation, 9 candidate causal genes were identified. On the ground of the expression profiles of trio and pathogenicity predictor algorithms, we identified an indel and a nonsynonymous point mutation in the rotatin (encoded by RTTN ) gene as the putative genetic defect responsible for cDCM. CRISPR/Cas9-mediated knockout of RTTN in healthy control iPSCs recapitulated cardiomyocyte defects, and the correction of the missense mutation in the disease iPSCs restored cardiomyocyte structure and function, confirming causality. Thus, rotatin is a new causal molecule for cDCM and plays an important role in cardiac regulation.