Genetics and Genomics of Single-Gene Cardiovascular Diseases: Common Hereditary Cardiomyopathies as Prototypes of Single-Gene Disorders

Journal of the American College of Cardiology

Volumn 68, Issue 25, 2016, Pages 2831-2849

  Marian, Ali J ^a   van Rooij, Eva ^b   Roberts, Robert ^c  

^a UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^b UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^c UNIVERSITY OF ARIZONA COLLEGE OF MEDICINE   (United States)

Author keywords

cardiomyopathy; mutation; noncoding RNA

Indexed keywords

ACETYLCYSTEINE; ELECLAZINE; LONG UNTRANSLATED RNA; MESSENGER RNA; MICRORNA; MITOCHONDRIAL DNA;

CARDIOMYOPATHY; CARDIOVASCULAR DISEASE; CLINICAL FEATURE; CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEAT; CONGESTIVE CARDIOMYOPATHY; DNA SEQUENCE; DRUG EFFECT; FAMILIAL HYPERTROPHIC CARDIOMYOPATHY; GENE STRUCTURE; GENETIC DISORDER; GENETIC VARIABILITY; GENOMICS; GENOTYPE PHENOTYPE CORRELATION; HEART LEFT VENTRICLE HYPERTROPHY; HISTONE MODIFICATION; HUMAN; LOSS OF FUNCTION MUTATION; MITOCHONDRIAL GENOME; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; REVIEW; SINGLE GENE CARDIOVASCULAR DISEASE; SINGLE NUCLEOTIDE POLYMORPHISM; STOP CODON; CARDIOMYOPATHIES; CARDIOVASCULAR DISEASES; GENETIC PREDISPOSITION; GENETIC SCREENING; GENETIC VARIATION; GENETICS; PROCEDURES;

CARDIOMYOPATHIES; CARDIOVASCULAR DISEASES; GENETIC PREDISPOSITION TO DISEASE; GENETIC TESTING; GENETIC VARIATION; GENOMICS; HUMANS; PHENOTYPE;

EID: 85006413279     PISSN: 07351097     EISSN: 15583597     Source Type: Journal    
DOI: 10.1016/j.jacc.2016.09.968     Document Type: Review

References (173)

1. 1 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing [Erratum in Nature 2011;473:544]. Nature 467 (2010), 1061–1073.
2. 2 Kong, A., Frigge, M.L., Masson, G., et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488 (2012), 471–475.
3. 3 Roach, J.C., Glusman, G., Smit, A.F., et al. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328 (2010), 636–639.
4. 4 Kidd, J.M., Cooper, G.M., Donahue, W.F., et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453 (2008), 56–64.
5. 5 Wang, J., Wang, W., Li, R., et al. The diploid genome sequence of an Asian individual. Nature 456 (2008), 60–65.
6. 6 Wheeler, D.A., Srinivasan, M., Egholm, M., et al. The complete genome of an individual by massively parallel DNA sequencing. Nature 452 (2008), 872–876.
7. 7 Francioli, L.C., Polak, P.P., Koren, A., et al. Genome-wide patterns and properties of de novo mutations in humans. Nat Genet 47 (2015), 822–826.
8. 8 De Sandre-Giovannoli, A., Bernard, R., Cau, P., et al. Lamin A truncation in Hutchinson-Gilford progeria. Science, 300, 2003, 2055.
9. 9 Marian, A.J., Belmont, J., Strategic approaches to unraveling genetic causes of cardiovascular diseases. Circ Res 108 (2011), 1252–1269.
10. 10 Marian, A.J., Genetic causality in complex traits: the case of uric acid. J Am Coll Cardiol 67 (2016), 417–419.
11. 11 Marian, A.J., Causality in genetics: the gradient of genetic effects and back to Koch's postulates of causality [Erratum in Circ Res 2014;114:e29]. Circ Res 114 (2014), e18–e21.
12. 12 Bhartiya, D., Jalali, S., Ghosh, S., et al. Distinct patterns of genetic variations in potential functional elements in long noncoding RNAs. Hum Mutat 35 (2014), 192–201.
13. 13 Marian, A.J., Hypertrophic cardiomyopathy: from genetics to treatment. Eur J Clin Invest 40 (2010), 360–369.
14. 14 Maron, B.J., Gardin, J.M., Flack, J.M., et al. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Circulation 92 (1995), 785–789.
15. 15 Nagueh, S.F., Kopelen, H.A., Lim, D.S., et al. Tissue Doppler imaging consistently detects myocardial contraction and relaxation abnormalities, irrespective of cardiac hypertrophy, in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation 102 (2000), 1346–1350.
16. 16 Nagueh, S.F., Bachinski, L.L., Meyer, D., et al. Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation 104 (2001), 128–130.
17. 17 Nagueh, S.F., McFalls, J., Meyer, D., et al. Tissue Doppler imaging predicts the development of hypertrophic cardiomyopathy in subjects with subclinical disease. Circulation 108 (2003), 395–398.
18. 18 Varnava, A.M., Elliott, P.M., Mahon, N., et al. Relation between myocyte disarray and outcome in hypertrophic cardiomyopathy. Am J Cardiol 88 (2001), 275–279.
19. 19 Maron, B.J., Sato, N., Roberts, W.C., et al. Quantitative analysis of cardiac muscle cell disorganization in the ventricular septum. Comparison of fetuses and infants with and without congenital heart disease and patients with hypertrophic cardiomyopathy. Circulation 60 (1979), 685–696.
20. 20 Maron, B.J., Roberts, W.C., Quantitative analysis of cardiac muscle cell disorganization in the ventricular septum of patients with hypertrophic cardiomyopathy. Circulation 59 (1979), 689–706.
21. 21 Chan, R.H., Maron, B.J., Olivotto, I., et al. Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy. Circulation 130 (2014), 484–495.
22. 22 Ismail, T.F., Jabbour, A., Gulati, A., et al. Role of late gadolinium enhancement cardiovascular magnetic resonance in the risk stratification of hypertrophic cardiomyopathy. Heart 100 (2014), 1851–1858.
23. 23 Maron, M.S., Olivotto, I., Betocchi, S., et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 348 (2003), 295–303.
24. 24 Guttmann, O.P., Rahman, M.S., O'Mahony, C., et al. Atrial fibrillation and thromboembolism in patients with hypertrophic cardiomyopathy: systematic review. Heart 100 (2014), 465–472.
25. 25 Maron, B.J., Shirani, J., Poliac, L.C., et al. Sudden death in young competitive athletes. Clinical, demographic, and pathological profiles. JAMA 276 (1996), 199–204.
26. 26 Bagnall, R.D., Weintraub, R.G., Ingles, J., et al. A prospective study of sudden cardiac death among children and young adults. N Engl J Med 374 (2016), 2441–2452.
27. 27 O'Mahony, C., Jichi, F., Pavlou, M., et al., for the Hypertrophic Cardiomyopathy Outcomes Investigators. A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM risk-SCD). Eur Heart J 35 (2014), 2010–2020.
28. 28 Christiaans, I., van Engelen, K., van Langen, I.M., et al. Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy: systematic review of clinical risk markers. Europace 12 (2010), 313–321.
29. 29 Nienaber, C.A., Hiller, S., Spielmann, R.P., et al. Syncope in hypertrophic cardiomyopathy: multivariate analysis of prognostic determinants. J Am Coll Cardiol 15 (1990), 948–955.
30. 30 Elliott, P.M., Poloniecki, J., Dickie, S., et al. Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. J Am Coll Cardiol 36 (2000), 2212–2218.
31. 31 Maron, B.J., Rowin, E.J., Casey, S.A., et al. Hypertrophic cardiomyopathy in adulthood associated with low cardiovascular mortality with contemporary management strategies. J Am Coll Cardiol 65 (2015), 1915–1928.
32. 32 Maron, B.J., Ommen, S.R., Semsarian, C., et al. Hypertrophic cardiomyopathy: present and future, with translation into contemporary cardiovascular medicine [Erratum in J Am Coll Cardiol 2014;64:1188]. J Am Coll Cardiol 64 (2014), 83–99.
33. 33 Klarich, K.W., Attenhofer Jost, C.H., Binder, J., et al. Risk of death in long-term follow-up of patients with apical hypertrophic cardiomyopathy [Erratum in Am J Cardiol 2013;112:1271]. Am J Cardiol 111 (2013), 1784–1791.
34. 34 Millat, G., Bouvagnet, P., Chevalier, P., et al. Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy. Eur J Med Genet 53 (2010), 261–267.
35. 35 Kaski, J.P., Syrris, P., Esteban, M.T., et al. Prevalence of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy. Circ Cardiovasc Genet 2 (2009), 436–441.
36. 36 Erdmann, J., Daehmlow, S., Wischke, S., et al. Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. Clin Genet 64 (2003), 339–349.
37. 37 Richard, P., Charron, P., Carrier, L., et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy [Erratum in Circulation 2004;109:3258]. Circulation 107 (2003), 2227–2232.
38. 38 Marian, A.J., Yu, Q.T., Mares, A. Jr., et al. Detection of a new mutation in the beta-myosin heavy chain gene in an individual with hypertrophic cardiomyopathy. J Clin Invest 90 (1992), 2156–2165.
39. 39 Kimura, A., Molecular genetics and pathogenesis of cardiomyopathy. J Hum Genet 61 (2016), 41–50.
40. 40 Ho, C.Y., Charron, P., Richard, P., et al. Genetic advances in sarcomeric cardiomyopathies: state of the art. Cardiovasc Res 105 (2015), 397–408.
41. 41 Osio, A., Tan, L., Chen, S.N., et al. Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy. Circ Res 100 (2007), 766–768.
42. 42 Chen, S.N., Czernuszewicz, G., Tan, Y., et al. Human molecular genetic and functional studies identify TRIM63, encoding Muscle RING Finger Protein 1, as a novel gene for human hypertrophic cardiomyopathy. Circ Res 111 (2012), 907–919.
43. 43 Marian, A.J., The case of “missing causal genes” and the practice of medicine: a Sherlock Holmes approach of deductive reasoning. Circ Res 119 (2016), 21–24.
44. 44 Kozor, R., Grieve, S.M., Tchan, M.C., et al. Cardiac involvement in genotype-positive Fabry disease patients assessed by cardiovascular MR. Heart 102 (2016), 298–302.
45. 45 Linhart, A., Kampmann, C., Zamorano, J.L., et al. Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey. Eur Heart J 28 (2007), 1228–1235.
46. 46 Monserrat, L., Gimeno-Blanes, J.R., Marin, F., et al. Prevalence of Fabry disease in a cohort of 508 unrelated patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 50 (2007), 2399–2403.
47. 47 Thomas, A.S., Hughes, D.A., Fabry disease. Pediatr Endocrinol Rev 12:Suppl 1 (2014), 88–101.
48. 48 Elstein, D.A., Altarescu, G., Beck, M., (eds.) Fabry Disease, 2010, Springer, New York, NY.
49. 49 Romeo, G., Migeon, B.R., Genetic inactivation of the α-galactosidase locus in carriers of Fabry's disease. Science 170 (1970), 180–181.
50. 50 Kamdar, F., Garry, D.J., Dystrophin-deficient cardiomyopathy. J Am Coll Cardiol 67 (2016), 2533–2546.
51. 51 Marian, A.J., Challenges in the diagnosis of Anderson-Fabry disease: a deceptively simple and yet complicated genetic disease. J Am Coll Cardiol 68 (2016), 1051–1053.
52. 52 Schiffmann, R., Pastores, G.M., Lien, Y.H., et al. Agalsidase alfa in pediatric patients with Fabry disease: a 6.5-year open-label follow-up study. Orphanet J Rare Dis, 9, 2014, 169.
53. 53 Hughes, D.A., Elliott, P.M., Shah, J., et al. Effects of enzyme replacement therapy on the cardiomyopathy of Anderson-Fabry disease: a randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa. Heart 94 (2008), 153–158.
54. 54 Weidemann, F., Breunig, F., Beer, M., et al. Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study. Circulation 108 (2003), 1299–1301.
55. 55 Schiffmann, R., Kopp, J.B., Austin, H.A. III, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA 285 (2001), 2743–2749.
56. 56 Gollob, M.H., Green, M.S., Tang, A.S., et al. Identification of a gene responsible for familial Wolff-Parkinson-White syndrome [Erratum in N Engl J Med 2001;345:552 and N Engl J Med 2002;346:300]. N Engl J Med 344 (2001), 1823–1831.
57. 57 Murphy, R.T., Mogensen, J., McGarry, K., et al. Adenosine monophosphate-activated protein kinase disease mimicks hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome: natural history. J Am Coll Cardiol 45 (2005), 922–930.
58. 58 Arad, M., Maron, B.J., Gorham, J.M., et al. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med 352 (2005), 362–372.
59. 59 Arad, M., Benson, D.W., Perez-Atayde, A.R., et al. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest 109 (2002), 357–362.
60. 60 Blair, E., Redwood, C., Ashrafian, H., et al. Mutations in the γ2 subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Hum Mol Genet 10 (2001), 1215–1220.
61. 61 Kim, M., Hunter, R.W., Garcia-Menendez, L., et al. Mutation in the γ2-subunit of AMP-activated protein kinase stimulates cardiomyocyte proliferation and hypertrophy independent of glycogen storage. Circ Res 114 (2014), 966–975.
62. 62 Marian, A.J., On genetic and phenotypic variability of hypertrophic cardiomyopathy: nature versus nurture. J Am Coll Cardiol 38 (2001), 331–334.
63. 63 Lopes, L.R., Rahman, M.S., Elliott, P.M., A systematic review and meta-analysis of genotype-phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations. Heart 99 (2013), 1800–1811.
64. 64 Daw, E.W., Lu, Y., Marian, A.J., et al. Identifying modifier loci in existing genome scan data. Ann Hum Genet 72 (2008), 670–675.
65. 65 Daw, E.W., Chen, S.N., Czernuszewicz, G., et al. Genome-wide mapping of modifier chromosomal loci for human hypertrophic cardiomyopathy. Hum Mol Genet 16 (2007), 2463–2471.
66. 66 Brugada, R., Kelsey, W., Lechin, M., et al. Role of candidate modifier genes on the phenotypic expression of hypertrophy in patients with hypertrophic cardiomyopathy. J Investig Med 45 (1997), 542–551.
67. 67 Marian, A.J., Yu, Q.T., Workman, R., et al. Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. Lancet 342 (1993), 1085–1086.
68. 68 Lechin, M., Quiñones, M.A., Omran, A., et al. Angiotensin-I converting enzyme genotypes and left ventricular hypertrophy in patients with hypertrophic cardiomyopathy. Circulation 92 (1995), 1808–1812.
69. 69 Lim, D.S., Roberts, R., Marian, A.J., Expression profiling of cardiac genes in human hypertrophic cardiomyopathy: insight into the pathogenesis of phenotypes. J Am Coll Cardiol 38 (2001), 1175–1180.
70. 70 Christodoulou, D.C., Wakimoto, H., Onoue, K., et al. 5′RNA-Seq identifies Fhl1 as a genetic modifier in cardiomyopathy. J Clin Invest 124 (2014), 1364–1370.
71. 71 Marston, S., Copeland, O., Gehmlich, K., et al. How do MYBPC3 mutations cause hypertrophic cardiomyopathy?. J Muscle Res Cell Motil 33 (2012), 75–80.
72. 72 Hwang, J.J., Allen, P.D., Tseng, G.C., et al. Microarray gene expression profiles in dilated and hypertrophic cardiomyopathic end-stage heart failure. Physiol Genomics 10 (2002), 31–44.
73. 73 Roncarati, R., Viviani Anselmi, C., Losi, M.A., et al. Circulating miR-29a, among other up-regulated microRNAs, is the only biomarker for both hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 63 (2014), 920–927.
74. 74 Fang, L., Ellims, A.H., Moore, X.L., et al. Circulating microRNAs as biomarkers for diffuse myocardial fibrosis in patients with hypertrophic cardiomyopathy. J Transl Med, 13, 2015, 314.
75. 75 Kuster, D.W., Mulders, J., Ten Cate, F.J., et al. MicroRNA transcriptome profiling in cardiac tissue of hypertrophic cardiomyopathy patients with MYBPC3 mutations. J Mol Cell Cardiol 65 (2013), 59–66.
76. 76 Derda, A.A., Thum, S., Lorenzen, J.M., et al. Blood-based microRNA signatures differentiate various forms of cardiac hypertrophy. Int J Cardiol 196 (2015), 115–122.
77. 77 Marian, A.J., Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy. Lancet 355 (2000), 58–60.
78. 78 Senthil, V., Chen, S.N., Tsybouleva, N., et al. Prevention of cardiac hypertrophy by atorvastatin in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circ Res 97 (2005), 285–292.
79. 79 Patel, R., Nagueh, S.F., Tsybouleva, N., et al. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation 104 (2001), 317–324.
80. 80 Lombardi, R., Rodriguez, G., Chen, S.N., et al. Resolution of established cardiac hypertrophy and fibrosis and prevention of systolic dysfunction in a transgenic rabbit model of human cardiomyopathy through thiol-sensitive mechanisms. Circulation 119 (2009), 1398–1407.
81. 81 Marian, A.J., Experimental therapies in hypertrophic cardiomyopathy. J Cardiovasc Transl 2 (2009), 483–492.
82. 82 Lim, D.S., Lutucuta, S., Bachireddy, P., et al. Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation 103 (2001), 789–791.
83. 83 Marian, A.J., Senthil, V., Chen, S.N., et al. Antifibrotic effects of antioxidant N-acetylcysteine in a mouse model of human hypertrophic cardiomyopathy mutation. J Am Coll Cardiol 47 (2006), 827–834.
84. 84 Nagueh, S.F., Lombardi, R., Tan, Y., et al. Atorvastatin and cardiac hypertrophy and function in hypertrophic cardiomyopathy: a pilot study. Eur J Clin Invest 40 (2010), 976–983.
85. 85 Bauersachs, J., Störk, S., Kung, M., et al. HMG CoA reductase inhibition and left ventricular mass in hypertrophic cardiomyopathy: a randomized placebo-controlled pilot study. Eur J Clin Invest 37 (2007), 852–859.
86. 86 Yamazaki, T., Suzuki, J., Shimamoto, R., et al. A new therapeutic strategy for hypertrophic nonobstructive cardiomyopathy in humans. A randomized and prospective study with an angiotensin II receptor blocker. Int Heart J 48 (2007), 715–724.
87. 87 Shimada, Y.J., Passeri, J.J., Baggish, A.L., et al. Effects of losartan on left ventricular hypertrophy and fibrosis in patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol HF 1 (2013), 480–487.
88. 88 Penicka, M., Gregor, P., Kerekes, R., et al., for the Candesartan use in Hypertrophic And Non-obstructive Cardiomyopathy Estate (CHANCE) Study Investigators. The effects of candesartan on left ventricular hypertrophy and function in nonobstructive hypertrophic cardiomyopathy: a pilot, randomized study. J Mol Diagn 11 (2009), 35–41.
89. 89 MacDonald, K.A., Kittleson, M.D., Larson, R.F., et al. The effect of ramipril on left ventricular mass, myocardial fibrosis, diastolic function, and plasma neurohormones in Maine Coon cats with familial hypertrophic cardiomyopathy without heart failure. J Vet Intern Med 20 (2006), 1093–1105.
90. 90 Axelsson, A., Iversen, K., Vejlstrup, N., et al. Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 3 (2015), 123–131.
91. 91 Ho, C.Y., Lakdawala, N.K., Cirino, A.L., et al. Diltiazem treatment for pre-clinical hypertrophic cardiomyopathy sarcomere mutation carriers: a pilot randomized trial to modify disease expression. J Am Coll Cardiol HF 3 (2015), 180–188.
92. 92 Jiang, J., Wakimoto, H., Seidman, J.G., et al. Allele-specific silencing of mutant Myh6 transcripts in mice suppresses hypertrophic cardiomyopathy. Science 342 (2013), 111–114.
93. 93 Codd, M.B., Sugrue, D.D., Gersh, B.J., et al. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975–1984. Circulation 80 (1989), 564–572.
94. 94 McNally, E.M., Golbus, J.R., Puckelwartz, M.J., Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest 123 (2013), 19–26.
95. 95 Manolio, T.A., Baughman, K.L., Rodeheffer, R., et al. Prevalence and etiology of idiopathic dilated cardiomyopathy (summary of a National Heart, Lung, and Blood Institute workshop. Am J Cardiol 69 (1992), 1458–1466.
96. 96 Petretta, M., Pirozzi, F., Sasso, L., et al. Review and metaanalysis of the frequency of familial dilated cardiomyopathy. Am J Cardiol 108 (2011), 1171–1176.
97. 97 Michels, V.V., Moll, P.P., Miller, F.A., et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med 326 (1992), 77–82.
98. 98 Goerss, J.B., Michels, V.V., Burnett, J., et al. Frequency of familial dilated cardiomyopathy. Eur Heart J 16:Suppl O (1995), 2–4.
99. 99 Mestroni, L., Rocco, C., Gregori, D., et al., for the Heart Muscle Disease Study Group. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. J Am Coll Cardiol 34 (1999), 181–190.
100. 100 Mangin, L., Charron, P., Tesson, F., et al. Familial dilated cardiomyopathy: clinical features in French families. Eur J Heart Fail 1 (1999), 353–361.
101. 101 Herman, D.S., Lam, L., Taylor, M.R., et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med 366 (2012), 619–628.
102. 102 Roberts, A.M., Ware, J.S., Herman, D.S., et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med, 7, 2015, 270ra6.
103. 103 Lombardi, R., Bell, A., Senthil, V., et al. Differential interactions of thin filament proteins in two cardiac troponin T mouse models of hypertrophic and dilated cardiomyopathies. Cardiovasc Res 79 (2008), 109–117.
104. 104 Davis, J., Davis, L.C., Correll, R.N., et al. A tension-based model distinguishes hypertrophic versus dilated cardiomyopathy. Cell 165 (2016), 1147–1159.
105. 105 Olson, T.M., Michels, V.V., Thibodeau, S.N., et al. Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. Science 280 (1998), 750–752.
106. 106 Guo, W., Schafer, S., Greaser, M.L., et al. RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat Med 18 (2012), 766–773.
107. 107 Maatz, H., Jens, M., Liss, M., et al. RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processing. J Clin Invest 124 (2014), 3419–3430.
108. 108 Cattin, M.E., Muchir, A., Bonne, G., 'State-of-the-heart' of cardiac laminopathies. Curr Opin Cardiol 28 (2013), 297–304.
109. 109 Bienengraeber, M., Olson, T.M., Selivanov, V.A., et al. ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating. Nat Genet 36 (2004), 382–387.
110. 110 McNair, W.P., Sinagra, G., Taylor, M.R., et al., for the Familial Cardiomyopathy Registry Research Group. SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism. J Am Coll Cardiol 57 (2011), 2160–2168.
111. 111 Veerman, C.C., Wilde, A.A., Lodder, E.M., The cardiac sodium channel gene SCN5A and its gene product NaV1.5: role in physiology and pathophysiology. Gene 573 (2015), 177–187.
112. 112 Olson, T.M., Alekseev, A.E., Moreau, C., et al. KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation. Nat Clin Pract Cardiovasc Med 4 (2007), 110–116.
113. 113 McLendon, P.M., Robbins, J., Desmin-related cardiomyopathy: an unfolding story. Am J Physiol Heart Circ Physiol 301 (2011), H1220–H1228.
114. 114 Dalakas, M.C., Park, K.Y., Semino-Mora, C., et al. Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene. N Engl J Med 342 (2000), 770–780.
115. 115 Thompson, R., Straub, V., Limb-girdle muscular dystrophies—international collaborations for translational research. Nat Rev Neurol 12 (2016), 294–309.
116. 116 Muntoni, F., Wilson, L., Marrosu, G., et al. A mutation in the dystrophin gene selectively affecting dystrophin expression in the heart. J Clin Invest 96 (1995), 693–699.
117. 117 Hermans, M.C., Pinto, Y.M., Merkies, I.S., et al. Hereditary muscular dystrophies and the heart. Neuromuscul Disord 20 (2010), 479–492.
118. 118 Marston, S.B., How do mutations in contractile proteins cause the primary familial cardiomyopathies?. J Cardiovasc Transl Res 4 (2011), 245–255.
119. 119 Long, C., Amoasii, L., Mireault, A.A., et al. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science 351 (2016), 400–403.
120. 120 Long, C., McAnally, J.R., Shelton, J.M., et al. Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA. Science 345 (2014), 1184–1188.
121. 121 Nelson, C.E., Hakim, C.H., Ousterout, D.G., et al. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 351 (2016), 403–407.
122. 122 Tabebordbar, M., Zhu, K., Cheng, J.K., et al. In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 351 (2016), 407–411.
123. 123 Corrado, D., Basso, C., Thiene, G., et al. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. J Am Coll Cardiol 30 (1997), 1512–1520.
124. 124 Dunn, K.E., Ashley, E.A., Arrhythmogenic right ventricular cardiomyopathy: toward a modern clinical and genomic understanding. Circ Cardiovasc Genet 8 (2015), 421–424.
125. 125 Lombardi, R., Marian, A.J., Arrhythmogenic right ventricular cardiomyopathy is a disease of cardiac stem cells. Curr Opin Cardiol 25 (2010), 222–228.
126. 126 Thiene, G., The research venture in arrhythmogenic right ventricular cardiomyopathy: a paradigm of translational medicine. Eur Heart J 36 (2015), 837–846.
127. 127 Mast, T.P., Teske, A.J., vd Heijden, J.F., et al. Left ventricular involvement in arrhythmogenic right ventricular dysplasia/cardiomyopathy assessed by echocardiography predicts adverse clinical outcome. J Am Soc Echocardiogr 28 (2015), 1103–1113.e9.
128. 128 Groeneweg, J.A., Bhonsale, A., James, C.A., et al. Clinical presentation, long-term follow-up, and outcomes of 1001 arrhythmogenic right ventricular dysplasia/cardiomyopathy patients and family members. Circ Cardiovasc Genet 8 (2015), 437–446.
129. 129 Corrado, D., Basso, C., Schiavon, M., et al. Screening for hypertrophic cardiomyopathy in young athletes. N Engl J Med 339 (1998), 364–369.
130. 130 Tabib, A., Loire, R., Chalabreysse, L., et al. Circumstances of death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and/or dysplasia. Circulation 108 (2003), 3000–3005.
131. 131 Pilmer, C.M., Kirsh, J.A., Hildebrandt, D., et al. Sudden cardiac death in children and adolescents between 1 and 19 years of age. Heart Rhythm 11 (2014), 239–245.
132. 132 Semsarian, C., Ingles, J., Wilde, A.A., Sudden cardiac death in the young: the molecular autopsy and a practical approach to surviving relatives. Eur Heart J 36 (2015), 1290–1296.
133. 133 McKoy, G., Protonotarios, N., Crosby, A., et al. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 355 (2000), 2119–2124.
134. 134 Protonotarios, N., Tsatsopoulou, A., Naxos disease and Carvajal syndrome: cardiocutaneous disorders that highlight the pathogenesis and broaden the spectrum of arrhythmogenic right ventricular cardiomyopathy. Cardiovasc Pathol 13 (2004), 185–194.
135. 135 Marcus, F.I., Epsilon waves aid in the prognosis and risk stratification of patients with ARVC/D. J Cardiovasc Electrophysiol 26 (2015), 1211–1212.
136. 136 Platonov, P.G., Calkins, H., Hauer, R.N., et al. High interobserver variability in the assessment of epsilon waves: Implications for diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm 13 (2016), 208–216.
137. 137 Burke, A.P., Farb, A., Tashko, G., et al. Arrhythmogenic right ventricular cardiomyopathy and fatty replacement of the right ventricular myocardium: are they different diseases?. Circulation 97 (1998), 1571–1580.
138. 138 Marcus, F.I., McKenna, W.J., Sherrill, D., et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J 31 (2010), 806–814.
139. 139 Rampazzo, A., Nava, A., Malacrida, S., et al. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 71 (2002), 1200–1206.
140. 140 Gerull, B., Heuser, A., Wichter, T., et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 36 (2004), 1162–1164.
141. 141 van Tintelen, J.P., Entius, M.M., Bhuiyan, Z.A., et al. Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation 113 (2006), 1650–1658.
142. 142 Heuser, A., Plovie, E.R., Ellinor, P.T., et al. Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 79 (2006), 1081–1088.
143. 143 Syrris, P., Ward, D., Evans, A., et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2. Am J Hum Genet 79 (2006), 978–984.
144. 144 Pilichou, K., Nava, A., Basso, C., et al. Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 113 (2006), 1171–1179.
145. 145 Haywood, A.F.M., Merner, N.D., Hodgkinson, K.A., et al. Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada. Eur Heart J 34 (2013), 1002–1011.
146. 146 Merner, N.D., Hodgkinson, K.A., Haywood, A.F.M., et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet 82 (2008), 809–821.
147. 147 Quarta, G., Syrris, P., Ashworth, M., et al. Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy. Eur Heart J 33 (2012), 1128–1136.
148. 148 van der Zwaag, P.A., van Rijsingen, I.A.W., Asimaki, A., et al. Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur J Heart Fail 14 (2012), 1199–1207.
149. 149 Taylor, M., Graw, S., Sinagra, G., et al. Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. Circulation 124 (2011), 876–885.
150. 150 Beffagna, G., Occhi, G., Nava, A., et al. Regulatory mutations in transforming growth factor-β3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovasc Res 65 (2005), 366–373.
151. 151 Xiong, Q., Cao, Q., Zhou, Q., et al. Arrhythmogenic cardiomyopathy in a patient with a rare loss-of-function KCNQ1 mutation. J Am Heart Assoc, 4, 2015, e001526.
152. 152 Norgett, E.E., Hatsell, S.J., Carvajal-Huerta, L., et al. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Human Mol Genet 9 (2000), 2761–2766.
153. 153 Alcalai, R., Metzger, S., Rosenheck, S., et al. A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair. J Am Coll Cardiol 42 (2003), 319–327.
154. 154 Chen, S.N., Gurha, P., Lombardi, R., et al. The Hippo pathway is activated and is a causal mechanism for adipogenesis in arrhythmogenic cardiomyopathy. Circ Res 114 (2014), 454–468.
155. 155 Asimaki, A., Tandri, H., Huang, H., et al. A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. N Engl J Med 360 (2009), 1075–1084.
156. 156 Garcia-Gras, E., Lombardi, R., Giocondo, M.J., et al. Suppression of canonical Wnt/β-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Invest 116 (2006), 2012–2021.
157. 157 Marian, A.J., On the diagnostic utility of junction plakoglobin in arrhythmogenic right ventricular cardiomyopathy. Cardiovasc Pathol 22 (2013), 309–311.
158. 158 Heallen, T., Zhang, M., Wang, J., et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332 (2011), 45–61.
159. 159 Lombardi, R., da Graca Cabreira-Hansen, M., Bell, A., et al. Nuclear plakoglobin is essential for differentiation of cardiac progenitor cells to adipocytes in arrhythmogenic right ventricular cardiomyopathy. Circ Res 109 (2011), 1342–1353.
160. 160 Lombardi, R., Dong, J., Rodriguez, G., et al. Genetic fate mapping identifies second heart field progenitor cells as a source of adipocytes in arrhythmogenic right ventricular cardiomyopathy. Circ Res 104 (2009), 1076–1084.
161. 161 Lombardi, R., Chen, S.N., Ruggiero, A., et al. Cardiac fibro-adipocyte progenitors express desmosome proteins and preferentially differentiate to adipocytes upon deletion of the desmoplakin gene. Circ Res 119 (2016), 41–54.
162. 162 Mertens, C., Hofmann, I., Wang, Z., et al. Nuclear particles containing RNA polymerase III complexes associated with the junctional plaque protein plakophilin 2. Proc Natl Acad Sci U S A 98 (2001), 7795–7800.
163. 163 Sommariva, E., Brambilla, S., Carbucicchio, C., et al. Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy. Eur Heart J 37 (2016), 1835–1846.
164. 164 Ellawindy, A., Satoh, K., Sunamura, S., et al. Rho-kinase inhibition during early cardiac development causes arrhythmogenic right ventricular cardiomyopathy in mice. Arterioscler Thromb Vasc Biol 35 (2015), 2172–2184.
165. 165 Gurha, P., Chen, X., Lombardi, R., et al. Knockdown of plakophilin 2 downregulates miR-184 through CpG hypermethylation and suppression of the E2F1 pathway and leads to enhanced adipogenesis in vitro. Circ Res 119 (2016), 731–750.
166. 166 Asimaki, A., Kapoor, S., Plovie, E., et al. Identification of a new modulator of the intercalated disc in a zebrafish model of arrhythmogenic cardiomyopathy. Sci Transl Med, 6, 2014, 240ra74.
167. 167 Chelko, S.P., Asimaki, A., Andersen, P., et al. Central role for GSK3β in the pathogenesis of arrhythmogenic cardiomyopathy. JCI Insight, 1, 2016, e85923.
168. 168 Sternberg, S.H., Doudna, J.A., Expanding the biologist's toolkit with CRISPR-Cas9. Mol Cell 58 (2015), 568–574.
169. 169 Yang, L., Jiang, J., Drouin, L.M., et al. A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection. Proc Natl Acad Sci U S A 106 (2009), 3946–3951.
170. 170 Ruozi, G., Bortolotti, F., Falcione, A., et al. AAV-mediated in vivo functional selection of tissue-protective factors against ischaemia. Nat Commun, 6, 2015, 7388.
171. 171 Ousterout, D.G., Kabadi, A.M., Thakore, P.I., et al. Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin mutations that cause Duchenne muscular dystrophy. Nat Commun, 6, 2015, 6244.
172. 172 Pardo, B., Gómez-González, B., Aguilera, A., DNA repair in mammalian cells: DNA double-strand break repair: how to fix a broken relationship. Cell Mol Life Sci 66 (2009), 1039–1056.
173. 173 Zetsche, B., Gootenberg, J.S., Abudayyeh, O.O., et al. Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system. Cell 163 (2015), 759–771.