Disorder Affected Gene(s) Phenotype assessment Reference(s) a1-antitrypsin deficiency SERPINA1 Aggregation of misfolded alpha1-antitrypsin in the endoplasmic reticulum [182] Adrenoleukodystrophy, X-linked Unknown iPSC-oligodendrocytes exhibit very long chain fatty acid level [183] Alzheimer’s disease, familial PSEN1, PSEN2 APP iPSC-neurons have increased amyloid β42 secretion, phosphorylated-Tau and active glycogen synthase kinase-3b as well as accumulation of large Rab5+ early endosomes [103,154] Alzheimer’s disease, sporadic Unknown Increased levels of amyloid-b, phosphorylated-Tau and active glycogen synthase kinase-3b as well as accumulation of large Rab5+ early endosomes [103] Amyotrophic lateral sclerosis, familial TARDBP or VAPB TARDBP iPSC neurons have elevated levels of soluble and detergent-resistant TDP-43 protein, decreased survival in longitudinal studies, and increased vulnerability to antagonism of the PI3K pathway; VAPB fibroblasts, iPSCs and hiPSC neurons have reduced levels of VAPB [184,185] Catecholaminergic polymorphic ventricular tachycardia type 1 CASQ2or RYR2 iPSC cardiomyocytes are arrhythmogenic, have delayed afterdepolarizations, after-contractions, and exhibit higher amplitudes and longer durations of spontaneous Ca2+-release [150,186-188] Chronic granulomatous disease, X-linked CYBB or NCF1 iPSC neutrophils or iPSC-macrophages lack ROS production [189,190] Chronic infantile neurological cutaneous and articular syndrome NLRP3 iPSC marcophages show abnormal IL1b secretion [191] Chronic myelogenous leukemia BCR-ABL iPSC mature but not immature hematopoietic cells are sensitive to imatinib [192] Dilated cardiomyopathy LMNA or Tnnt2 iPSC-fibroblasts have nuclear membrane abnormalities, increased senescence and susceptibility to apoptosis; iPSC-cardiomyocytes show altered regulation of Ca2+, decreased contractility, abnormal distribution of sarcomeric α-ACTININ, and cellular stress upon stimulation with a β-adrenergic agonist [193,194] Down syndrome Trisomy 21 iPSC teratoma microvessel density is significantly reduced (reference 195; iPSC-neurons processed the transmembrane APP protein, resulting in secretion of the pathogenic peptide fragment amyloid-β42, a feature of Alzheimer’s disease (reference 196) [195,196] Dyskeratosis congenita DKC1, TERC or TCAB1 iPSC show progressive telomere shortening and loss of self-renewal [197,198] Familial Dysautonomia IKBKAP Decreased expression of genes involved in neurogenesis and neuronal differentiation; defects in neural crest migration [151] Familial Hypercholesterolemia LDLR hiPSC-derived hepatocytes have an impaired ability to incorporate LDL, increased secretion of lipidated ApoB-100 [182,199] Fragile X syndrome FMR1 iPSC show aberrant neuronal differentiation with loss of expression of FMRP [200] Gaucher’s disease type III GBA iPSC-neurons have compromised lysosomal protein degradation, accumulation of α-SYNUCLEIN and neurotoxicity through aggregation-dependent mechanisms [201] Glycogen storage disease type 1A G6PC iPSC-hepatocytes hyperaccumulate glycogen and lipid, and have excessive production of lactic acid [182] Huntington’s disease HTT iPSC-neural stem/progenitor cells show enhanced caspase activity upon growth factor deprivation; iPSC asctrocytes show cytoplasmic vacuolation; iPSC but not iPSC neurons have significantly increased lysosomal activity [115,202-205] Hurler syndrome (Mucopolysaccharidosis type I) IDUA iPSC have an imbalance between production and clearance of unprocessed GAG and show lysosomal storage defects [206] Hutchinson-Gilford progeria LMNA iPSC mesenchymal stem cells, vascular smooth muscle cells and fibroblasts display progerin accumulation, increased DNA damage, and nuclear abnormalities; iPSC- vascular smooth muscle cells also show premature senescence, blebbing and increased apoptosis [193,207,208] Juvenile Diabetes * LDLR iPSC hepatocytes show features of hypercholesteremia [199] LEOPARD syndrome PTPN11 iPSC cardiomyocytes reveal features of cardiac hypertrophy (increased size, increased sarcomere organization and increased nuclear localization of NFATC4) [140] Long QT 3 and Brugada overlap syndrome SCN5A1798insD/+ iPSC cardiomyocytes show reduced upstroke velocity and longer action potential duration [209] Long QT syndromes KCNQ1 (LQT1); KCNH2 (LQT2), SCN5A (LQT3), CACNA1C (LQT8/Timothy syndrome) iPSC cardiomyocytes have a prolonged action potential duration reminiscent of delayed repolarization, early afterdepolarization (LQT3), and irregular contraction, excess Ca2+ influx, irregular electrical activity and abnormal calcium transients (LQT8/Timothy syndrome) [210-215] Machado-Joseph disease ATXN3 iPSC neurons show formation of SDS-insoluble aggregates after Ca2+-dependent proteolysis of ATXN3 [216] Marfan syndrome FBN1 iPSC show inhibition of osteogenic differentiation, enhanced TGFb-signaling, and chondrogenic differentiation without TGF b1 media supplementation [217] Mucopolysaccharidosis type IIIB NAGLU iPSCs and differentiated neurons derived from patients show defects in storage vesicles and Golgi apparatus [218] Parkinson’s disease, familial LRRK2, SNCA or PINK1 iPSC dopaminergic neurons show impaired mitochondrial function; iPSC dopaminergic neurons have increased expression of key oxidative stress response genes and α-synuclein protein, and increased sensitivity to oxidative-stress; accumulation of autophagic vacuoles [156,219-223] Polycythaemia vera JAK2 iPSC hematopoietic cells have enhanced erythropoiesis [224] Pompe disease GAA iPSC cardiomyocytes show high levels of glycogen and multiple ultrastructural aberrances [225] Prader-Willi syndrome Translocation of the paternally expressed chromosome 15q11-q13 region to chromosome 4 iPSCs express reduced levels of the disease-associated small nucleolar RNA HBII-85/SNORD116 [226] Retinitis pigmentosa RP1, RP9, PRPh2 or RHO iPSC rod cells numbers are decreased, express markers for oxidation or endoplasmic reticulum stress, and show different responses to vitamin E [227] Rett Syndrome MECP2 iPSC neurons have decreased synapse number, reduced number of spines, a reduction in soma size, altered calcium signaling, and elevated LINE1 retrotransposon mobility [153,228-231] Schizophrenia Unknown iPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression; iPSC neurons have an increase in extra-mitochondrial oxygen consumption as well as elevated levels of reactive oxygen species [104,105] Sickle cell disease HBB Marginally increased HBB mRNA levels [117] Spinal muscular atrophy SMN1 iPSC motor neurons have a reduced size and decrease in numbers over time; show an abnormality in neurite outgrowth [152,232] Timothy syndrome CACAN1C iPSC cardiomyocytes have irregular contraction, excess Ca2+ influx, prolonged action potentials, irregular electrical activity and abnormal calcium transients iPSC cortical neurons have defects in Ca2+-signaling and activity-dependent gene expression, as well as abnormalities in cortical neuron differentiation [212,233] Werner syndrome, atypical LMNA iPSC fibroblasts show nuclear membrane abnormalities, increased senescence and susceptibility to apoptosis [193] Wilson’s disease ATP7B iPSC hepatocytes mislocalize mutated ATP7B and have defective copper transport [234] *see also Familial Hypercholesteremia

Table 1: Patient-specific iPSCs with described disease phenotypes.