Table 2.

List of cardiovascular diseases and their pathogenic variants identified from hiPSC-based disease modeling in combination with genome editing and NGS methodologies.

Disease Name	Causative Gene	Mutation/SNP	Altered Signaling Pathway	Technology Used	References
Barth Syndrome	TAZ gene	point mutations, deletions, and duplications	Mitochondrial ROS production and energy metabolism.	CRISPR/Cas9	[61,62]
Type I Brugada Syndrome	SCN5A gene	Single-Nucleotide Polymorphism	Inward sodium current pathway, increased triggered activity, and abnormal calcium transients	CRISPR/Cas9	[63]
Long QT syndrome	CALM1-3 gene	relatively unknown	Abnormal electrophysiological properties of LQT15-hiPSC-CMs which was prolonged APD (dominant-negative suppression of LTCC inactivation)	Cas9 double nickase system	[64]
Long QT syndrome	KCNH2 gene	heterozygous c.A2987T mutation	IKr reduction with consequential action potential (AP) duration (APD) prolongation	Homologous recombination using Cre recombinase	[65]
Cardiomyopathy	LMNA gene	frameshift mutation	PDGF signaling pathway	TALEN	[66]
Congenital defect of the bicuspid valve	N1 gene	heterozygous nonsense mutations in N1	Notch signaling pathway	TALEN	[28]
Doxorubicin-induced cardiotoxicity (DIC)	RARG-S427L gene	missense mutation	Differential regulation pathway of topoisomerase IIβ (TOP2B)	CRISPR/Cas9	[67]
Bicuspid Aortic Valve (BAV)	GATA4	missense mutation	The transition of endothelial into mesenchymal cells (EndoMT pathway), a critical step in heart valve formation	CRISPR/Cas9	[68]
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C)	SCN5A	missense desmosomal mutation	Amino acid substitution in Nav1.5 revealed changes in the sodium current amplitude and structural deficit in the organization of a protein directly relevant to cell adhesion (N-Cadherin)	CRISPR/Cas9	[69]
Fabry Cardiomyopathy	GLA gene	Base substitution at intron 4 and insertion between exon 4 and 5	Proinflammatory pathway; NF-κB and MAPK signaling pathway.	CRISPR/Cas9	[70]
Marfan Syndrome	FBN1	missense mutation at exon 30	Inhibition of fibrillin-1 and TGF-β pathway	CRISPR/Cas9	[71]
Dilated cardiomyopathy	RBM20	missense mutation	Impaired interactions with spliceosomal proteins	CRISPR/Cas9	[72]
Dilated cardiomyopathy	PLN	PLN R14del mutation	Ca(2+) handling abnormalities, electrical instability	TALEN	[73]
Dilated cardiomyopathy	SPEG E1680K	missense mutation	Striated muscle enriched protein kinase pathway	CRISPR/Cas9	[74]
congenital heart diseases	NAA15	loss of function and missense variant	Consequences of amino acid sequence variants of unknown significance on NAA15 function	CRISPER/Cas9	[75]
Friedreich’s ataxia	FXN	intronic expansion of GAA repeats	Altered iron homeostasis regulation	ZFN	[76]