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. 2018 Oct 15;471(5):755–768. doi: 10.1007/s00424-018-2214-0

Table 2.

Studies reporting cardiomyocyte phenotypes in hiPSC-CM from patients with genetically determined HCM or syndromes associated with HCM phenotypes or from hiPSC lines in which mutations had been introduced

Mutation Disease Peak force T1 T2 Cell size Disarray Other phenotypes CRISPR/TALEN Ctr. Karyotype Ctr. Reference
MYH7
Het p.Arg663His		 HCM n.d. n.d. n.d. + 60% n.d. Multinucleation 50 vs. 20%, mRNA of NPPA, NPPB, MYH7 up, higher nuclear NFAT, Ca2+-induced arrhythmias, DAD, higher basal [Ca2+], Iso-induced DAD No No [50]
MYBPC3
3 Pts, 3 Ctr
p.Gly999-Gln1004del, 2 w/o identified mut		 HCM n.d. n.d. n.d. + 20% + 50–100% NPPA, TNNT2 up, MYBPC3–20% in mut, stronger hypertrophic, disarray and NFAT response to ET1, contractile abnormalities linked to disarray No No [90]
MYBPC3
Exon 25, 3 pts.		 HCM n.d. n.d. n.d. + 50–100% n.d. No further hypertrophic response to stimuli No Yes [18]
MYH7
Het p.Arg442Gly		 HCM n.d. n.d. n.d. + 15% + 200% Higher nuclear NFAT; arrhythmias + 300%, APD prolongation + 60%, resting [Ca2+] up 20%, ICa and INa up No Yes [32]
MYBPC3
Het c.2373dupG		 HCM − 50% n.d. n.d. +/− n.d. cMyBPC haploinsufficiency No No [7]
GAA
Hom del in exon 18
and CpHet c.1441delT/c.2237G>A
2 lines each		 Pompe +/− or − 60% +/− +/− n.d. n.d. Glycogen accumulation, glycan processing abnormality, but normal autophagic flux No Yes [77]
GAA
CpHet c.796C>T/ c.1316T>A,
3 clones from pt., 1 clone from ctr		 Pompe n.d. n.d. n.d. no n.d. Glycogen accumulation, no functional data No No [82]
ALPK3
Hom p.W1264X		 DCM/HCM n.d. n.d. n.d. n.d. + 230% Irregular Ca2+ transients + 400%, MEA FP + 100% No Yes [73]
BRAF
Het p.Thr599Arg		 HCM
Syndromic		 0 to + 40% − 30% − 30% n.d. n.d. Less negative FFR, increased Iso-sensitivity, mRNA of NPPA + 300% and SERCA2a + 40% (ns) No No [12]
BRAF
Het p.Thr599Arg
Het p.Gln257Arg		 HCM Syndromic n.d. n.d. n.d. + 300% + 260% mRNA of NPPA, NPPB, MYH7 up, PLN down, higher Ca2+ transients and store, calcium arrhythmias, “fibroblast” profibrotic phenotype No Yes [41]
FXN
GAA triplet repeat		 Friedreich’s ataxia n.d. n.d. n.d. n.d. n.d. ROS, unusual iron responses No No [51]
MYBPC3
Het p.Gln1061X (n = 2)
or TPM1
Het p.Asp175Asn (n = 2)		 HCM n.d. n.d. n.d. + 200% (M), not clear in T n.d. More multinucleation (40 vs 20%), Ca2+ arrhythmias (T, not M), more DAD in M, not T, APD high in T, RMP − 75, NPPA +/−, NPPB, MYH7 and many others up, more in M than T, cMyBPC +/−, TPM up in T No Yes [72]
MYH7
Het p.Glu848Gly		 HCM − 54% n.d. n.d. n.d. Yes,
not quantified		 Skinned myofiber from hiPSC-CM: Fmax 8.2 vs. 18.6 mN/mm2 (adult 110), KAct + 62%, increased Ca2+ sensitivity No No [74]
MYH7
Het p.Val698Ala		 HCM n.d. n.d. n.d. n.d. n.d. n.d. N.d. Yes [80]
GLA
Hemizygote
c.919+4G >A		 Fabry n.d. n.d. n.d. n.d. n.d. Gal act. down, GB3 accumulation, low beating rate, arrhythmias No [15]
LAMP2
Het c.129–
130insAT)
Het c.64+1G>A 		Danon n.d. n.d. n.d. n.d. n.d. Mitochondrial abnormalities, decreased autophagic flux No Yes [34]
MYBPC3
Het c.1358_1359insC		 HCM n.d. n.d. n.d. + 65% n.d. cMyBPC haploinsufficiency, BNP, MYH7 and others up Corrected by gene therapy No [76]
PRKAG2
Het Arg302Gln		 HCM + WPW n.d. n.d. n.d. + 10–30% n.d. MDP, APD +/−, If +/−, AP irregularity, RR scatter + 500% Yes Yes [5]
SCO2
Hom c.577G>A
CpHet c.418G>A/c.17Ins19		 HCM syndrome +/− (??) n.d. n.d. n.d. n.d. Mitochondrial abnormalities, no Iso or Ca2+ response, DAD, arrhythmic response to Iso No Yes [31]
MT-RNR2
m.2336T>C		 Mitochondrial HCM n.d. n.d. n.d. + 30% n.d. NPPA, NPPB, NFAT up, slightly increased intracellular calcium, SR store, reduced ICa, APD prolonged, arrhythmias, RMP − 55, upstroke 5–10 v/s, DAD No Yes [52]
MYL3
Het c.170C-A,
Exac 0.0001154, introduced 170C-g
and
MYBPC3
Het p.Val321Met		 HCM-associated VUS n.d. n.d. n.d. +/− (also in mut) n.d. No phenotype detected in VUS, mean cell size 1800 μm2, NPPA and MYH7 up in the two diseased, contraction and rel velocity slightly up, arrhythmias, good stats Yes Yes [57]
TNNT2
Het p.Ile79Asn		 HCM + 75% n.d. + 40% +/− yes Sarcomere length +/− (1.8 μm), smaller caffeine transient, higher Ca2+ buffering, shorter APD, Ca2+ beat to beat instability, triangulation, NCX-sensitive Yes Yes [100]
MYH7 and MYH6; Het/Hom p.Arg453Cys, frameshift KO, +MYH6 frameshift HCM − 20% (het), − 70% (hom) − 80% (KO) + 20% +/− or + 10% (+MYH6 fs) + 50% yes NPPB up, multinucleation, basal and max. respiration up, ATP production up, Ca2+ transient irregularities, nifedipine- and ranolazine-sensitive; MYH7/MYH6 ratio up Yes Yes [69]

ANP/BNP atrial/brain natriuretic peptides, AP action potential, APD action potential duration, ALPK3 α-kinase 3, BRAF B-Raf proto-oncogene, serine/threonine kinase, cMyBPC cardiac myosin-binding protein C, CpHet compound heterozygous, CRISPR clustered regularly interspaced short palindromic repeats/Cas9 gene correction, Ctr control, DAD delayed after depolarizations, Del deletion, Disarray abnormal sarcomeric organization, ET1 endothelin 1, FFR force-frequency relation, Fmax maximal force development, FXN frataxin gene, GAA α-glycosidase gene, GLA α-galactosidase A, GB3 glycosphingolipids, Het heterozygous, Hom homozygous, ICa L-type Ca2+ current, INa Na+ current, Iso isoprenaline, KAct rate constant reflecting crossbridge turnover rate, LAMP2 lysosome-associated membrane protein 2 gene, MEA FP multielectrode array field potentials, MT-RNR2 mitochondrially encoded 16S RNA gene, Mut mutation, MYBPC3 cardiac myosin-binding protein C gene/mRNA, MYL3 myosin light chain 3 (MLC1v) gene, MYH6/MYH7 gene or mRNA of α-/β-myosin heavy chain, NCX sodium-calcium exchanger, NFAT nuclear factor of activated T cells, NPPA atrial natriuretic peptide mRNA, NPPB brain natriuretic peptide mRNA, PLN phospholamban gene/mRNA, Pt(s) patient(s), RMP resting membrane potential, ROS reactive oxygen species, RR scatter beat-to-beat irregularity, SERCA2a sarcoplasmic reticulum ATPase, SCO2 cytochrome c oxidase assembly protein gene, T1 time to peak force, T2 time from peak to relaxation, TALEN transcription activator-like effector nuclease-mediated gene correction, TNNT2 cardiac troponin T gene, TnT cardiac troponin T, TPM1 α-tropomyosin, VUS variant of unknown significance