Abstract
Congenital heart disease (CHD) is the most common cause of infant death associated with birth defects. Recent next-generation genome sequencing has uncovered novel genetic etiologies of CHD, from inherited and de novo variants to non-coding genetic variants. The next phase of understanding the genetic contributors of CHD will be the functional illustration and validation of this genome sequencing data in cellular and animal model systems. Human induced pluripotent stem cells (iPSCs) have opened up new horizons to investigate genetic mechanisms of CHD using clinically relevant and patient-specific cardiac cells such as cardiomyocytes, endothelial/endocardial cells, cardiac fibroblasts and vascular smooth muscle cells. Using cutting-edge CRISPR/Cas9 genome editing tools, a given genetic variant can be corrected in diseased iPSCs and introduced to healthy iPSCs to define the pathogenicity of the variant and molecular basis of CHD. In this review, we discuss the recent progress in genetics of CHD deciphered by large-scale genome sequencing and explore how genome-edited patient iPSCs are poised to decode the genetic etiologies of CHD by coupling with single-cell genomics and organoid technologies.
Highlights
Congenital heart disease (CHD) is a leading cause of birth defect-related death and affects ∼1% of live births in the United States (Hoffman and Kaplan, 2002; Nees and Chung, 2019)
Septation defects consist of atrial septal defects (ASD), ventricular septal defects (VSD) and atrioventricular septal defects (AVSD) while common conotruncal and aortic arch artery anomalies include tetralogy of Fallot (TOF), persistent truncus arteriosus and interrupted aortic arch
We explore the fascinating perspectives on using patient-specific induced pluripotent stem cells (iPSCs) and CRISPR genome editing to functionally study the genetic and epigenetic determinants of CHD
Summary
Congenital heart disease (CHD) is a leading cause of birth defect-related death and affects ∼1% of live births in the United States (Hoffman and Kaplan, 2002; Nees and Chung, 2019). Human iPSCs are promising models for studying genetic mechanisms of isolated CHD caused by single-gene defects.
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