Table 2.

Overview about important iPSC lines carrying mutations in genes associated with genetic cardiomyopathies or related diseases.

Gene	Protein	Mutation(s)	Method of Generation	Main Phenotypic Findings	Associated Disease	References
ACTC1	Cardiac Actin	p.E99K	▪Sendai virus transduction ▪Isogenic controls using CRISPR-Cas9 (PiggyBac)	Arrhythmias	HCM/LVNC	[380]
ALPK3	α-Kinase 3	p.W1264Xhom	Electroporation with episomal plasmids	▪Sarcomeric disarray ▪Ca2+ handling defects	HCM	[381]
BAG3	Bcl-2 Associated Athanogene 3	▪p.R90X ▪p.R90Xhom ▪p.R123X	▪Electroporation with episomal plasmids ▪& genome editing using ▪CRISPR-Cas9 ▪TALENs	▪Decreased BAG3 expression ▪Sarcomeric disarray after prolonged culture ▪Decreased contraction	DCM	[374]
BRAF	B-Raf Proto-Oncogene, Serine/Threonine Kinase	▪p.Q257R ▪p.T599R	▪Retroviral transduction ▪Electroporation with episomal plasmids	▪Cellular hypertrophy ▪Pro-hypertrophic gene expression ▪Ca2+ handling defects ▪Abnormal TGFβ signaling	CFCS/HCM	[382]
CAV	Caveolin	▪c.303G > C ▪c.233C > A ▪c.∆184-192	Electroporation with episomal plasmids	NA	MP	[383]
CRYAB	αB-Crystallin	▪c.343delThet ▪c.343delThom	Retroviral transduction and genome editing (zinc finger nucleases)	▪No detectable expression of mutant αB-Crystallin ▪Loss of function mechanism	MFM	[384]
DES	Desmin	p.N116S	Lentiviral transduction	NA	ACM	[385]
DES	Desmin	c.735+1G > A	Sendai virus transduction	NA	DRC	[386]
DES	Desmin	p.A285V	Retroviral transduction	▪Desmin aggregation ▪Z-disk streaming ▪Decreased spontaneous beating rate	DCM	[387]
DMD	Dystrophin	▪∆Ex8-12 ▪c.5899C > T	Sendai virus transduction	▪Electrophysiological alterations ▪Arrhythmias ▪Prolonged action potential	DMD	[388]
DMD	Dystrophin	▪∆Ex8-9 ▪∆Ex6-9 ▪∆Ex7-11 ▪∆Ex3-9	Sendai virus transduction in combination with CRISPR-Cas9	▪Out of frame deletion ∆Ex8-9 reduce contraction force ▪Second deletions to correct the reading fame of DMD restores the contractility	DMD	[379]
DMD	Dystrophin	▪c.263delG ▪∆Ex50	Lentiviral transduction CRISPR-Cas9	▪Reduced contractility ▪Ca2+ handling defects	DMD	[389,390]
DSG2	Desmoglein-2	p.G638R	Sendai virus transduction	▪Electrophysiological alterations ▪Ion channel dysfunction	ACM	[391]
DSP	Desmoplakin	p.R451G	Sendai virus transduction & genome editing for correction (CRISPR-Cas9)	Reduced desmoplakin expression	ACM	[392]
FBN1	Fibrillin 1	c.4028G > A	Sendai virus transduction	NA	Marfan Syndrome (HCM)	[393]
FKRP	Fukutin Related Protein	c.826C > Ahom	Lentiviral transduction	▪Abnormal action potential ▪Electrophysiological alterations ▪Decreased expression of SCN5A and CACNA1C	Limb-Girdle Muscular Dystrophy (DCM)	[394]
FXN	Frataxin	Expanded GAA repeats	Retroviral transduction	▪Iron homeostasis defects ▪Disorganized mitochondria ▪Cellular hypertrophy ▪Increased BNP expression ▪Ca2+ handling defects	Friedreich Ataxia (HCM)	[395]
FXN	Frataxin	Expanded GAA repeats ▪800/600 ▪900/400	Lentiviral transduction	▪Impaired mitochondrial function ▪Decreased mitochondrial membrane potential ▪Degeneration of mitochondria	Friedreich Ataxia (HCM)	[396]
GLA	Galactosidase α	IVS4+919G > A	Retroviral transduction	▪Decreased α-galactosidase activity ▪Cellular hypertrophy ▪Upregulation of fibrotic genes	Fabry Disease (HCM)	[397,398]
LAMP2	Lysosomal Associated Membrane Protein 2	IVS6+1_4delGTGA	Sendai virus transduction	Autophagy dysfunction	Danon Disease (CM)	[399]
LAMP2	Lysosomal Associated Membrane Protein 2	▪c.129-130insAT ▪IVS-1.c64+1G > A	Unknown	▪Mitochondrial-oxidative stress ▪Apoptosis ▪Disrupted mitophagic flux ▪Mitochondrial respiratory deficiency	Danon Disease (CM)	[400]
LAMP2	Lysosomal Associated Membrane Protein 2	▪c.1082delA ▪c.247C > T ▪c.64+1G > A	▪Retroviral transduction ▪Sendai virus transduction ▪CRISPR-Cas9 for correction	▪Defects in autophagic fusion ▪Mitochondrial abnormalities ▪Contractile abnormalities	Danon Disease (CM)	[401]
LMNA	Lamin A/C	p.S143P	Sendai virus transduction	▪Sarcomere damage after hypoxia ▪Arrhythmias after β-adrenergic stimulation ▪Ca2+ handling defects	DCM	[402]
LMNA	Lamin A/C	p.S18fsX	Combined lentiviral and retroviral transduction	Normal nuclear membrane morphology	DCM	[403]
LMNA	Lamin A/C	p.R225X	Lentiviral transduction	▪Reduced expression of lamin A/C ▪Increased cellular apoptosis under electrical stimulation	DCM	[404]
LMNA	Lamin A/C	▪p.R225X ▪p.Q354X ▪p.T518fsX29	Lentiviral transduction	▪Increased nuclear blebbing under electrical stimulation ▪Increased apoptosis under electrical stimulation ▪Haploinsufficiency ▪Treatment with PTC124 reverse the phenotypic findings	DCM & conduction disorders	[405]
LMNA	Lamin A/C	p.K219T	Lentiviral transduction	▪Electrophysiological alterations ▪Downregulation of SCN5A expression by epigenetic modulation of the promoter	DCM & conduction disorders	[406]
MT-RNR2	Mitochondrially Encoded 16S rRNA	m.2336T > C	Retroviral transduction	▪Decreased stability of 16S rRNA ▪Mitochondrial dysfunction ▪Reduced ATP/ADP ratio ▪Reduced mitochondrial potential ▪Electrophysiological alterations	HCM	[407]
MYBPC3	Myosin Binding Protein C3	▪p.V321M ▪p.V219L ▪c.2905+1G > A	Sendai virus transduction	Abnormal Ca2+ handling	HCM	[408]
MYBPC3	Myosin Binding Protein C3	p.R326Q	Electroporation with episomal plasmids	Ca2+ handling deficits	HCM	[409]
MYBPC3	Myosin Binding Protein C3	c.2373	Lentiviral transduction	▪Cellular hypertrophy ▪Contractile defect	HCM	[410,411]
MYBPC3	Myosin Binding Protein C3	p.R502W	Electroporation with episomal plasmids	NA	HCM	[412]
MYBPC3	Myosin Binding Protein C3	▪p.R502W ▪p.W792VfsX41	CRISPR-Cas9	▪Hypercontractility ▪P53 activation ▪Oxidative stress ▪Metabolic stress	HCM	[413]
MYBPC3	Myosin Binding Protein C3	▪p.R943X ▪p.R1073fsX4	Sendai virus transduction & genome editing for correction (CRISPR-Cas9)	▪Reduced expression of MYBPC3 at the mRNA level but not at the protein level ▪Ca2+ handling defects ▪Activation of nonsense-mediated mRNA decay	HCM	[414,415]
MYBPC3	Myosin Binding Protein C3	p.G999-Q1004del	Sendai virus transduction	▪Cellular hypertrophy ▪Myofibrillar disarray ▪Reduced MYBPC3 expression ▪Increased ANP expression	HCM	[416]
MYBPC3	Myosin Binding Protein C3	p.Q1061X	▪Sendai virus transduction ▪Retroviral transduction	Arrhythmias	HCM	[417,418]
MYBPC3	Myosin Binding Protein C3	p.V454CfsX21	Retroviral transduction	▪Haploinsufficiency (at the mRNA and protein level) ▪Cellular hypertrophy ▪Altered gene expression ▪Efficient gene replacement using AAV9 reduce phenotypic findings	HCM	[419]
MYBPC3	Myosin Binding Protein C3	∆25 bp in intron 32 including the splicing branch point & p.D389V (same allele)	Sendai virus transduction	▪Cellular hypertrophy ▪Ca2+ handling deficits	HCM	[420]
MYBPHL	Myosin Binding Protein H-Like	p.R255X	Electroporation with episomal plasmids	Haploinsufficiency by nonsense mediated mRNA decay	DCM & conduction disorders	[187]
MYH7	Myosin Heavy Chain 7	p.R663H	Sendai virus transduction	Abnormal Ca2+ handling	HCM	[408]
MYH7	Myosin Heavy Chain 7	▪p.R453Chet ▪p.R453Chom	CRISPR-Cas9	▪Cellular hypertrophy ▪Sarcomeric disarray ▪Increased expression of hypertrophy markers ▪Ca2+ handling deficits	HCM	[421]
MYH7	Myosin Heavy Chain 7	▪p.R403Q ▪p.V606M	CRISPR-Cas9	▪Hypercontractility ▪P53 activation ▪Oxidative stress ▪Metabolic stress	HCM	[413]
MYH7	Myosin Heavy Chain 7	p.V698A	Electroporation with episomal plasmids	NA	HCM	[422]
MYH7	Myosin Heavy Chain 7	p.E848G	Electroporation with episomal plasmids	Reduced contractile function	HCM	[423,424]
MYH7	Myosin Heavy Chain 7	p.R403Q	Electroporation with episomal plasmids	NA	HCM	[425]
MYH7	Myosin Heavy Chain 7	p.R633H	Lentiviral transduction	▪Ca2+ handling deficits ▪Arrhythmias ▪Cellular hypertrophy	HCM	[414,426]
MYH7	Myosin Heavy Chain 7	p.R442G	Retroviral transduction	▪Disorganized sarcomeres ▪Increased expression of genes involved in cell proliferation ▪Electrophysiological alterations	HCM	[427]
MYL2	Myosin Light Chain 2	p.R58Q	Non-integrating mRNA/miRNA technology	▪Cellular hypertrophy ▪Myofibrillar disarray ▪Irregular contraction ▪Decreased Ca2+ transients	HCM	[428]
MYL3	Myosin Light Chain 3	▪p.A57Dhet ▪p.A57Dhom ▪p.A57Ghet	CRISPR-Cas9	▪Asymptomatic ▪Classification of benign GSVs	HCM	[375]
PKP2	Plakophilin-2	p.L614P	Retroviral transduction	▪Reduced expression of plakophilin-2 ▪Adipogenic phenotype	ACM	[429]
PKP2	Plakophilin-2	▪c.2484C > Thom ▪c.2013delC	Retroviral transduction	▪Lipogenesis ▪Apoptosis ▪Ca2+ handling deficits ▪Pro-fibrotic gene expression ▪Dysregulation of genes, encoding cell-cell connections.	ACM	[430,431,432]
PKP2	Plakophilin-2	c.972insT	Retroviral transduction	▪Reduced expression of plakophilin-2 ▪Changes of the desmosomal structure ▪Lipid droplet accumulation	ACM	[433]
PKP2	Plakophilin-2	▪c.354delT ▪p.K859R	Sendai virus transduction	NA	ACM	[434]
PKP2	Plakophilin-2	c.2569_3018del50	Electroporation with episomal plasmids	NA	ACM	[435]
PLN	Phospholamban	p.R9C	CRISPR-Cas9	▪Cellular hypertrophy ▪Ca2+ handling deficits ▪Increased expression of hypertrophic markers ▪Altered metabolic state ▪Changes of miRNA expression ▪Increased expression of profibrotic genes	DCM	[414,436]
PLN	Phospholamban	p.R14del	Transfection with mRNAs& genome editing (TALENs) for mutation correction	▪Ca2+ handling deficits ▪Abnormal cytoplasmic localization of phospholamban ▪Increased expression of hypertrophic markers ▪Gene correction reverses the phenotypic findings	DCM	[437,438]
PRGAG2	Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 2	p.R302Q	Sendai virus transduction & genome editing for correction (CRISPR-Cas9)	▪Arrhythmias ▪Electrophysiological alterations ▪Cellular hypertrophy ▪Gene correction using CRISPR-Cas9 reverses the phenotypic findings	Wolff–Parkinson–White Syndrome (HCM)	[439]
PRKAG2	Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 2	p.N488I	Lentiviral transduction & genome editing for correction (TALEN)	▪Activated AMPK remodeled metabolism ▪Cellular hypertrophy	HCM	[440]
PTPN11	Protein Tyrosine Phosphatase Non-Receptor Type 11	p.T468M	Retroviral transduction	▪Cellular hypertrophy ▪Impaired sarcomere structure	LEOPARD Syndrome (HCM)	[360]
PTPN11	Protein Tyrosine Phosphatase Non-Receptor Type 11	p.Q510P	Sendai virus transduction	NA	LEOPARD Syndrome (HCM)	[441]
RAF1	Raf-1 Proto-Oncogene, Serine/Threonine Kinase	p.S257L	Electroporation of episomal plasmids & genome editing for correction (CRISPR-Cas9)	▪Cellular hypertrophy ▪Myofibrillar disarray ▪Hyperactivation of MEK1/2 pathway ▪Increased ERK5 signaling	Noonan Syndrome (HCM)	[442]
RBM20	RNA Binding Motif Protein 20	p.S635A	Lentiviral transduction	▪Altered Ca2+ handling ▪Impaired sarcomere structure ▪Reduced titin N2B isoform expression	DCM	[443]
RBM20	RNA Binding Motif Protein 20	p.R636S	Sendai virus transduction	▪Impaired sarcomere structure ▪Altered transcriptome ▪Altered Ca2+ handling ▪Apoptotic changes ▪Therapeutic treatment using β-blockers or Ca2+ channel blockers reverse phenotypic findings	DCM	[444,445]
RYR2	Ryanodine Receptor 2	p.F2483I	Retroviral transduction	▪Arrhythmias ▪Altered Ca2+ handling	CPVT	[350]
RYR2	Ryanodine Receptor 2	▪p.S404R & p.N685S ▪p.G3946S & p.G1885E	Sendai virus transduction	▪Altered Ca2+ handling ▪Calmodulin-dependent protein kinase II inhibition reverse the arrhythmias	CPVT	[376]
SCN5A	Sodium Voltage-Gated Channel Alpha Subunit 5	▪p.S1898R	Sendai virus transduction & CRISPR-Cas9 for correction	▪Reduction in peak sodium channel	ACM	[446]
SCN5A	Sodium Voltage-Gated Channel Alpha Subunit 5	p.R219H	Sendai virus transduction	▪Proton leakage ▪Disrupted ion homeostasis ▪Structural abnormalities ▪Electrophysiological alterations ▪Reduced contraction	ACM/DCM	[447]
SCO2	SCO2 Cytochrome C Oxidase Assembly Protein	▪p.E140K ▪p.G193Shom	Sendai virus transduction	▪Structural abnormalities ▪Altered Ca2+ handling	HCM	[448]
TAZ	Tafazzin	▪c.517delG ▪c.328T > C	Transfection with synthetic mRNAs & CRISPR-Cas9 for correction	▪Impaired sarcomere structure ▪Decreased contraction ▪Increased reactive oxygen species	Barth Syndrome	[449]
TBX20	T-Box Factor 20	▪p.T262M ▪p.Y317X	Sendai virus transduction	▪Perturbed TGFβ signaling ▪Reduced expression of cardiac transcription factors	LVNC	[450]
TNNT2	Cardiac Troponin T	p.R92W	Sendai virus transduction & CRISPR-Cas9 for correction	Abnormal Ca2+ handling	HCM	[408]
TNNT2	Cardiac Troponin T	p.R173W	Lentiviral transduction	▪Decreased contractility ▪Altered Ca2+ handling ▪Impaired sarcomere structure	DCM	[414,451,452,453,454]
TNNT2	Cardiac Troponin T	▪Compound heterozygous: ∆5bp and ∆2bp deletions in exon 2 leading to frameshifts ▪Heterozygous ∆27bp deletion in exon 2 leading to a frameshift	TALEN	▪Sarcomere disassembly ▪Altered Ca2+ handling	DCM/HCM	[453]
TNNT2	Cardiac Troponin T	p.I79N	CRISPR-Cas9	▪Impaired sarcomere structure ▪Increased systolic function ▪Impaired relaxation ▪Altered Ca2+ handling	HCM	[455,456]
TPM1	Tropomyosin-1	p.D175N	▪Sendai virus transduction ▪Retroviral transduction	Arrhythmias	HCM	[417,418]
TTN	Titin	▪p.W976R+/- ▪p.V6382fs+/- ▪p.V6382fs-/- ▪p.A22352fs+/- ▪p.P22582fs+/- ▪p.N22577fs+/- ▪p.N22577fs-/- ▪p.T33520fs-/-	▪Lentiviral transduction (for patient specific iPSC) ▪CRISPR-Cas9 (for generation of isogenic iPSC)	▪Impaired sarcomere structure ▪Decreased contractility ▪Diminished activation of growth factors, hypoxia regulating factors and MAP kinases	DCM	[457]
TTN	Titin	p.S14450fsX4	Sendai virus transduction	Antisense-mediated exon skipping restores titin expression	DCM	[377]
TTN	Titin	▪c.86076dupA ▪c.70690dupAT	Lentiviral transduction	▪Sarcomere defects ▪Diminished inotropic and lusitropic responses	DCM	[458]
TTR	Transthyretin	p.L55P	Lentiviral transduction	Increased oxidative stress	Hereditary Transthyretin Amyloidosis	[459]

ACM—Arrhythmogenic cardiomyopathy; CFCS—Cardio facio cutaneous syndrome; CM—Cardiomyopathy; CPVT—Catecholaminergic polymorphic ventricular tachycardia; DCM—Dilated cardiomyopathy; DMD—Duchenne muscular dystrophy; DRC—Desmin-related cardiomyopathy; HCM—Hypertrophic cardiomyopathy; LVNC—Left-ventricular non-compaction cardiomyopathy; MFM—Myofibrillar myopathy; MP—Myopathy; NA—Not assessed; RCM—Restrictive cardiomyopathy.