Table 2.

Overview of current iPSC models of genetic-based cardiac disease including the genetic mutation responsible, the reprogramming and differentiation methods applied, and disease phenotypes observed.

Disease model	Genetic cause	Source of somatic cells	Reprogramming strategy	Cardiac differentiation	Disease phenotypes observed		Rescue
LEOPARD syndrome (Carvajal-Vergara et al., 2010)	ptpn11 (SHP2) T468M substitution	Skin	Retrovirus: oct4, sox2, klf4, and c- myc	EB, staged, defined	Increased cell size and sarcomeric organization; Nuclear localization of NFATC4		N/A
Long QT 1 (Moretti et al., 2010)	kcnq1 (IKs) R190Q missense mutation	Skin	Retrovirus: oct4, sox2, klf4, and c- myc	EB, serum- based	Catecholamine-induced tachyarrhythmia		Propanolol
Long QT 2 (Itzhaki et al., 2011)	kcnh2/herg (IKr) A614V missense mutation	Skin	Retrovirus: oct4, sox2, and klf4	EB, serum- based	Prolongation of AP duration	EAD; Triggered arrhythmias	Nifepidine, Pinacidil, and Ranolazine
Long QT 2 (Matsa et al., 2011)	kcnh2/herg (IKr) G1681A point mutation	Skin	Lentivirus: oct4, sox2, nanog, and lin28	EB, serum- based	Deficient IKr activity	Arrhythmias and EAD triggered by E4031 and isoproterenol	Propanolol, Nadalol, Nicorandil, and PD118057
Long QT 2 (Lahti et al., 2012)	kcnh2/herg (IKr) R176W missense mutation	Skin	Retrovirus: oct4, sox2, klf4, and c- myc	Co-culture with END2		Spontaneous arrhythmogenic activity, aggravated by E4031 and sotalol	N/A
Timothy syndrome (Yazawa et al., 2011)	cacna1c (CaV1.2) G406R missense mutation	Skin	Retrovirus: oct4, sox2, klf4, and c- myc	EB, serum- based	Irregular contraction, prolonged action potentials, altered Ca2+ influx, and transients in ventricular-like cells		Roscovitine
Catecholaminergic polymorphic ventricular tachycardia (Itzhaki et al., 2012)	RYR2 M4109R point mutation	Skin	Retrovirus: oct4, sox2, and klf4	EB, serum- based	DAD and abnormal Ca2+ handling	Isoproterenol and forskolin increased frequency and magnitude of AD, also leading to development of triggered activity; Whole-cell Ca2+ transient irregularities, worsened with adrenergic stimulation and Ca2+ overload	Flecainide, Thapsighargin, and Propanolol
Catecholaminergic polymorphic ventricular tachycardia (Fatima et al., 2011)	ryr2 p.F2483I mutation	Skin	Retrovirus: oct4, sox2, klf4, and c- myc	Co-culture with END2		Development arrhythmogenic behaviors and DAD following isoproterenol treatment; Higher amplitude and longer duration of spontaneous local Ca2+ releasing events	N/A
Catecholaminergic polymorphic ventricular tachycardia (Jung et al., 2012)	RYR2 S406L missense mutation	Skin	Retrovirus: oct4, sox2, klf4, and c- myc	EB, serum- based	DAD and abnormal Ca2+ handling	Prolongation of Ca2+ sparks	Dantrolene
Catecholaminergic polymorphic ventricular tachycardia (Kujala et al., 2012)	RYR2 P2328S mutation	Skin	Retrovirus: oct4, sox2, klf4, and c- myc	Co-culture with END2 cells		Abnormal Ca2+ signaling and arrhythmias upon catecholaminergic stress; Reduced SR Ca2+ content, indicating leakage of Ca2+ from the SR; DAD during spontaneous beating and in response to adrenaline; EAD during spontaneous beating	N/A
Familial dilated cardiomyopathy (Sun et al., 2012)	TNNT2 (cTNT) R173W point mutation	Adipose tissue	Retrovirus: oct4, sox2, klf4, and c- myc	EB, staged, defined	Abnormal sarcomeric structure and contractility, aggravated by β-adrenergic stimulation; Alterations in Ca2+ handling		Metoprolol and forced overexpression of Serca2a
Arrhythmogenic right ventricular cardiomyopathy (Ma et al., 2012)	plakophilin-2 c.1841T.C nucleotide change	Skin	Retrovirus oct4, sox2, klf4, and c- myc	EB, serum- based	Increased lipid accumulation in AC CMs following	Reduced plakoglobin expression. Larger and denser lipid droplets	N/A
Arrhythmogenic right ventricular cardiomyopathy (Kim et al., 2013)	plakophilin-2 homozygous c.2484C.T frameshift mutation and c.2013delC frameshift mutation	Skin	Retrovirus oct4, sox2, klf4, and c- myc	EB, serum- based	adipogenic conditions	Nuclear localization of plakoglobin, reduced β-catenin activity, and increased apoptosis. Metabolic shift from FAO towards glycolysis. Deficient Ca2+ relaxation and reduced serca2a and ncax1 expression	Forced expression of plakophilin-2. N-acetyl cysteine and ascorbic acid; GW966, T0070907, and GW6471
Overlapping Na+ channel disease syndrome (Davis et al., 2012)	SCN5A (INa) 1795insD insertion mutation	Skin	Floxed lentivirus: oct4, sox2, klf4, and c-myc	Co-culture with END2 cells	Decrease in peak INa and an increase in persistent INa		N/A

EAD = Early afterdepolarizations; DAD = delayed afterdepolarizations; FAO = fatty acid oxidation.