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ONLINE APPENDIX The genes detailed in these supplemental tables represent those associated with a given cardiomyopathy phenotype in the literature. Genes with high-quality evidence that meet all criteria for defining disease pathogenicity listed in Table 1 of the manuscript are defined as “definitive” disease-causing genes. All others are listed as “putative” disease genes. With advances in nextgeneration sequencing and molecular genetics technologies, great efforts are being made at confirming the pathogenicity of specific genes. Thus, we expect these data to change rapidly in the next several years, causing some putative disease genes to be reclassified as definitive disease-causing genes and others to be recognized as genes that do no cause cardiomyopathy. It is also important to recognize that not all novel variants found in a gene, even those that definitively cause disease, will be causative. Hence, new mutations identified in known diseasecausing genes still require careful validation. Supplemental Table 1. Genes associated with hypertrophic cardiomyopathy Gene Symbol Encoded protein Definitive disease causing genes MYBPC3 (1,2) Cardiac myosin binding protein C MYH7 (3,4) -myosin heavy chain MYL2 (5) Regulatory myosin light chain MYL3 (5) Essential myosin light chain TNNI3 (6) Cardiac troponin I TNNT2 (7,8) Cardiac troponin T TPM1 (7,8) -tropomyosin ACTC1 (9,10) Cardiac -actin Putative disease genes ACTN2 (11,12) -actinin 2 MYOZ2 (13) Myozenin 2 CSRP3 (11,14Cardiac LIM protein 17) MYPN (18) Myopalladin TNNC1 (19-21) Cardiac troponin C MYH6 (17,22) -myosin heavy chain NEXN (23) Nexilin TCAP (15,24) Telethonin ANKRD1 (25) Cardiac ankyrin repeat protein LDB3 (11) LIM binding domain 3 protein* VCL (26,27) Vinculin Cellular Location Sarcomere, thick filament Sarcomere, thick filament Sarcomere, thick filament Sarcomere, thick filament Sarcomere, thin filament Sarcomere, thin filament Sarcomere, thin filament Sarcomere, thin filament Sarcomere, Z-disc Sarcomere, Z-disc Sarcomere, Z-disc Sarcomere, Z-disc Sarcomere, thin filament Sarcomere, thick filament Sarcomere, Z-disc Sarcomere, Z-disc Sarcomere, Z-disc Sarcomere, Z-disc Sarcomere, Z-disc, intercalated disc and sarcolemma JPH2 (28) Junctophilin 2 Sarcolemma CAV3 (24) Caveolin-3 Sarcolemma PLN (29,30) Phospholamban Sarcoplasmic reticulum CALR3 (29) Calreticulin 3 Sarcoplasmic reticulum *LIM binding domain 3 protein is also commonly known as Cypher/ZASP Supplemental Table 2. Genes associated with metabolic cardiomyopathies Gene GLA (31,32) LAMP2 (33,34) PRKAG2 (34-36) GAA(37) Encoded Protein -galactosidase A Disease Fabry disease Inheritance X-linked Lysosome-associated membrane protein 2 AMP-activated protein kinase, 2 subunit (noncatalytic) -glucosidase Danon disease X-linked PRKAG2 cardiomyopathy Pompe disease Autosomal dominant Autosomal recessive Supplemental Table 3. Genes associated with dilated cardiomyopathy Gene Encoded Protein Definitive disease causing genes TTN(38,39) Titin MYH7(40,41) -myosin heavy chain ACTC1(42) Cardiac -actin TNNT2(40) Cardiac troponin T TPM1(43) -tropomyosin TNNI3(44,45) Cardiac troponin I BAG3 (46-48) Bcl2-associated athanogene 3 DES (49-51) Desmin DMD (52-55) Dystrophin DNAJC19 (56,57) EMD (1,58) DNAJ (Hsp40) homolog LMNA (59) Lamin A/C Emerin PLN (60-62) RBM20 (63-66) SCN5A (67-69) Phospholamban RNA-binding protein, 20 Voltage gated sodium channel type V, -subunit TAZ (70) Tafazzin Putative disease genes MYBPC3(71,72) Cardiac myosin binding protein C TNNC1(73,74) Cardiac troponin C ANKRD1 Cardiac ankyrin repeat protein (75,76) LDB3 (77) LIM binding domain 3 protein NEXN (78) Nexilin SGCD (79,80) -sarcoglycan EYA4 (81) PSEN1 (82) MYPN (18,83,84) FBXO32 (85) GATAD1 (86) GATA4 (87) CHRM2 (88) Eyes absent homolog 4 Presenilin-1 Myopalladin F-box protein 32/atrogin-1 GATA zinc finger domain containing 1 protein GATA binding protein 4 Muscarinic cholinergic receptor Possible Coexistant Phenotypes None None None None None None None Skeletal myopathy, conduction system disease Duchenne’s muscular dystrophy, Becker’s muscular dystrophy DCMA Emery-Dreifuss muscular dystrophy type 1 Conduction system disease, EmeryDreifuss muscular dystrophy type 2 None None Supraventricular and ventricular arrhythmias Barth syndrome None None None Myofibrillar myopathy None Limb-girdle muscular dystrophy, type 2F Sensorineural hearing loss None* None None None None Supraventricular and ventricular arrhythmias MYH6 (22) ACTN2 (89) CSRP3 (89,90) TCAP (24,91) ABCC9 (92) TBX20 (93) NKX2-5 (94) CTF1 (95) VCL (96) SGCB (97) -myosin heavy chain -actinin 2 Cardiac LIM protein Telethonin Sulfonylurea receptor 2 T-box 20 NK2 homeobox 5 Cardiotrophin-1 Vinculin -sarcoglycan SGCA (98) -sarcoglycan FHL2 (99) Four and a half limb domains 2 FKTN (100,101) Fukutin FOXD4 (102) Forkhead box protein D4 None None Limb girdle muscular dystrophy None Cantú syndrome CHD CHD None None Limb-girdle muscular dystrophy, type 2E Limb-girdle muscular dystrophy, type 2D None Fukuyama-type muscular dystrophy Obsessive compulsive disorder and suicidality None None None* LAMA4 (103) Laminin, 4 ILK (103) Integrin-linked kinase PSEN2 (82) Presenilin-2 SDHA (104) Succinate dehydrogenase subunit A CRYAB Skeletal myopathy -B crystallin (105,106) MURC (107) Muscle-related coiled-coil protein None SYNE1 Nesprin-1 Emery-Dreifuss muscular dystrophy (108,109) type 4 PRDM16 (110) PR domain containing 16 LVNC PGM1 (111) Phosphoglucomutase 1 Glycogenosis type XIV TMPO (112) Thymopoietin None DSC2 (113,114) Desmocollin 2 None DSG2 (113) Desmoglein 2 None DSP (115) Desmoplakin Plantopalmar keratoderma PKP2 (113) Plakophilin 2 None Genetic loci linked to DCM without a known disease-associated mutation 9q13-q22 (116) MIM CMD1B None 2q14-q22 (117) MIM CMD1H Conduction system disease 6q12-q16 (118) MIM CMD1K None 7q22-q31 (119) MIM CMD1Q None 1p36.13 (48) Unknown None * - Allelic variants in Alzheimer’s dementia DCMA – dilated cardiomyopathy with ataxia; MIM – Mendelian Inheritance in Man; CHD – congenital heart disease Supplemental Table 4. Genes associated with left ventricular non-compaction cardiomyopathy Gene Encoded Protein Associated findings or syndromes* Definitive disease genes TAZ(120,121) Tafazzin DCM, Barth syndrome MIB1 (122) Mindbomb homolog 1 None MYH7(123,124) Myosin heavy chain None Putative disease genes LDB3(77,125) LIM binding domain 3 protein DCM, myofibrillar myopathy DTNA(121) None -dystrobrevin ACTC1(126,127) Cardiac -actin Apical HCM TNNT2(127,128) Cardiac troponin T None NKX2.5(129) NK2 homeobox 5 None TPM1(130,131) -tropomyosin None MYBPC3(131) Cardiac myosin binding protein C None PRDM16(110) PR domain containing 16 1p36 deletion syndrome Genetic loci linked to LVNC without a known disease-associated mutation 11p15(132) MIM LVNC2 None * All LVNC-associated genes are also associated with a variety of other congenital heart defects, which are not listed here MIM – Mendelian Inheritance in Man Supplemental Table 5. Genes associated with arrhythmogenic right ventricular dysplasia/cardiomyopathy Gene Encoded Protein Associated syndromes Definitive disease genes JUP(133-135) Plakoglobin Naxos syndrome DSP(115,136,137) Desmoplakin Carvajal syndrome PKP2 (138-140) Plakophilin 2 None DSG2 (141,142) Desmoglein 2 None DSC2 (143,144) Desmocollin 2 None TMEM43 (145Transmembrane protein 43 None 147) Putative disease genes TGFB3 (148) None Transforming growth factor 3 PLN (149) Phospholamban None TTN (150) Titin None Genetic loci linked to ARVC without a known disease-associated mutation 14q12-q22 (151) MIM ARVD3 None 2q32.1-q32.3 (152) MIM ARVD4 None 10p14-p12 (153) MIM ARVD6 None MIM – Mendelian Inheritance in Man Supplemental References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. Bonne G, Carrier L, Bercovici J et al. Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy. Nat Genet 1995;11:438-40. 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